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Genetics of type 1 diabetes mellitus


At least 20 different chromosomal regions have been linked to type 1 diabetes (T1D) susceptibility in humans, using genome screening, candidate gene testing, and studies of human homologues of mouse susceptibility genes. The largest contribution from a single locus (IDDM1) comes from several genes located in the MHC complex on chromosome 6p21.3, accounting for at least 40% of the familial aggregation of this disease. Approximately 30% of T1D patients are heterozygous for HLA-DQA1*0501–DQB1*0201/DQA1*0301–DQB1*0302 alleles (formerly referred to as HLA-DR3/4 and for simplification usually shortened to HLA-DQ2/DQ8), and a particular HLA-DQ6 molecule (HLA-DQA1*0102–DQB1*0602) is associated with dominant protection from the disease. There is evidence that certain residues important for structure and function of both HLA-DQ and DR peptide-binding pockets determine disease susceptibility and resistance. Independent confirmation of the IDDM2 locus on chromosome 11p15.5 has been achieved in both case-control and family-based studies, whereas associations with the other potential IDDM loci have not always been replicated. Several possibilities to explain these variable results from different studies are discussed, and a key factor affecting both linkage and association studies is that the genetic basis of T1D susceptibility may differ between ethnic groups. Some future strategies to address these problems are proposed. These include increasing the sample size in homogenous ethnic groups, high throughput genotyping and genomewide linkage disequilibrium (LD) mapping to establish disease associated ancestral haplotypes. Elucidation of the function of particular genes (‘functional genomics’) in the pathogenesis of T1D will be a most important element in future studies in this field, in addition to more sophisticated methods of statistical analyses.


Diabetes mellitus represents a heterogeneous group of disorders. Some distinct diabetic phenotypes can be identified in terms of specific aetiology and/or pathogenesis, but in many cases overlapping phenotypes make etiological and pathogenic classification difficult.

Type 1 (insulin-dependent) diabetes mellitus (T1D) [MIM 222100] develops as a result of pancreatic beta-cell destruction and is characterised by absolute insulin deficiency, an abrupt onset of symptoms, proneness to ketosis and dependency on exogenous insulin to sustain life. It is the most common form of diabetes among children and young adults in populations of Caucasoid origin, where the prevalence is approximately 0.4%. The overall age-adjusted incidence of T1D varies from 0.1/100.000 per year in China and Venezuela to 36/100.000 per year in Sardinia and Finland.1 T1D is a leading cause of end-stage renal disease, blindness and amputation and is also a major cause of cardiovascular disease and premature death in the general population.2,3

Genetics of T1D

Rare monogenic and oligogenic forms of T1D have been described, and genetic studies in families affected by these disorders, have allowed mapping of the corresponding genes.4,5,6,7,8,9 However, in general, T1D is considered as a complex genetic trait, ie, not only do multiple genetic loci contribute to susceptibility, but environmental factors also play a major role in determining risk. A large body of evidence indicates that inherited genetic factors influence both susceptibility and resistance to the disease. There is significant familial clustering of T1D with an average prevalence risk in siblings of 6% compared to 0.4% in the general population.1,10 The familial clustering (λs),11 which can be calculated from the increased T1D risk in siblings over population prevalence (6.0/0.4), results in an λs value of 15. Genetic susceptibility in family members is clearly dependent on the degree of genetic identity with the proband, and in fact the risk of T1D in families has a non-linear correlation with the number of alleles shared with the proband; the highest risk is observed in monozygotic twins (100% sharing), followed by first and second degree relatives (50% and 25% sharing respectively).

The genetics of T1D has a long history of studies evaluating candidate genes for association with disease status in either case-control or family-based studies. Two chromosomal regions have emerged with consistent and significant evidence of association with T1D across multiple studies. These are the human leukocyte antigen (HLA) region, at chromosome 6p21.3, and the insulin gene region at chromosome 11p15.

In the 1970s, association and affected-sib pair linkage studies established the role of HLA genes in T1D predisposition (the HLA locus contribution to disease is referred to as IDDM1).12,13,14 HLA studies also demonstrated that T1D and type 2 (non insulin-dependent) diabetes mellitus (T2D) were distinct disease entities, since T2D generally does not show an association with HLA, although certain subsets may demonstrate some association.15 The variability in rates of T1D disease concordance in siblings who share two, one or zero parental HLA haplotypes in addition to the different concordance rates in monozygotic vs dizygotic twins, the risk in relatives, and the population prevalence implicates the existence of additional non-HLA genetic factors.

More recently genome-wide linkage analysis has been used to try to identify the genetic determinants for T1D. Five complete genome scans,16,17,18,19,20 including a combined analysis of the UK and US genome scan data,21 and several specific linkage studies of certain regions or chromosomes have now been reported.22,23,24,25,26,27,28,29,30 Together these studies suggest that close to 20 genomic intervals, with variable degrees of linkage evidence, might be influencing T1D risk. The most up-to-date reports are probably from the two recent studies by Cox et al21 and by the European Consortium for IDDM Genetic Studies (ECIGS).20 The first study is a combined analysis of US and UK families from previously published genome scans,16,18,19 including a new collection of 225 US multiplex families. In total, the combined sample comprised 831 affected sib-pairs (ASPs).21 The ECIGS study included 464 Scandinavian ASPs, which have never before been included in previous genome scans. It is significant that both studies provide evidence of interaction between the different T1D susceptibility loci.20,21

For all these loci the etiological mutation(s) in sensu strictu has not been identified. Even in the HLA region several genes seem to be involved (see below). Most of the other putative T1D loci comprise regions of 1–40 centimorgans (cM) in size, corresponding roughly to 1–40 Mb, which may contain several genes. Mapping these genes will be a major challenge of the genome era. Currently, little is known about the nature of genetic variation underlying T1D, which makes it difficult to be confident about strategies used to address this problem. One hypothesis proposes that the genetic basis of T1D will involve alleles that are themselves common in the population at large.31,32 Assumptions about genetic factors contributing to T1D are relevant to the approach undertaken. Under the ‘common disease, common variant’ hypothesis, it may be possible to generate a catalogue of common SNPs and use association mapping to identify disease-susceptibility polymorphisms.33,34,35 In this regard strategies to identify SNPs that delineate the different haplotypes of a gene or a region of linkage disequilibrium (LD)36,37,38,39 seem most promising. Interestingly, very recent studies suggest that much of the difficulty in mapping T1D susceptibility genes results from inadequate sample sizes and the study of mixed ethnic groups.21,40

The genes

HLA-encoded susceptibility to T1D

The best evidence for a genetic component in the susceptibility to T1D comes from studies of the HLA genes in both populations and families as well as from animal models. It has been estimated that HLA (IDDM1) provides up to 40–50% of the familial clustering of T1D.11,41 The HLA region is a cluster of genes located within the major histocompatibility complex (MHC) on chromosome 6p21. Identification of the genes involved has proved to be extremely elusive, despite tremendous efforts, involving several complementary approaches eg functional studies and animal models. This is due to several complicating factors, amongst which is the strong LD between neighbouring genes in the HLA complex, and the fact that several HLA-linked genes, acting in concert, may determine disease susceptibility.

The contribution of the IDDM1 region is easily detectable in genome-wide linkage analyses, as indicated by a LOD score of 65.8, recently reported in a consensus analysis of 767 multiplex T1D families.21 The genes of the MHC region are classified into four families, classes I, II, III and IV.42,43,44 The statistically strongest genetic association with T1D is conferred by HLA class II gene alleles. From both human genetics and animal model studies there is good evidence that particular alleles of the HLA-DQA1, DQB1 and DRB1 loci all are primarily involved in the genetic predisposition to T1D.45,46,47,48,49,50 However, due to the strong LD between these loci it has been very difficult to study the effect of individual HLA-DQ or -DR genes separately. It is clear that some combinations of HLA-DQ genes, eg those encoding DQ8 (ie. DQA1*03–DQB1*0302) and DQ2 (ie DQA1*05–DQB1*02), and particularly those present in HLA-DQ2/DQ8 heterozygotes are associated with susceptibility to T1D (Table 1). Approximately 30% of T1D patients are HLA-DQ2/DQ8 heterozygotes.51 By contrast, a particular DQ6 molecule, encoded by HLA-DQA1*0102–DQB1*0602, is associated with strong protection from the disease, even in the presence of T1D-associated autoantibodies and/or of high-risk HLA alleles,52 and has been reported in less than 1% of patients in most populations studied (Table 1). Thus, this HLA-DQB allele appears to confer dominant protection.53,54 It has been more difficult to ascertain the roles of separate HLA-DR genes.45,55 Analysis of the linkage between HLA-DQ and DR alleles on DQ8-haplotypes, demonstrated that the frequencies of only certain HLA-DR4-associated DRB1 alleles are increased among T1D patients.55 This has since been confirmed in larger studies by other groups.56,57,58 The varying risk conferred by different HLA-DR4 haplotypes is illustrated in Table 2. There is evidence that the different risk categories are determined by the predicted structure and action of the peptide-binding pockets, P1 and P4, of the DRB1 molecule.59

Table 1 Type 1 diabetes-associated HLA class II alleles and haplotypes
Table 2 Critical polymorphic residues of the HLA-DRB1*04 beta chain associated with predisposition to type 1 diabetes

The fact that several different class II HLA alleles and combinations of alleles may be associated with T1D can be reconciled by a hypothesis implicating a factor common to all these alleles that is central to disease susceptibility, eg presence of specific amino acid residues. Indeed, certain amino acids of the HLA-DQB1 and DRB1 chains correlate well with disease susceptibility and resistance. These residues are known to be critical for the peptide-binding function of the class II molecule.59,60,61,62,63 In particular, aspartic acid (Asp) at residue 57, which is in pocket 9 of the HLA-DQB1 molecule, is encoded by a HLA-DQB protective allele, whilst an alanine, valine or serine residue at the same position characterises predisposing alleles. In the absence of aspartic acid the charge at the ‘right hand’ end of the peptide-binding pocket becomes more positive.64 Nevertheless, and despite the fact that residue 57 has indeed a pronounced role in the function of class II molecules with respect to peptide binding,65,66 it cannot completely account for all the complexity of HLA and T1D associations, eg Asp 57 is not associated with T1D in Japanese.67,68 Interestingly, the major DQB1 allele associated with T1D in Japan, 0401, has a different residue 56 than other Asp57 bearing allotypes, and it was recently suggested that residue 56, which is also in pocket 9, may influence the structure and function of this pocket in peptide binding and T1D susceptibility.59,63

Other loci in the class II region have been associated with T1D besides HLA-DQ and DR. Most interestingly, an independent association with HLA-DPB1*0301 has been observed,69,70,71 although this may not be the case on DR4-positive haplotypes.72 Also, HLA-DPB1*0402 may be associated with protection on HLA-DR4 negative haplotypes.73 Additional susceptibility loci in the class II region include the antigen-processing genes (TAP1, TAP2, LMP2, and LMP7), although current evidence suggests that these are not directly involved in T1D.74,75,76

A number of observations indicate that class II genes cannot explain all of the MHC associations with T1D. A role for MHC complex genes other than class II genes was first suggested by Thomsen et al77 and Pociot et al78 by studying HLA-DR3/4 heterozygous individuals, and by Robinson et al79 using a family study design, which to some degree eliminated the LD effects involving HLA-DQ/DR loci; however, in all these studies the number of subjects/families was small. Subsequently, several studies have supported a role for both MHC HLA class IV and class I genes in T1D predisposition. The most studied class IV genes are tumour necrosis factor and lymphotoxin (TNFA and TNFB).78,80,81,82 The strongest evidence for susceptibility genes in the class I region comes from recent systematic assessment of microsatellite markers spanning this region.83,84,85,86,87,88,89

Non-HLA encoded susceptibility to T1D

HLA-encoded T1D susceptibility may account for less than 50% of the inherited disease risk and thus, there is a substantial role for non-HLA encoded susceptibility. Genome-wide linkage analysis has been used in an attempt to identify the T1D genetic determinants. This approach has the advantage of being a comprehensive search for genetic factors that does not require a priori knowledge of the underlying biology or risk alleles. However, linkage analysis thus far has had only limited success.40 Specifically, most studies have failed to generate strong evidence of linkage (except for IDDM1), and those few regions with significant results have proven difficult to replicate (Table 3). Nevertheless, several loci have now been linked to T1D, providing evidence that this disease is a polygenic disorder in most patients studied.

Table 3 Summary of previous linkage results

T1D susceptibility loci mapped by different genome screenings are listed in Table 3. The symbols of these putative loci, approved by the Human Gene Nomenclature Committee, are IDDM1–IDDM18 ( nomenclature). The symbols IDDM9 and IDDM14 have not yet been approved, even though these symbols have been reserved by particular researchers, based upon preliminary data suggesting evidence of linkage of new chromosomal regions to T1D.

Based upon current analyses of completed genome screens, these non-HLA region genes may contribute relatively smaller (but significant) increments in genetic risk on an individual basis. For example, the IDDM2 locus (see below), which is the only other generally accepted genetic contributor to T1D risk has an odds ratio (OR) 3, but an estimated sibling genetic risk ratio (λs) of only 1.12. Other locus-specific effects, excluding HLA, range from 1.05–1.3. Power analyses suggest that 4.300 affected sib-pair families will be required to achieve 80% power to detect a linkage at the suggested significance level with P < 2.2 × 10−5 90 at these levels of risk.

IDDM2—the insulin gene (INS) region

The immune-mediated process leading to development of T1D is highly specific to pancreatic beta cells. The insulin gene, therefore, is a plausible candidate susceptibility locus since insulin or insulin precursors may act as autoantigens. Alternatively, insulin levels could modulate the interaction between the immune system and the beta cells.

A unique minisatellite (VNTR), which arises from tandem repetition of a 14–15 bp oligonucleotide sequence, is located in the 5′ regulatory region of the human insulin gene (INS) on chromosome 11p15.5. The number of tandem repeats varies from about 26 to over 200, and VNTR alleles occur in three discrete size classes: class I (26–63 repeats), class II (mean of 80 repeats), and class III (141–209 repeats).91,92,93 Class II alleles are virtually absent in Caucasoid populations, in whom the frequencies of class I and class III alleles are 0.71 and 0.29 respectively. The class I/I homozygous genotype is associated with a two- to five-fold increase in risk of developing T1D, whereas class III alleles seem to provide dominant protection.93,94,95,96,97,98,99,100,101,102

This susceptibility locus, IDDM2 [MIM 125852], has been mapped to chromosome 11p15.5, and most likely corresponds to the INS VNTR locus,93 although it has been pointed out that the T1D association extends beyond the 4.1 kb region originally identified97 towards the tyrosine hydroxylase gene.103 This is important because subsequent studies including those cited above, which followed this original mapping, presumed that the 4.1 kb was the minimal region—in other words haplotypes were analysed within the 4.1 kb region and not outside it, and eventually provided substantial evidence for the insulin VNTR being the primary locus. However, without actually searching more thoroughly for associations in the TH gene and beyond, the question remains whether there may be a second susceptibility locus or in fact that the major determinant may lie outside the 4.1 kb region, and that the insulin VNTR is in LD with the true etiological variant. This seems unlikely, but until the mapping study is done it remains a possibility. The existing evidence for IDDM2 as a true locus comes from multiple replications of the disease association studies in both case-control and family-based cohorts. High-resolution genotyping has revealed that variable degrees of susceptibility are associated with each VNTR allele and probably reflect sequence heterogeneity within the VNTR that may affect its function and physical state.104,105,106,107,108 There are also data to suggest that the VNTR may modulate INS transcription in pancreas and thymus93,101,109,110,111,112,113 and that INS class III alleles, as compared with class I alleles, correlate with low INS mRNA levels in the pancreas but with higher levels in the thymus (on average 2–3 fold). Greater thymic expression of INS may explain the dominant protective effect of class III VNTR alleles, reported in T1D, by enhancing tolerance to the preproinsulin protein.114,115


IDDM1 and IDDM2 (the HLA and INS components) were both originally identified by a candidate gene approach, based on case-control studies. The remaining IDDM loci, ie IDDM3–IDDM18, with the exception of IDDM17, have all been discovered by linkage studies using affected sib-pair families, either in whole or partial genome scans. For most of these regions positional candidate genes have been further analyzed. IDDM3 [MIM 600318] was originally reported to be located near the D15S107 marker on chromosome 15q26, in a collection of 250 Caucasoid families from the US, UK and Canada.22 Interestingly, those families possessing HLA genes that provided less predisposition to T1D produced most of the evidence for linkage to the D15S107 marker. Although some support for linkage and association to the IDDM3 locus has been published,24,116 most other studies have failed to replicate this original observation,18,19,20,21,26 and so far no positionally identified candidate genes have been investigated in this region.

Evidence for IDDM4 [MIM 600319], which is located near the fibroblast growth factor 3 (FGF3) locus on chromosome 11q13, was reported simultaneously by two different groups.16,17 A major effort has been expended to fine-map IDDM4 by LD analysis. In a two-stage approach 2042 families were genotyped for markers from this region, and a specific haplotype comprising alleles of the two polymorphic markers, D11S1917 and H0570polyA, showed decreased transmission (46.4%) to affected offspring and increased transmission (56.6%) to unaffected siblings.117 Several potential candidate genes map to the region near FGF3 in humans, including ZFM1 (zinc finger protein 162), which encodes a putative nuclear protein demonstrable in the pancreas.118 The gene encoding the Fas-associated death domain protein (FADD) has also been mapped to this region.119 Transduction of an apoptotic signal depends on association and interaction between the intracellular ‘death domain’ of Fas with FADD. Recent experimental findings indicate that binding of the Fas ligand (FasL) on cytotoxic T cells to Fas expressed on beta cells may trigger apoptosis in the insulin-producing beta cells.120,121 Analyses of FADD polymorphisms by transmission disequilibrium testing (TDT) failed to provide any evidence for association with this candidate gene; however, ETDT analysis did reveal significant association/linkage with the D11S987 marker (P = 0.0004), which is 4.4 cM upstream the FADD gene.122 A gene encoding a novel transmembrane protein has been identified by sequence analysis of the IDDM4 locus.123 This gene, termed low-density lipoprotein receptor related protein (LRP5), encodes a protein that contains conserved sequences, characteristic of the low-density lipoprotein receptor family. LRP5 is in close proximity to the two markers, D11S1917 and H0570PolyA, and the exon encoding the signal peptide of LPR-5 is only 3 kb downstream the H0570polyA marker. In addition, two novel genes were recently identified in this region, C11orf23 and C11orf24.124 The C11orf24 gene has no known sequence similarity to other genes, and its function is unknown. C11orf23 has sequence similarity to the SIT4 (sporulation-induced transcript 4)-associated protein (SAP) family of yeast proteins, which are involved in regulation of the cell cycle. The full-length C11orf23 cDNA is the first mammalian orthologue of the yeast SAP family to be identified.124

Three regions on chromosome 6q, with varying degree of linkage, have been identified through genome screenings. These are IDDM5 [MIM 600320] on 6q25, IDDM8 [MIM 600883] on 6q27, and IDDM15 [MIM 601666] on 6q21. Initial evidence of linkage for IDDM5 was found for the ESR1, oestrogen receptor 1, marker.16 IDDM5 is one of the few susceptibility regions that have been replicated in multiple studies, although partly overlapping family collections were used.16,26,28,125 In the recent joint analysis IDDM5 featured with a LOD score of 1.96.21 IDDM5 maps to a region approximately 40 cM centromeric to IDDM8, and fine mapping analysis has placed the IDDM5 locus within a 5 cM region between the D6S476 and D6S473 markers.26 The gene encoding manganese superoxide dismutase (SOD2) maps close to this region.126 There is evidence to support a role for free oxygen radicals (FOR) in the immune-mediated beta-cell destruction,31,127 and protection of beta cells from cytokine exposure is correlated with superoxide dismutase (MnSOD) expression/activity.128,129 Furthermore, polymorphisms of the SOD2 gene have been associated with T1D susceptibility.130 Structural variants of the MnSOD protein with reduced activity have been reported,131 and such variants might be hypothesised to increase predisposition to T1D.

Because of previous evidence of linkage of the 18q12–q21 region containing the Kidd blood group132 and the D18S64 marker16 to T1D, fine mapping of this region, now designated IDDM6 [MIM 601941], has been performed.133,134 In 1708 families from seven different countries, a haplotype designated ‘10–2–4’ composed of the markers 129, II-IO43 and 56-D18S487 showed some positive evidence of association with T1D.134 However, in an independent set of 627 families no association was detected, although there was evidence for linkage.135 Whether the differences in TDT results between data sets is due, in part, to the presence of more than one common disease-associated haplotype (allelic heterogeneity), which confounded the analysis of individual alleles by TDT133,134,135 or simply indicates that the original observation of association was false is at present not clear. A candidate gene, deleted in colorectal carcinoma (DCC), was tested for association with autoimmunity in one of these studies,135 and evidence for an association with autoimmunity was reported (P = 5 × 10−6). Another candidate gene, ZNF236, which encodes a Kruppel-like zinc-finger protein, has recently been identified in this region; this gene may be a candidate for diabetic nephropathy136 in particular. Also, the anti-apoptotic molecule, bcl-2, maps to the IDDM6 region. One Japanese study137 has reported an association of T1D with an Ala43Thr polymorphism of BCL2; however, this association has not been confirmed in a recent study of different Caucasoid populations.138

Several loci on chromosome 2q have been linked to T1D. IDDM7 [MIM 600321] on chromosome 2q31 was identified by linkage of D2S326 in one of the first genome scans.16 Subsequent linkage and TDT studies have located IDDM7 to D2S152 in several populations, although some controversy exists.139,140,141 It is important in this regard that a single peak near the D2S1391 marker, with a LOD score of 2.62, was reported in the study by Cox et al.21 Part of this region is homologous to the region of mouse chromosome 1 containing the murine T1D susceptibility locus, idd5, in the non-obese diabetic (NOD) mouse.142,143 A number of genes have been proposed and investigated as candidate genes for the IDDM7 region. These include genes of the interleukin-1 gene cluster (ie IL1R1,144,145,146 IL1B,130,147,148 and IL1RN130,149) HOXD8,150 GAD1,151 GALNT3,141 and NEUROD.152,153,154 However, linkage or association has not been convincingly demonstrated for any of these candidate genes.

IDDM8 was initially mapped to chromosome 6q2716,24 and significant evidence of linkage was subsequently obtained through multipoint analyses in additional data sets.26 Supporting evidence for this locus was reported in other studies, using partially overlapping sets of families.19,28,155 Combined evidence from these studies (non-overlapping families), as well as results from the consensus analysis by Cox et al,21 suggest that IDDM8 meets the criteria for confirmed linkage for complex diseases.90,156 Although the IDDM9 symbol has not been approved, IDDM9 has been proposed for a region on chromosome 3q21–q25, demonstrating some evidence of linkage of the D3S1303 marker in the UK genome scans,16,19 where strongest evidence was found in HLA-DR3/4 heterozygous diabetic offspring.19 However, further studies are needed for confirmation of this locus.

Linkage of T1D to chromosome 10p11–q11 (marker D10S193) has provided evidence for a susceptibility locus in this region,16,19,157 which has been designated IDDM10 [MIM 601942]. In the recent consensus analysis of US and UK T1D multiplex families, evidence of linkage was also observed at chromosome 10p11, near the D10S565 marker, with a LOD score of 2.8.21 The chromosomal location of this marker corresponds approximately to that of IDDM10,19,157 and GAD2, encoding GAD65, is also closely linked to this region. However, several studies have failed to demonstrate evidence of linkage of GAD2 to T1D.151,157

IDDM11 [MIM 601208] is the symbol for a possible susceptibility locus on 14q24.3–q31, which was identified by the finding of significant linkage to D14S67.25 Most support for linkage of this marker came from the subset of families in which affected children did not show increased sharing of HLA genes. Significant linkage heterogeneity between HLA-defined subsets of families suggests that IDDM11 may be an important susceptibility locus in families lacking strong HLA region predisposition. However, no further studies have been able to replicate this original observation. Two candidate genes have been identified in the region. The ENSA gene encodes α-endosulfine, an endogenous regulator of beta-cell K (ATP) channels,158 and the recombinant α-endosulfine has been shown to inhibit sulfonylurea binding to beta-cell membranes, to reduce K(ATP) channel currents, and to stimulate insulin secretion.158 Furthermore the SEL1L gene,159,160 which is an important negative regulator of the Notch signalling pathway161 and involved in proper development of pancreatic endocrine cells,162,163,164 maps to this region. SEL1L exhibits high mRNA levels only in adult pancreata160 and in islets of Langerhans,165 but not in the other tissues that were tested. However, a recent study, analysing two intragenic microsatellite markers,166 was unable to find evidence for SEL1L as a plausible candidate gene for IDDM11-conferred susceptibility. Furthermore, mutation scanning of the SEL1L promoter and cDNA sequences did not reveal any disease-associated polymorphisms.167

The IDDM12 [MIM 601388] locus maps to chromosome 2q33 and strongest evidence for linkage to IDDM12 has been obtained for the D2S72–CTLA4–D2S116 region.168 Candidate genes at this locus include those that encode the T-cell costimulatory receptors, CD28 and CTLA-4 (cytotoxic T lymphocyte antigen 4, also called CD152). Although the evidence linking both of these molecules is inconclusive, CTLA-4 is the leading candidate gene in this region for T1D susceptibility. This is partly due to the fact that markers used in linkage and association studies map within CTLA-4. In addition, knowledge of the functional properties of CTLA-4 supports this possibility169 and a single study did not find support for CD28 as the candidate gene of this region.170 There is a microsatellite marker in the 3′UTR of the CTLA4 sequence, and several polymorphisms have been detected at CTLA4.39 These polymorphisms, in particular the exon 1 (49 G>A) SNP, have been investigated by TDT analysis in several populations,41,140,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186 and combined data sets from these large studies support linkage of the CTLA4 locus to T1D.168,171,187 Interestingly, some evidence has also been produced to suggest that CTLA4 polymorphisms may influence gene expression.174,188,189 The role of this gene has been examined in various autoimmune diseases and there is evidence for a general role of CTLA-4 in autoimmunity,190,191 as the gene is expressed only on activated T lymphocytes and functions by downregulating T-cell function.192,193 Chronic blockade of this pathway will lead to maintenance of T cells in an activated state and results in an autoimmune syndrome in wild-type mice.194 Interestingly, recent data arising from the completion of the human genome sequence and from a series of functional studies, using genetic knockouts, suggest that an additional costimulatory receptor, the inducible costimulator (ICOS),195,196 which is structurally and functionally related to CD28 and CTLA-4, may be an additional candidate gene for this region on chromosome 2q33.

Sequence data closely link ICOS to both CD28 and CTLA-4, and the gene encoding ICOS is separated by only approximately 100,000 bases from that encoding CTLA-4 (, indicating that both genes are completely within the limits of resolution of current genetic studies. Studies using ICOS knock- outs197,198,199 have demonstrated that ICOS is essential for development of normal T cell help and plays a protective role during induction of experimental autoimmune disease.197 These data suggest that there may be more autoimmune disease genes at chromosome 2q33 and that the immune response is a dynamic process, wherein there is obviously a large potential for multiple costimulatory signals.

The IDDM13 [MIM 610318] locus maps to 2q34, and the strongest evidence for linkage has been obtained for the D2S137–D2S164 region.27 Thus, IDDM12 and IDDM13 are separated by only 17–18 cM, and IDDM7, IDDM12 and IDDM13 cover a region of approximately 27 cM. Additional evidence for IDDM13 has been obtained in two other studies.140,187 A recent study found evidence for association to T1D of the D2S1327–D2S1471 region, which spans 3.5 cM.187 Several IDDM13 candidate genes have been investigated, including IA-2,140 IGFBP2,172 IGFBP5,172 and NRAMP1140 but no disease-associated mutations have been identified in these genes.

IDDM15 is a putative susceptibility locus that has been mapped to 6q21, in the region of D6S283–D6S1580,28 which is linked to HLA, with an estimated recombination rate (θ) of 0.32 in male meiosis, and 0.47 in female meiosis.28 Therefore, statistical evaluation of cosegregation of IDDM15 with disease should take these gender related recombination rates into account. In a recent genome scan of Scandinavian T1D families20 suggestive evidence of linkage was found at marker D6S283, with a P value of 0.002. These data were then combined with results from French and US multiplex families, since no locus heterogeneity was observed between these populations.20 Taking into account the 95% confidence interval for the estimate of the distance between HLA and D6S283,28 it was estimated that the P value in the combined family set would be 3 × 10−5 to 5 × 10−8 (7 × 10−7 for the recombination rates given above).20 Additional support for this locus was also reported in combined studies of US and UK families.18,21 Thus, the combined evidence in favour of IDDM15 is the most compelling that has been reported thus far for any of the putative T1D-susceptibility loci, apart from IDDM1 and IDDM2. Interestingly, it has also been suggested that this region on chromosome 6 contains a gene responsible for transient neonatal diabetes mellitus, which could also be a candidate gene for IDDM15 in this region.200,201

A very recent report provides evidence for a locus in the immunoglobin heavy chain region on chromosome 14q32.3 producing susceptibility to T1D,30 this locus has been designated IDDM16. Support for linkage was obtained in 351 North American and UK families (P = 0.002).30 Replication in 241 Danish T1D families did not confirm linkage, but there was significant evidence for association (P = 0.019).30 Between 1984 and 1991, more than 20 studies examined serologically-detected Gm allotypes in T1D (reviewed in Dugoujon and Cambon-Thomsen202). Although none of these studies found direct evidence of linkage or association with T1D, many reported evidence of immunoglobin heavy chain (IGH) region involvement through interaction with HLA genes. Over the last decade, there have been very few new studies of IGH markers in T1D. A Finnish study found no evidence for linkage to IGH variable region markers, but there was significant association for two of the four markers.203 This evidence for association but not for linkage is similar to the observation in the Danish dataset in the study by Field et al.30 Immunoglobulin molecules have a central role in immune response to foreign and self-antigens, and it is therefore conceivable that genetically controlled differences in immunoglobulin structure and function could alter a person’s immune response to such antigens and affect T1D risk. Also, this locus needs replication in other populations to be confirmed.

IDDM17 [MIM 603266] was identified on the basis of a genomic search for linkage to T1D in a large Bedouin Arab family.6 A locus contributing to T1D susceptibility was located on chromosome 10q25. The family contained 19 affected relatives, all of whom carried one or two high-risk HLA-DR3 haplotypes that were rarely found in other family members. This susceptibility locus was mapped to an 8 cM interval between D10S1750 and D10S1773, and two adjacent markers, D10S592 and D10S554, showed evidence of linkage disequilibrium with the disease locus. The FAS gene maps to this region (10q24.1), but has been excluded as the disease-contributing locus. Also, the FAS gene has been excluded in population-based family studies,204 and this particular region has not been identified in other genome scans.16,17,18,19,20 However, increased LOD scores were observed near the putative IDDM17 locus in the consensus analysis of UK and US ASPs.21 These increased LOD scores occurred in the subset of families in which all affected individuals were HLA-DR3/non-HLA-DR4, which is consistent with the original report.6 Thus, this study suggests that T1D may also be an oligogenic disease rather than a polygenic disease in some circumstances, and that perhaps just two or three genes may suffice to explain all the inherited susceptibility in a given family.

Recently, a new susceptibility locus, IDDM18 [MIM 605598], was identified and mapped to chromosome 5q31.1–q33.1, close to the gene for the p40 subunit of the interleukin 12 gene, IL 12B.29,205 IL-12p40 production influences T-cell responses, and may therefore be important in T1D susceptibility.206 IL-12 drives the differentiation of T-lymphocytes into the Th1 subset, characterised by production of cytokines leading to cell-mediated immunity.207,208 Furthermore, in the NOD mouse, IL-12 has been shown to play a primary role in T1D induction,206,209,210 and in addition, plays a key role in immune reactivity against infections. However, it has been shown that in the absence of infection, IL-12-induced autoreactive T cell responses might predispose to self-destructive immunity.211,212 Several polymorphisms have been identified in the IL 12B locus.205,213 A 3′UTR (untranslated region) single base change showed strong linkage disequilibrium with the T1D susceptibility locus in Australian and British diabetes families,29 but this observation needs to be replicated in other populations.214

Other susceptibility loci

A number of additional chromosomal regions demonstrating some evidence of linkage to T1D have been identified. Regions with multipoint LOD scores >1.5 identified in the two recent genome scans20,21 are listed in Table 4. Due to the size of these studies, and the fact that there is no overlap between the families analysed, these regions are probably more likely to harbour genes predisposing to T1D than some of the previously designated IDDM loci (Table 3) with the exception of IDDM1 and IDDM2.

Table 4 ‘New’ non-HLA regions with multipoint LOD scores >1.5 in unconditional analyses from references a21 and b20

Interestingly, the ECIGS study20 identified a region on chromosome 2p12, marker D2S113, near the gene for eukaryotic translation-initiation factor-2 α kinase-3 (EIF2AK3), in which disease-causing mutations have been identified in patients with Wolcott-Rallison syndrome (neonatal insulin-dependent diabetes and epiphyseal dysplasia).7 On that basis additional markers were selected to cover the EIF2AK3 region, and evidence of linkage at this locus increased to a LOD score of 2.6 in HLA-DR3/4 positive ASPs.20 Also, a region on chromosome 4p was identified,20 which demonstrated linkage to T1D in conditional analysis of the UK multiplex families.215 The region incorporates the Wolfram syndrome (phenotype includes insulin-dependent diabetes and optic atrophy) locus, WFS1.216,217 Several mutations have been identified in WFS1,216,217,218 and it has been suggested that variations in the WFS1 locus could play a minor role in the more common forms of diabetes mellitus.216 Thus, these examples suggest that genes identified in oligogenic forms of diabetes may contribute to T1D susceptibility in the general population.

The effects of gender and HLA genotype complicate studies of the contribution of genes on the X chromosome to T1D susceptibility but there is some evidence for linkage to Xp13-p11 in HLA-DR3/X affected sibpairs.20,219

There is also increasing evidence of the key role of vitamin D levels in T1D susceptibility.220,221,222 Vitamin D has important immunomodulatory properties223 and depletion or relative resistance may play a part in the aetiology of both T1DM and T2DM, possibly through effects on insulin secretion.224 It has been shown that allelic variations in the vitamin D receptor (VDR) gene is a significant determinant of the amount of VDR mRNA and VDR protein expressed,225 and may also affect plasma concentrations of 1,25(OH)2D3, and the response to oral vitamin D.226 An association between VDR polymorphisms and T1DM has been reported in South Indian, German and Taiwanese populations,227,228,229 although not necessarily with the same VDR polymorphisms.

As illustrated above, a complex disease like T1D most often involves multiple interacting genetic determinants. However, statistical methods in current use for localizing such genes essentially work under single gene models, either implicitly or explicitly, thus not allowing identification of such complex traits. Therefore new methods have been developed. These include variance components methods for quantitative trait loci (QTL);230,231 conditional tests for QTL by multiple regression analysis;232,233 conditional and simultaneous search methods from high-resolution maps of identity-by-descent,234 methods for searching for an additional locus given an established susceptibility locus,235,236 interaction analysis,237 and multi-locus nonparametric linkage analysis with neural networks.238 Most of these newer methods focus on two-loci traits and their statistical properties (applications) for genome-wide searches of susceptibility genes are not well known. In current practice, the majority of whole genome scans for complex trait loci are conducted by multipoint methods16,17,18,19,20,21,239,240 that work under the implicit assumption of a single trait locus or multiple trait loci, unrelated to each other. Therefore there is an urgent need for the exploration of new strategies for detecting sets of marker loci, which are linked to multiple interacting disease genes. At present, evidence of statistical interactions between unlinked loci is either calculated by evaluation of correlations between family-specific LOD scores for pairs of loci237 or by conditioning on other loci eg on specific HLA genotypes or age-at-onset.19,20,21 Although the data, at this point in time, should be considered preliminary, interesting results have emerged from recent studies and should be explored further.20,21

Conclusion and future strategies

In addition to candidate-gene driven and genome-wide linkage studies other approaches may be useful in identifying new T1D susceptibility/resistance regions. Identification of syntenic regions, ie regions demonstrating correspondence in gene-order between the chromosomes of different species, and conferring susceptibility/resistance to diabetes in the spontaneous animal models (the NOD mouse241 and the BB rat242), will be useful for identification of similar genes in man. Characterisation of overlapping regions identified through genome scans in other autoimmune or inflammatory diseases is another approach.191,243,244 The occurrence of common features of autoimmune diseases and the co-association of multiple autoimmune diseases in the same individual or family support the notion of common genetic factors that predispose to autoimmunity. Indeed, by correlating data from existing genome scans in other human autoimmune disease, overlaps with already identified T1D susceptibility loci are revealed (Table 5). This clustering of autoimmune susceptibility loci suggests that there may be related genetic backgrounds contributing to susceptibility of clinically distinct disease, and that the genes identified in these clusters are most likely to be involved in primary or secondary regulation of the immune system.

Table 5 IDDM loci for which susceptibility loci for other autoimmune diseases have been mapped to the same region

Several analytical approaches to identification and/or clarification of the contributions of loci to T1D susceptibility have been used over the last decade. Obviously, the most effective strategy seems also to be one of the most simple ie increasing sample size.21,40 This can be accomplished by performing new larger genome scans and/or by merging data from previous studies. Given the number of families already investigated in linkage studies worldwide, the obvious approach to further progress in the identification of genes predisposing to T1D would be through the efforts of a consortium to merge and jointly analyse all existent datasets for linkage, although power calculations (see above) suggest that even more families are needed.

Furthermore, genome-wide LD mapping may be more powerful than linkage analysis. By determining the extended haplotypes at any given locus in a population, it is possible to identify which SNPs will be redundant and which will be essential in association studies. This will make genome-wide SNP typing much more feasible. It was recently suggested that for an initial catalogue of ‘haplotype tag SNPs’, including all the coding region and 3 kb of up- and downstream sequence, each gene should be re-sequenced in a minimum of 30 individuals.39 This will result in >95% power to detect all variants with frequencies higher than 5%.

An enormous amount of genomics and genetics still have to be carried out using adequately sized datasets. Several regions have been implicated but not yet confirmed. These studies are still difficult to perform due to the fact that the human genome sequence is not completed, and the gene content is very uncertain. Finally, when all the genes have been identified there is likely to be a great increase in demand for functional genomics. The number of identified susceptibility genes may continue to grow, but the elucidation of their function in the pathogenesis of T1D will be the most important factor towards understanding the molecular pathogenesis. The approaches used will vary according to the function of these genes, but will include expression studies and generation of transgenic and knockout animal models.


  1. 1

    Karvonen M, Viik-Kajander M, Moltchanova E, Libman I, LaPorte R, Tuomilehto J . Incidence of childhood type 1 diabetes worldwide Diabetes Care 2000 23: 1516–1526

    CAS  PubMed  Google Scholar 

  2. 2

    Borch-Johnsen K . The prognosis of insulin-dependent diabetes mellitus. An epidemiological approach Dan Med Bull 1989 36: 336–348

    CAS  PubMed  Google Scholar 

  3. 3

    Ng YC, Jacobs P, Johnson JA . Productivity losses associated with diabetes in the US Diabetes Care 2001 24: 257–261

    CAS  PubMed  Google Scholar 

  4. 4

    Nagamine K, Peterson P, Scott HS et al. Positional cloning of the APECED gene Nat Genet 1997 17: 393–398

    CAS  Google Scholar 

  5. 5

    Finnish-German APECED consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. The Finnish-German APECED Consortium. Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Nat Genet 1997 17: 399–403

    Google Scholar 

  6. 6

    Verge CF, Vardi P, Babu S et al. Evidence for oligogenic inheritance of type 1 diabetes in a large Bedouin Arab family J Clin Invest 1998 102: 1569–1575

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Delépine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C . EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome Nat Genet 2000 25: 406–409

    PubMed  Google Scholar 

  8. 8

    Wildin RS, Ramsdell F, Peake J et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy Nat Genet 2001 27: 18–20

    CAS  Google Scholar 

  9. 9

    Bennett CL, Christie J, Ramsdell F et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3 Nat Genet 2001 27: 20–21

    CAS  Google Scholar 

  10. 10

    Karvonen M, Toumilehto J, Libman I, LaPorte R WHO DIAMOND project group. A review of the recent epidemiological data on the worldwide incidence of type 1 (insulin-dependent) diabetes mellitus Diabetologia 1993 36: 883–892

    CAS  PubMed  Google Scholar 

  11. 11

    Risch N . Assessing the role of HLA-linked and unlinked determinants of disease Am J Hum Genet 1987 40: 1–14

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Singal DP, Blajchman MA . Histocompatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus Diabetes 1973 22: 429–432

    CAS  PubMed  Google Scholar 

  13. 13

    Nerup J, Platz P, Andersen OO et al. HLA antigens and diabetes mellitus Lancet 1974 ii: 864–866

    Google Scholar 

  14. 14

    Thomsen M, Platz P, Andersen OO et al. MLC typing in juvenile diabetes mellitus and idiopathic Addisons disease Transpl Rev 1975 22: 125–147

    CAS  Google Scholar 

  15. 15

    Pandey JP, Zamani M, Cassiman JJ . Epistatic effects of genes encoding tumor necrosis factor-alpha, immunoglobulin allotypes, and HLA antigens on susceptibility to non-insulin-dependent (type 2) diabetes mellitus Immunogenetics 1999 49: 860–864

    CAS  PubMed  Google Scholar 

  16. 16

    Davies JL, Kawaguchi Y, Bennett ST et al. A genome-wide search for human susceptibility genes Nature 1994 371: 130–136

    CAS  Google Scholar 

  17. 17

    Hashimoto L, Habita C, Beressi J et al. Genetic mapping of a susceptibility locus for insulin-dependent mellitus on chromosome 11q Nature 1994 371: 161–164

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Concannon P, Gogolinewens K, Hinds D et al. A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes-mellitus Nat Genet 1998 19: 292–296

    CAS  Google Scholar 

  19. 19

    Mein C, Esposito L, Dunn M et al. A search for type-1 diabetes susceptibility genes in families from the United Kingdom Nat Genet 1998 19: 297–300

    CAS  Google Scholar 

  20. 20

    European Consortium for IDDM genome Studies. A genome-wide scan for type 1 diabetes susceptibility genes in Scandinavian families. Identification of new loci with evidence of interaction Am J Hum Genet 2001 69: 1301–1313

  21. 21

    Cox N, Wapelhurst B, Morrison A et al. Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families Am J Hum Genet 2001 69: 820–830

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Field LL, Tobias R, Magnus T . A locus on chromosome 15q26 (IDDM3) produces susceptibility to insulin-dependent diabetes mellitus Nat Genet 1994 8: 189–194

    CAS  PubMed  Google Scholar 

  23. 23

    Rowe RE, Wapelhorst B, Bell GI, Risch N, Spielman RS, Concannon P . Linkage and association between insulin-dependent diabetes mellitus (IDDM) susceptibility and markers near the glucokinase gene on chromosome 7 Nat Genet 1995 10: 240–242

    CAS  PubMed  Google Scholar 

  24. 24

    Luo D-F, Bui MM, Muir A, MacLaren NK, Thomson G, She J-X . Affected sib-pair mapping of a novel susceptibility gene to insulin-dependent diabetes mellitus (IDDM8) on chromosome 6q25–q27 Am J Hum Genet 1995 57: 911–919

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Field LL, Tobias R, Thomson G, Plon S . Susceptibility to insulin-dependent diabetes mellitus maps to a locus (IDDM11) on human chromosome 14q24.3–q31 Genomics 1996 33: 1–8

    CAS  PubMed  Google Scholar 

  26. 26

    Luo D-F, Buzzetti R, Rotter JI et al. Confirmation of three susceptibility genes to insulin-dependent diabetes mellitus: IDDM4, IDDM5 and IDDM8 Hum Mol Genet 1996 5: 693–698

    CAS  Google Scholar 

  27. 27

    Morahan G, Huang D, Tait BD, Colman PG, Harrison LC . Markers on distal chromosome 2q linked to insulin-dependent diabetes mellitus Science 1996 272: 1811–1813

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Delépine M, Pociot F, Habita C et al. Evidence of a non-HLA susceptibility locus in type 1 diabetes linked to HLA on chromosome 6 Am J Hum Genet 1997 60: 174–187

    PubMed  PubMed Central  Google Scholar 

  29. 29

    Morahan G, Huang DX, Ymer SI et al. Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL 12B allele Nat Genet 2001 27: 218–221

    CAS  Google Scholar 

  30. 30

    Field LL, Larsen ZM, Pociot F, Nerup J, Tobias R, Bonnevie-Nielsen V . Evidence for a locus (IDDM16) in the immunoglobin heavy chain region on chromosome 14q32.2 producing susceptibility to type 1 diabetes Genes Immun 2002 (in press)

  31. 31

    Nerup J, Mandrup-Poulsen T, Helqvist S et al. On the pathogenesis of IDDM Diabetologia 1994 37 (Suppl 2): S82–S89

    Google Scholar 

  32. 32

    Chakravarti A . Population genetics—making sense out of sequence Nat Genet 1999 21: 56–60

    CAS  Google Scholar 

  33. 33

    Risch N, Merikangas K . The future of genetic studies of complex diseases Science 1996 273: 1516–1517

    CAS  Article  Google Scholar 

  34. 34

    Cargill M, Altshuler D, Ireland J et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes Nat Genet 1999 22: 231–238

    CAS  Article  Google Scholar 

  35. 35

    Halushka MK, Fan JB, Bentley K et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis Nat Genet 1999 22: 239–247

    CAS  Article  Google Scholar 

  36. 36

    Jeffreys AJ, Kauppi L, Neumann R . Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex Nat Genet 2001 29: 217–222

    CAS  Google Scholar 

  37. 37

    Rioux JD, Daly MJ, Silverberg MS et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease Nat Genet 2001 29: 223–228

    CAS  Google Scholar 

  38. 38

    Daly MJ, Rioux JD, Schaffner SE, Hudson TJ, Lander ES . High-resolution haplotype structure in the human genome Nat Genet 2001 29: 229–232

    CAS  Google Scholar 

  39. 39

    Johnson GCL, Esposito L, Barratt BJ et al. Haplotype tagging for the identification of common disease genes Nat Genet 2001 29: 233–237

    CAS  Google Scholar 

  40. 40

    Altmüller J, Palmer LJ, Fischer G, Scherb H, Wjst M . Genomewide scans of complex diseases: True linkage is hard to find Am J Hum Genet 2001 69: 936–950

    PubMed  PubMed Central  Google Scholar 

  41. 41

    Noble JA, Valdes AM, Cook M, Klitz W, Thomson G, Erlich HA . The role of hla class-ii genes in insulin-dependent diabetes-mellitus—molecular analysis of 180 caucasian, multiplex families Am J Hum Genet 1996 59: 1134–1148

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Campbell RD, Trowsdale J . Map of the human MHC Immunol Today 1993 14: 349–352

    CAS  PubMed  Google Scholar 

  43. 43

    Gruen JR, Weissman SM . Evolving views of the major histocompatibility complex Blood 1997 90: 4252–4265

    CAS  PubMed  Google Scholar 

  44. 44

    Ruuls SR, Sedgwick JD . Unlinking tumor necrosis factor biology from the major histocompatibility complex: Lessons from human genetics and animal models Am J Hum Genet 1999 65: 294–301

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    She J-X . Susceptibility to type 1 diabetes: HLA-DQ and DR revisited Immunol Today 1996 17: 323–329

    CAS  PubMed  Google Scholar 

  46. 46

    Cucca F, Todd J . HLA susceptibility to Type 1 diabetes In: Browning M, McMichaels A (eds) HLA and MHC: genes,molecules and function BIOS Scientific Publishers Ltd; Oxford 1996 pp 383–406

    Google Scholar 

  47. 47

    Thorsby E . HLA associated diseases Hum Immunol 1997 53: 1–11

    CAS  PubMed  Google Scholar 

  48. 48

    Dorman JS, Bunken CH . HLA-DQ locus of the human leukocyte antigen complex and type 1 diabetes mellitus: a HuGE review Epidemiol Rev 2000 22: 218–227

    CAS  PubMed  Google Scholar 

  49. 49

    Undlien DE, Lie BA, Thorsby E . HLA complex genes in type 1 diabetes and other autoimmune diseases Which genes are involved? Trends Genet 2001 17: 93–100

    CAS  PubMed  Google Scholar 

  50. 50

    Rønningen KS, Keiding N, Green A . EURODIAB ACE Study Group. Correlations between the incidence of childhood-onset of type 1 diabetes in Europe and HLA genotypes Diabetologia 2001 44 (Suppl 3): B51–B59

    Google Scholar 

  51. 51

    Thomson G, Robinson WP, Kuhner MK et al. Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus Am J Hum Genet 1988 43: 799–816

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Pugliese A, Gianani R, Moromisato R et al. HLA-DQB1*0602 is associated with dominant protection from diabetes even among islet cell antibody-positive first-degree relatives of patients with IDDM Diabetes 1995 44: 608–613

    CAS  PubMed  Google Scholar 

  53. 53

    Baisch JM, Weeks T, Giles R, Hoover M, Stastny P, Capra JD . Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus N Engl J Med 1990 322: 1836–1841

    CAS  PubMed  Google Scholar 

  54. 54

    Nepom GT . A unified hypothesis for the complex genetics of HLA associations with IDDM Diabetes 1990 39: 1153–1157

    CAS  PubMed  Google Scholar 

  55. 55

    Sheehy MJ, Scharf SJ, Rowe JR et al. A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and DQ alleles J Clin Invest 1989 83: 830–835

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Caillat-Zucman S, Garchon HJ, Timsit J et al. Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus J Clin Invest 1992 90: 2242–2250

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Cucca F, Lampis R, Frau F et al. The distribution of DR4 haplotypes in Sardinia suggests a primary association of type 1 diabetes with DRB1 and DQB1 loci Hum Immunol 1995 43: 301–308

    CAS  PubMed  Google Scholar 

  58. 58

    Undlien DE, Friede T, Rammensee HG et al. HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection Diabetes 1997 46: 143–149

    CAS  PubMed  Google Scholar 

  59. 59

    Cucca F, Lampis R, Congia M et al. A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins Hum Mol Genet 2001 10: 2025–2037

    CAS  PubMed  Google Scholar 

  60. 60

    Chao CC, Sytwu HK, Chen EL, Toma J, McDevitt HO . The role of MHC class II molecules in susceptibility to type 1 diabetes: identification of peptide epitopes and characterization of the T cell repertoire Proc Natl Acad Sci USA 1999 96: 9299–9304

    CAS  PubMed  Google Scholar 

  61. 61

    Latek RR, Suri A, Petzold SJ et al. Structural basis of peptide binding and presentation by the type I diabetes-associated MHC class II molecule of NOD mice Immunity 2001 12: 699–710

    Google Scholar 

  62. 62

    Stratmann T, Apostolopoulos V, Mallet-Designe V et al. TheI-Ag7 MHC class II molecule linked to murine diabetes is a promiscuous peptide binder J Immunol 2000 165: 3214–3225

    CAS  PubMed  Google Scholar 

  63. 63

    Lee KH, Wucherpfennig KW, Wiley DC . Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes Nat Immunol 2001 2: 501–507

    CAS  PubMed  Google Scholar 

  64. 64

    McDevitt HO . Closing in on type 1 diabetes N Engl J Med 2001 345: 1060–1061

    CAS  PubMed  Google Scholar 

  65. 65

    Kwok WW, Domeier ME, Johnson ML, Nepom GT, Koelle DM . HLA-DQB1 codon 57 is critical for peptide binding and recognition J Exp Med 1996 183: 1253–1258

    CAS  PubMed  Google Scholar 

  66. 66

    Corper AL, Stratmann T, Apostolopoulos V et al. A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes Science 2000 288: 505–511

    CAS  PubMed  Google Scholar 

  67. 67

    Awata T, Kuzuya T, Matsuda A et al. High frequency of aspartic acid at position 57 of HLA-DQ beta-chain in Japanese IDDM patients and nondiabetic subjects Diabetes 1990 39: 266–269

    CAS  PubMed  Google Scholar 

  68. 68

    Yamagata K, Hanafusa T, Nakajima H et al. HLA-DQA1*1 contributes to resistance and A1*3 confers susceptibility to type 1 (insulin-dependent) diabetes mellitus in Japanese subjects Diabetologia 1991 34: 133–136

    CAS  PubMed  Google Scholar 

  69. 69

    Erlich HA, Rotter JI, Chang JD et al. Association of HLA-DPB1*0301 with IDDM in Mexican-Americans Diabetes 1996 45: 610–614

    CAS  PubMed  Google Scholar 

  70. 70

    Noble JA, Valdes AM, Thomson G, Erlich HA . The HLA class II locus DPB1 can influence susceptibility to type 1 diabetes Diabetes 2000 49: 121–125

    CAS  PubMed  Google Scholar 

  71. 71

    Valdes AM, Noble JA, Genin E, Clerget-Darpoux F, Erlich HA, Thomson G . Modeling of HLA class II susceptibility to type I diabetes reveals an effect associated with DPB1 Genet Epidemiol 2001 21: 212–223

    CAS  PubMed  Google Scholar 

  72. 72

    Lie BA, Akselsen HE, Joner G et al. HLA associations in insulin-dependent diabetes mellitus: no independent association to particular DP genes Hum Immunol 1997 55: 170–175

    CAS  PubMed  Google Scholar 

  73. 73

    Cucca F, Dudbridge F, Loddo M et al. The HLA-DPB1-associated component of the IDDM1 and its relationship to the major loci HLA-DQB1, -DQA1, and -DRB1 Diabetes 2001 50: 1200–1205

    CAS  PubMed  Google Scholar 

  74. 74

    Endert PMv, Liblau R, Patel SD et al. Major histocompatibility complex-encoded antigen processing gene polymorphism in IDDM Diabetes 1994 43: 110–117

    PubMed  Google Scholar 

  75. 75

    Caillat-Zucman S, Daniel S, Djilali-Saiah I et al. Family study of linkage disequilibrium between TAP2 transporter and HLA class II genes. Absence of TAP2 contribution to association with insulin-dependent diabetes mellitus Hum Immunol 1995 44: 80–87

    CAS  PubMed  Google Scholar 

  76. 76

    Undlien DE, Akselsen HE, Joner G et al. No independent associations of LMP2 and LMP7 polymorphisms with susceptibility to develop IDDM Diabetes 1997 46: 307–312

    CAS  PubMed  Google Scholar 

  77. 77

    Thomsen M, Mcvig J, Zerbib A et al. The susceptibility to insulin-dependent diabetes mellitus is associated with C4 allotypes independently of the association with HLA-DQ alleles in HLA-DR3, 4 heterozygotes Immunogenetics 1988 28: 320–327

    CAS  PubMed  Google Scholar 

  78. 78

    Pociot F, Mcvig J, Wogensen L et al. A tumour necrosis factor beta gene polymorphism in relation to monokine secretion and insulin-dependent diabetes mellitus J Scand Immunol 1991 33: 37–49

    CAS  Google Scholar 

  79. 79

    Robinson WP, Barbosa J, Rich SS, Thomson G . Homozygous parent affected sib pair method for detecting disease predisposing variants—application to insulin-dependent diabetes-mellitus Genet Epidemiol 1993 10: 273–288

    CAS  PubMed  Google Scholar 

  80. 80

    Pociot F, Briant L, Jongeneel CV et al. Association of tumor necrosis factor (TNF) and class II MHC alleles with the secretion of TNFa and TNFb by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus Eur J Immunol 1993 23: 224–231

    CAS  PubMed  Google Scholar 

  81. 81

    Bidwell J, Keen L, Gallagher G et al. Cytokine gene polymorphism in human disease: on-line databases Genes Immun 1999 1: 3–19

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Bidwell J, Keen L, Gallagher G et al. Cytokine gene polymorphism in human disease: on-line databases, supplement 1 Genes Immun 2001 2: 61–70

    CAS  PubMed  Google Scholar 

  83. 83

    Moghaddam PH, Zwinderman AH, de-Knijff P et al. TNFa microsatellite polymorphism modulates the risk of IDDM in Caucasians with the high-risk genotype HLA DQA1*0501– DQB1*0201/DQA1*0301–DQB1*0302. Belgian Diabetes Regis- try Diabetes 1997 46: 1514–1515

    CAS  PubMed  Google Scholar 

  84. 84

    Nejentsev S, Reijonen H, Adojaan B et al. The effect of HLA-B allele on the IDDM risk defined by DRB1*04 subtypes and DQB1*0302 Diabetes 1997 46: 1888–1892

    CAS  PubMed  Google Scholar 

  85. 85

    Lie BA, Todd JA, Pociot F et al. The predisposition to type 1 diabetes linked to the human leukocyte antigen complex includes at least one non-class II gene Am J Hum Genet 1999 64: 793–800

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Nejentsev S, Gombos Z, Laine AP et al. Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B Diabetes 2000 49: 2217–2221

    CAS  PubMed  Google Scholar 

  87. 87

    Herr M, Dudbridge F, Zavattari P et al. Evaluation of fine mapping strategies for a multifactorial disease locus: systematic linkage and association analysis of IDDM1 in the HLA region on chromosome 6p21 Hum Mol Genet 2000 9: 1291–1301

    CAS  PubMed  Google Scholar 

  88. 88

    Cordell HJ, Clayton DG . A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes Am J Hum Genet 2002 70: 124–141

    CAS  Google Scholar 

  89. 89

    Zavattari P, Lampis R, Motzo C et al. Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1 in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, -DRB1 disease loci Hum Mol Genet 2001 10: 881–889

    CAS  PubMed  Google Scholar 

  90. 90

    Lander E, Kruglyak L . Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results Nat Genet 1995 11: 241–247

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Bell GI, Selby MJ, Rutter WJ . The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences Nature 1982 295: 31–35

    CAS  PubMed  Google Scholar 

  92. 92

    Rotwein P, Yokoyama S, Didier DK, Chirgwin JM . Genetic analysis of the hypervariable region flanking the human insulin gene Am J Hum Genet 1986 39: 291–299

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Bennett ST, Lucassen AM, Gough SCL et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus Nat Genet 1995 9: 284–292

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Owerbach D, Nerup J . Restriction fragment length polymorphism of the insulin gene in diabetes mellitus Diabetes 1982 31: 275–277

    CAS  PubMed  Google Scholar 

  95. 95

    Bell GI, Horita S, Karam JH . A polymophic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus Diabetes 1984 33: 1504–1509

    Google Scholar 

  96. 96

    Julier C, Hyer RN, Davies J et al. Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility Nature 1991 354: 155–159

    CAS  PubMed  Google Scholar 

  97. 97

    Lucassen AM, Julier C, Beressi J-P et al. Susceptibility to insulin-dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR Nat Genet 1993 4: 305–310

    CAS  PubMed  Google Scholar 

  98. 98

    Owerbach D, Gabbay KH . Localization of a type I diabetes susceptibility locus to the variable tandem repeat region flanking the insulin gene Diabetes 1993 42: 1708–1714

    CAS  PubMed  Google Scholar 

  99. 99

    Julier C, Lucassen A, Villedieu P et al. Multiple DNA variant association analysis: application to the insulin gene region in type 1 diabetes Am J Hum Genet 1994 55: 1247–1254

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Undlien DE, Bennett ST, Todd JA et al. Insulin gene region-encoded susceptibility to IDDM maps upstream of the insulin gene Diabetes 1995 44: 620–625

    CAS  PubMed  Google Scholar 

  101. 101

    Bennett ST, Wilson AJ, Cucca F et al. IDDM2–VNTR-encoded susceptibility to type 1 diabetes—predisposition, protection and parental transmission of alleles of the insulin gene-linked locus J Autoimmunity 1996 9: 415–421

    CAS  Google Scholar 

  102. 102

    Bennett ST, Wilson AJ, Esposito L et al. Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele Nat Genet 1997 17: 350–352

    CAS  Google Scholar 

  103. 103

    Doria A, Lee J, Warram JH, Krolewski AS . Diabetes susceptibility at IDDM2 cannot be positively mapped to the VNTR locus of the insulin gene Diabetologia 1996 39: 594–599

    CAS  PubMed  Google Scholar 

  104. 104

    Owerbach D, Poulsen S, Billesbolle P, Nerup J . DNA insertion sequences near the insulin gene affect glucose regulation Lancet 1982 1: 880–883

    CAS  PubMed  Google Scholar 

  105. 105

    Cocozza S, Riccardi G, Monticelli A et al. Polymorphism at the 5′ end flanking region of the insulin gene is associated with reduced insulin secretion in healthy individuals Eur J Clin Invest 1988 18: 582–586

    CAS  PubMed  Google Scholar 

  106. 106

    Hammond-Kosack MC, Dobrinski B, Lurz R, Docherty K, Kilpatrick MW . The human insulin gene linked polymorphic region exhibits an altered DNA structure Nucleic Acids Res 1992 20: 231–236

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Hammond-Kosack MC, Kilpatrick MW, Docherty K . The human insulin gene-linked polymorphic region adopts a G-quartet structure in chromatin assembled in vitro J Mol Endocrinol 1993 10: 121–126

    CAS  PubMed  Google Scholar 

  108. 108

    Lew A, Rutter WJ, Kennedy GC . Unusual DNA structure of the diabetes susceptibility locus IDDM2 and its effect on transcription by the insulin promoter factor Pur-1/MAZ Proc Natl Acad Sci USA 2000 97: 12508–12512

    CAS  PubMed  Google Scholar 

  109. 109

    Lucassen AM, Screaton GR, Julier C, Elliot TJ, Lathrop M, Bell JI . Regulation of insulin gene expression by IDDM associated, insulin locus haplotype Hum Mol Genet 1995 4: 501–506

    CAS  PubMed  Google Scholar 

  110. 110

    Kennedy GC, German MS, Rutter WJ . The minisatellite in the diabetes susceptibility locus IDDM2 regulates insulin transcription Nat Genet 1995 9: 293–298

    CAS  PubMed  Google Scholar 

  111. 111

    Pugliese A, Zeller M, Fernandez A et al. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type-1 diabetes Nat Genet 1997 15: 293–297

    CAS  PubMed  Google Scholar 

  112. 112

    Vafiadis P, Bennett S, Todd J et al. Insulin expression in human thymus is modulated by INS VNTR Nat Genet 1997 15: 289–292

    CAS  PubMed  Google Scholar 

  113. 113

    Vafiadis P, Ounissi-Benkalha H, Palumbo M et al. Class III alleles of the variable number of tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose to type 1 diabetes J Clin Endocrinol Metab 2001 86: 3705–3710

    CAS  PubMed  Google Scholar 

  114. 114

    Werdelin O, Cordes U, Jensen T . Aberrant expression of tissue-specific proteins in the thymus: a hypothesis for the development of central tolerance Scand J Immunol 1998 47: 95–100

    CAS  PubMed  Google Scholar 

  115. 115

    Hanahan D . Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance and autoimmunity Curr Opin Immunol 1998 10: 656–662

    CAS  PubMed  Google Scholar 

  116. 116

    Zamani M, Pociot F, Reymaekers P, Nerup J, Cassiman J-J . Linkage of type 1 diabetes to 15q26 (IDDM3) in the Danish population Hum Genet 1996 98: 491–496

    CAS  PubMed  Google Scholar 

  117. 117

    Nakagawa Y, Kawaguchi Y, Twells R et al. Fine mapping of the diabetes susceptibility gene IDDM4 on chromosome 11q13 Am J Hum Genet 1998 63: 547–556

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Sawicki M, Arnold E, Ebrahimi S et al. A transcript map encompassing the multiple endocrine neoplasia type-1 (MEN1) locus on chromosome 11q13 Genomics 1997 42: 405–412

    CAS  PubMed  Google Scholar 

  119. 119

    Kim P, Dutra A, Chandrasekharappa S, Puck J . Genomic structure and mapping of the human FADD, an intracellular mediator of lymphocyte apoptosis J Immunol 1996 157: 5461–5466

    CAS  PubMed  Google Scholar 

  120. 120

    Signore A, Annovazzi A, Gradini R, Liddi R, Ruberti G . Fas and Fas ligand-mediated apoptosis and its role in autoimmune diabetes Diabetes Metab Rev 1998 14: 197–206

    CAS  Google Scholar 

  121. 121

    Mandrup-Poulsen T . beta-cell apoptosis: stimuli and signaling Diabetes 2001 50: (Suppl 1): S58–S63

    Google Scholar 

  122. 122

    Eckenrode S, Marron MP, Nicholls R et al. Fine-mapping of the type 1 diabetes locus (IDDM4) on chromosome 11q and evaluation of two candidate genes (FADD and GALN) by affected sibpair and linkage-disequilibrium analyses Hum Genet 2000 106: 14–18

    CAS  PubMed  Google Scholar 

  123. 123

    Hey P, Twells R, Phillips M et al. Cloning of a novel member of member of the low-density lipoprotein receptor family Gene 1998 216: 103–111

    CAS  PubMed  Google Scholar 

  124. 124

    Twells RCJ, Metzker ML, Brown SD et al. The sequence and gene characterization of a 400-kb candidate region for IDDM4 on chromosome 11q13 Genomics 2001 72: 231–242

    CAS  PubMed  Google Scholar 

  125. 125

    Davies JL, Cucca F, Goy JV et al. Saturation multipoint linkage mapping of chromosome 6q in type-1 diabetes Hum Mol Genet 1996 5: 1071–1074

    CAS  PubMed  Google Scholar 

  126. 126

    Church SL, Grant JW, Meese EU, Trent JM . Sublocalization of the gene encoding manganese superoxide dismutase (MnSOD/SOD2) to 6q25 by fluorescence in situ hybridization and somatic cell hybrid mapping Genomics 1992 14: 823–825

    CAS  Google Scholar 

  127. 127

    Ho E, Bray TM . Antioxidants, NFkappaB activation, and diabetogenesis Proc Soc Exp Biol Med 1999 222: 205–213

    CAS  PubMed  Google Scholar 

  128. 128

    Andrade J, Conde M, Ramirez R et al. Protection from nicotinamide inhibition of interleukin-1 beta-induced RIN cell nitric oxide formation is associated with induction of MnSOD enzyme activity Endocrinology 1996 137: 4806–4810

    CAS  PubMed  Google Scholar 

  129. 129

    Hohmeier HE, Thigpen A, Tran VV, Davis R, Newgard CB . Stable expression of manganese superoxide dismutase (MnSOD) in insulinoma cells prevents IL-1beta-induced cytotoxicity and reduces nitric oxide production J Clin Invest 1998 101: 1811–1820

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130

    Pociot F, Rningen KS, Bergholdt R et al. Genetic susceptibility markers in Danish patients with type 1 (insulin-dependent) diabetes—evidence for polygenecity in man Autoimmunity 1994 19: 169–178

    CAS  PubMed  Google Scholar 

  131. 131

    Borgstahl GE, Parge HE, Hickey MJ, Beyer WF, Hallewell RA, Tainer JA . The structure of human mitochondrial manganese superoxide dismutase reveals a novel tetrameric interface of two 4-helix bundles Cell 1992 71: 107–118

    CAS  PubMed  Google Scholar 

  132. 132

    Hodge SE, Anderson CE, Neiswanger K et al. Close genetic linkage between diabetes mellitus and kidd blood group Lancet 1981 2: 893–895

    CAS  PubMed  Google Scholar 

  133. 133

    Merriman T, Twells R, Merriman M et al. Evidence by allelic association-dependent methods for a type 1 diabetes polygene (IDDM6) to chromosome 18q12 Hum Mol Genet 1997 6: 1003–1010

    CAS  PubMed  Google Scholar 

  134. 134

    Merriman T, Eaves I, Twells R et al. Transmission of haplotypes of microsatellite markers rather than single markers alleles in the mapping of a putative type 1 diabetes susceptibility gene (IDDM6) Hum Mol Genet 1998 7: 517–524

    CAS  PubMed  Google Scholar 

  135. 135

    Merriman TR, Cordell HJ, Eaves IA et al. Suggestive evidence for association of human chromosome 18q12–q21 and its orthologue on rat and mouse chromosome 18 with several autoimmune diseases Diabetes 2001 50: 184–194

    CAS  Google Scholar 

  136. 136

    Holmes DI, Wahab NA, Mason RM . Cloning and characterization of ZNF236, a glucose-regulated Kruppel-like zinc-finger gene mapping to human chromosome 18q22–q23 Genomics 1999 60: 105–109

    CAS  Google Scholar 

  137. 137

    Komaki S, Kohno M, Matsuura N et al. The polymorphic 43Thr bcl-2 protein confers relative resistance to autoimmunity: an analytical evaluation Hum Genet 1998 103: 435–440

    CAS  PubMed  Google Scholar 

  138. 138

    Heding PE, Karlsen AE, Veijola R, Nerup J, Pociot F . No evidence of a functionally significant polymorphism of the BCL2 gene in Danish, Finnish and Basque type 1 diabetes families Genes Immun 2001 2: 398–400

    CAS  PubMed  Google Scholar 

  139. 139

    Copeman JB, Hearne C, Cornall RJ et al. Fine localisation of a type 1 diabetes susceptibility gene (IDDM7) to human chromosome 2q by linkage disequilibrium mapping Nat Genet 1995 9: 80–85

    CAS  Google Scholar 

  140. 140

    Esposito L, Hill NJ, Pritchard LE et al. Genetic analysis of chromosome 2 in type 1 diabetes: analysis of putative loci IDDM7, IDDM12, and IDDM13 and candidate genes NRAMP1 and IA-2 and the interleukin-1 gene cluster. IMDIAB Group Diabetes 1998 47: 1797–1799

    CAS  Google Scholar 

  141. 141

    Kristiansen OP, Pociot F, Bennett EP et al. IDDM7 links to insulin-dependent diabetes mellitus in Danish multiplex families but linkage is not explained by novel polymorphisms in the candidate gene GALNT3. The Danish Study Group of Diabetes in Childhood and The Danish IDDM Epidemiology andGenetics Group Hum Mutat 2000 15: 295–296

    CAS  PubMed  Google Scholar 

  142. 142

    Cornall RJ, Prins JB, Todd JA et al. Type 1 diabetes is linked to the interleukin-1 receptor and Ish/ity/bcg genes on chromosome 1 Nature 1991 353: 262–265

    CAS  PubMed  Google Scholar 

  143. 143

    Garchon H-J, Bedossa P, Eloy L, Bach J-F . Identification and mapping to chromosome 1 of a susceptibility gene for periinsulitis in non-obese diabetic mice Nature 1991 353: 260–262

    CAS  PubMed  Google Scholar 

  144. 144

    Bergholdt R, Karlsen AE, Johannesen J et al. Characterization of polymorphisms of an interleukin-1 receptor type 1 gene (IL1RI) promoter region (P2) and their relation to insulin-dependent diabetes mellitus (IDDM) Cytokine 1995 7: 727–732

    CAS  PubMed  Google Scholar 

  145. 145

    Metcalfe KA, Hitman GA, Pociot F et al. An association between type 1 diabetes and the interleukin-1 receptor type 1 gene Hum Immunol 1996 51: 41–48

    CAS  PubMed  Google Scholar 

  146. 146

    Bergholdt R, Larsen ZM, Andersen NA et al. Characterization of new polymorphisms in the 5′ UTR of the human interleukin-1 receptor type 1 (IL1R1) gene: linkage to type 1 diabetes and correlation to IL-1RI plasma level Genes Immun 2000 1: 495–500

    CAS  PubMed  Google Scholar 

  147. 147

    Pociot F, Mvig J, Wogensen L, Worsaae H, Nerup J . A Taql polymorphism in the human interleukin-1b (IL-1b) gene correlates with IL-1b secretion in vitro Eur J Clin Invest 1992 22: 396–402

    CAS  Google Scholar 

  148. 148

    Kristiansen OP, Pociot F, Johannesen J et al. Linkage disequilibrium testing of four interleukin-1 gene-cluster polymorphisms in Danish multiplex families with insulin-dependent diabetes mellitus Cytokine 2000 12: 171–175

    CAS  PubMed  Google Scholar 

  149. 149

    Mandrup-Poulsen T, Pociot F, Mvig J et al. Monokine antagonism is reduced in patients with IDDM Diabetes 1994 43: 1242–1247

    CAS  PubMed  Google Scholar 

  150. 150

    Owerbach D, Gabbay KH . The HOXD8 locus (2q31) is linked to type I diabetes. Interaction with chomosome 6 and 11 disease susceptibility genes Diabetes 1995 44: 132–136

    CAS  PubMed  Google Scholar 

  151. 151

    Rambrand T, Pociot F, Rønningen KS, Nerup J, Michelsen B the Danish Study Group of Diabetes in Childhood. Genetic markers for glutamic acid decarboxylase do not predict insulin-dependent diabetes mellitus in pairs of affected siblings Hum Genet 1997 99: 177–185

    CAS  PubMed  Google Scholar 

  152. 152

    Iwata I, Nagafuchi S, Nakashima H et al. Association of polymorphism in the NeuroD/BETA2 gene with type 1 diabetes in the Japanese Diabetes 1999 48: 416–419

    CAS  PubMed  Google Scholar 

  153. 153

    Dupont S, Dina C, Hani EH, Froguel P . Absence of replication in the french population of the association between BETA2/NEUROD-A45T polymorphism and Type 1 diabetes Diabetes Metab 1999 25: 516–517

    CAS  PubMed  Google Scholar 

  154. 154

    Hansen L, Jensen JN, Urioste S et al. NeuroD/BETA2 gene variability and diabetes: no associations to late-onset type 2 diabetes but an A45 allele may represent a susceptibility marker for type 1 diabetes among Danes. Danish Study Group of Diabetes in Childhood, and the Danish IDDM Epidemiology and Genetics Group Diabetes 2000 49: 876–878

    CAS  PubMed  Google Scholar 

  155. 155

    Owerbach D . Physical and genetic mapping of IDDM8 on chromosome 6q27 Diabetes 2000 49: 508–512

    CAS  PubMed  Google Scholar 

  156. 156

    Nyholt DR . All LODs are not created equal Am J Hum Genet 2000 67: 282–288

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Reed P, Cucca F, Jenkins S et al. Evidence for a type-1 diabetes susceptibility locus (iddm 10) on human-chromosome 10p11–q11 Hum Mol Genet 1997 6: 1011–1016

    CAS  PubMed  Google Scholar 

  158. 158

    Heron L, Virsolvy A, Apiou F, Le-Cam A, Bataille D . Isolation, characterization, and chromosomal localization of the human ENSA gene that encodes alpha-endosulfine, a regulator of beta-cell K(ATP) channels Diabetes 1999 48: 1873–1876

    CAS  PubMed  Google Scholar 

  159. 159

    Harada Y, Ozaki K, Suzuki M et al. Complete cDNA sequence and genomic organization of a human pancreas-specific gene homologous to Caenorhabditis elegans sel-1 J Hum Genet 1999 44: 330–336

    CAS  PubMed  Google Scholar 

  160. 160

    Biunno I, Bernard L, Dear P et al. SEL1L, the human homolog of C-elegans sel-1: refined physical mapping, gene structure and identification of polymorphic markers Hum Genet 2000 106: 227–235

    CAS  PubMed  Google Scholar 

  161. 161

    Weinmaster G . Notch signal transduction: a real Rip and more Curr Opin Genet Dev 2000 10: 363–369

    CAS  PubMed  Google Scholar 

  162. 162

    Apelqvist A, Li H, Sommer L et al. Notch signalling controls pancreatic cell differentiation Nature 1999 400: 877–881

    CAS  Google Scholar 

  163. 163

    Jensen J, Pedersen EE, Galante P et al. Control sf endodermal endocrine development by Hes-1 Nat Genet 2000 24: 36–44

    CAS  PubMed  Google Scholar 

  164. 164

    Jensen J, Heller RS, Funder-Nielsen T et al. Independent development of pancreatic alpha- and beta-cells from Neurogenin3-expressing precursors—A role for the notch pathway in repression of premature differentiation Diabetes 2000 49: 163–176

    CAS  Google Scholar 

  165. 165

    Donoviel DB, Donoviel MS, Fan E, Hadjantonakis AK, Bernstein A . Cloning and characterization of Sel-11, a murine homolog of the C-elegans sel-1 gene Mech Dev 1998 78: 203–207

    CAS  PubMed  Google Scholar 

  166. 166

    Pociot F, Larsen ZM, Zavattari P et al. No evidence for SEL1L as a candidate gene for IDDM11- conferred susceptibility Diabetes-Metab Res Rev 2001 17: 292–295

    CAS  PubMed  Google Scholar 

  167. 167

    Larsen ZL, Angelo AD, Cattaneo M et al. Complete mutation scanning of the human SEL1L gene—a candidate gene for type 1 diabetes Acta Diabetologica 2001 38: 191–192

    CAS  PubMed  Google Scholar 

  168. 168

    Nisticò L, Buzzetti R, Pritchard LE et al. The ctla-4 gene region of chromosome 2q33 is linked to, and associated with, type-1 diabetes Hum Mol Genet 1996 5: 1075–1080

    PubMed  Google Scholar 

  169. 169

    Bluestone JA . Is ctla-4 a master switch for peripheral t-cell tolerance J Immunol 1997 158: 1989–1993

    CAS  PubMed  Google Scholar 

  170. 170

    Marron MP, Zeidler A, Raffel LJ et al. Genetic and physical mapping of a type 1 diabetes susceptibility gene (IDDM12) to a 100-kb phagemid artificial chromosome clone containing D2S72–CTLA4–D2S105 on chromosome 2q33 Diabetes 2000 49: 492–499

    CAS  PubMed  Google Scholar 

  171. 171

    Marron MP, Raffel LJ, Garchon H-J et al. Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups Hum Mol Genet 1997 6: 1275–1282

    CAS  PubMed  Google Scholar 

  172. 172

    Owerbach D, Naya FJ, Tsai M-J, Allander SV, Powell DR, Gabbay KH . Analysis of candidate genes for susceptibility to type 1 diabetes. A case-control and family-association study of genes on chromosome 2q31–35 Diabetes 1997 46: 1069–1074

    CAS  PubMed  Google Scholar 

  173. 173

    Donner H, Rau H, Walfish PG et al. CTLA4 alanine-17 confers genetic susceptibility to Graves’ disease and to type 1 diabetes mellitus J Clin Endocrinol Metabol 1997 82: 143–146

    CAS  Google Scholar 

  174. 174

    Barnes R, Grabs R, Polychronakos C . A CTLA-4 polymorphism affects lymphocyte mRNA levels but is not associated with type 1 diabetes in a Canadian dataset Diabetologia 1997 40 (Suppl 1): A51

    Google Scholar 

  175. 175

    van der Auwera BJ, Vandewalle CL, Schuit FC et al. CTLA-4 gene polymorphism confers susceptibility to insulin-dependent diabetes mellitus (IDDM) independently from age and from other genetic or immune disease markers Clin Exp Immunol 1997 110: 98–103

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176

    Donner H, Seidl C, Braun J et al. CTLA4 gene haplotypes cannot protect from IDDM in the presence of high-risk HLA DQ8 or DQ2 alleles in German families Diabetes 1998 47: 1158–1160

    CAS  PubMed  Google Scholar 

  177. 177

    Djilali-Saiah I, Larger E, Harfouch-Hammoud E et al. No major role for the CTLA-4 gene in the association of autoimmune thyroid disease with IDDM Diabetes 1998 47: 125–127

    CAS  PubMed  Google Scholar 

  178. 178

    Awata T, Kurihara S, Iitaka M et al. Association of CTLA-4 gene A-G polymorphism (IDDM12) with acute-onset and insulin-depleted IDDM as well as autoimmune thyroid disease (Graves’ disease and Hashimoto’s thyroiditis) in the Japanese population Diabetes 1998 47: 128–129

    CAS  PubMed  Google Scholar 

  179. 179

    Krokowski M, Bodalski J, Bratek A, Machejko P, Caillat-Zucman S . CTLA-4 gene polymorphism is associated withpredisposition to IDDM in a population from central Poland Diabetes Metab 1998 24: 241–243

    CAS  PubMed  Google Scholar 

  180. 180

    Abe T, Takino H, Yamasaki H et al. CTLA4 gene polymorphism correlates with the mode of onset and presence of ICA512 Ab in Japanese type 1 diabetes Diabetes Res Clin Pract 1999 46: 169–175

    CAS  PubMed  Google Scholar 

  181. 181

    Perez-de NG, Bilbao JR, Nistico L et al. No evidence of association of chromosome 2q with Type I diabetes in the Basque population Diabetologia 1999 42: 119–120

    Google Scholar 

  182. 182

    Hayashi H, Kusaka I, Nagasaka S et al. Association of CTLA-4 polymorphism with positive anti-GAD antibody in Japanese subjects with type 1 diabetes mellitus Clin Endocrinol (Oxf) 1999 51: 793–799

    CAS  Google Scholar 

  183. 183

    Lowe RM, Graham J, Sund G et al. The length of the CTLA-4 microsatellite (AT)N-repeat affects the risk for type 1 diabetes. Diabetes Incidence in Sweden Study Group Autoimmunity 2000 32: 173–180

    CAS  Google Scholar 

  184. 184

    Lee YJ, Huang FY, Lo FS et al. Association of CTLA4 gene A-G polymorphism with type 1 diabetes in Chinese children Clin Endocrinol (Oxf) 2000 52: 153–157

    CAS  Google Scholar 

  185. 185

    McCormack RM, Maxwell AP, Carson D, Patterson CC, Bingham A, Savage DA . Possible association between CTLA4 DNA polymorphisms and early onset type 1 diabetes in a UK population Genes Immun 2001 2: 233–235

    CAS  PubMed  Google Scholar 

  186. 186

    Ihara K, Ahmed S, Nakao F et al. Association studies of CTLA-4, CD28, and ICOS gene polymorphisms with type 1 diabetes in the Japanese population Immunogenetics 2001 53: 447–454

    CAS  PubMed  Google Scholar 

  187. 187

    Larsen Z, Kristiansen OP, Mato E et al. IDDM12 (CTLA4) and IDDM13 on 2q34 in genetic susceptibility to Type 1 diabetes (insulin-dependent) Autoimmunity 1999 31: 35–42

    CAS  PubMed  Google Scholar 

  188. 188

    Kouki T, Sawai Y, Gardine CA, Fisfalen ME, Alegre ML, DeGroot LJ . CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves’ disease J Immunol 2000 165: 6606–6611

    CAS  PubMed  Google Scholar 

  189. 189

    Ligers A, Teleshova N, Masterman T, Huang WX, Hillert J . CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms Genes Immun 2001 2: 145–152

    CAS  PubMed  Google Scholar 

  190. 190

    Karandikar NJ, Vanderlugt CL, Walunas TL, Miller SD, Bluestone JA . CTLA-4: a negative regulator of autoimmune disease J Exp Med 1996 184: 783–788

    CAS  PubMed  Google Scholar 

  191. 191

    Kristiansen OP, Larsen ZM, Pociot F . CTLA-4 in autoimmune diseases–a general susceptibility gene to autoimmunity? Genes Immun 2000 1: 170–184

    CAS  Google Scholar 

  192. 192

    Linsley PS, Nadler SG, Bajorath J et al. Binding stoichiometry of the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4). A disulfide-linked homodimer binds two CD86 molecules J Biol Chem 1995 270: 15417–15424

    CAS  PubMed  Google Scholar 

  193. 193

    Greene JL, Leytze GM, Emswiler J et al. Covalent dimerization of CD28/CTLA-4 and oligomerization of CD80/CD86 regulate T cell costimulatory interactions J Biol Chem 1996 271: 26762–26771

    CAS  PubMed  Google Scholar 

  194. 194

    Takahashi T, Tagami T, Yamazaki S et al. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4 J Exp Med 2000 192: 303–310

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195

    Hutloff A, Dittrich AM, Beier KC et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28 Nature 1999 397: 263–266

    CAS  PubMed  Google Scholar 

  196. 196

    Coyle AJ, Lehar S, Lloyd C et al. The CD28-related molecule ICOS is required for effective T cell-dependent immune responses Immunity 2000 13: 95–105

    CAS  PubMed  Google Scholar 

  197. 197

    Dong C, Juedes AE, Temann UA et al. ICOS co-stimulatory receptor is essential for T-cell activation and function Nature 2001 409: 97–101

    CAS  PubMed  Google Scholar 

  198. 198

    Tafuri A, Shahinian A, Bladt F et al. ICOS is essential for effective T-helper-cell responses Nature 2001 409: 105–109

    CAS  PubMed  Google Scholar 

  199. 199

    McAdam AJ, Greenwald RJ, Levin MA et al. ICOS is critical for CD40-mediated antibody class switching Nature 2001 409: 102–105

    CAS  PubMed  Google Scholar 

  200. 200

    Temple IK, Gardner RJ, Mackay DJ, Barber JC, Robinson DO, Shield JP . Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes Diabetes 2000 49: 1359–1366

    CAS  PubMed  Google Scholar 

  201. 201

    Cave H, Polak M, Drunat S, Denamur E, Czernichow P . Refinement of the 6q chromosomal region implicated in transient neonatal diabetes Diabetes 2000 49: 108–113

    CAS  PubMed  Google Scholar 

  202. 202

    Dugoujon JM, Cambon-Thomsen A . Immunoglobulin allotypes (GM and KM) and their interactions with HLA antigens in autoimmune diseases: a review Autoimmunity 1995 22: 245–260

    CAS  PubMed  Google Scholar 

  203. 203

    Veijola R, Knip M, Puukka R, Reijonen H, Cox DW, Ilonen J . The immunoglobulin heavy-chain variable region in insulin-dependent diabetes mellitus: affected-sib-pair analysis and association studies Am J Hum Genet 1996 59: 462–470

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204

    Nolsoe RL, Kristiansen OP, Sangthongpitag K et al. Complete molecular scanning of the human Fas gene: mutational analysis and linkage studies in families with type I diabetes mellitus. The Danish Study Group of Diabetes in Childhood and The Danish IDDM Epidemiology and Genetics Group Diabetologia 2000 43: 800–808

    CAS  PubMed  Google Scholar 

  205. 205

    Huang D, Cancilla MR, Morahan G . Complete primary structure, chromosomal localisation, and definition of polymorphisms of the gene encoding the human interleukin-12 p40 subunit Genes Immun 2000 1: 515–520

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 206

    Adorini L . Interleukin 12 and autoimmune diabetes Nat Genet 2001 27: 131–132

    CAS  PubMed  Google Scholar 

  207. 207

    Liblau RS, Singer SM, McDevitt HO . Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases Immunol Today 1995 16: 34–38

    CAS  Google Scholar 

  208. 208

    Tian J, Olcott AP, Hanssen LR, Zekzer D, Middleton B, Kaufman DL . Infectious th1 and th2 autoimmunity in diabetes-prone mice Immunol Rev 1998 164: 119–127

    CAS  PubMed  Google Scholar 

  209. 209

    Trembleau S, Penna G, Bosi E, Mortara A, Gately MK, Adorini L . Interleukin-12 administration induces t-helper type-1 cells and accelerates autoimmune diabetes in nod mice J Exp Med 1995 181: 817–821

    CAS  PubMed  PubMed Central  Google Scholar 

  210. 210

    Lamont AG, Adorini L . II-12—a key cytokine in immune regulation Immunol Today 1996 17: 214–217

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211

    Segal BM, Shevach EM . II-12 unmasks latent autoimmune-disease in resistant mice J Exp Med 1996 184: 771–775

    CAS  PubMed  Google Scholar 

  212. 212

    Segal BM, Klinman DM, Shevach EM . Microbial products induce autoimmune-disease by an il-12-dependent pathway J Immunol 1997 158: 5087–5090

    CAS  PubMed  Google Scholar 

  213. 213

    Hall MA, McGlinn E, Coakley G et al. Genetic polymorphism of IL-12 p40 gene in immune-mediated disease Genes Immun 2000 1: 219–224

    CAS  PubMed  Google Scholar 

  214. 214

    Johansson S, Lie BA, Thorsby E, Undlien DE . The polymorphism in the 3′untranslated region of IL 12B has a negligible effect on the susceptibility to develop type 1 diabetes inNorway Immunogenetics 2001 53: 603–605

    CAS  PubMed  Google Scholar 

  215. 215

    Paterson AD, Petronis A . Age of diagnosis-based linkage analysis in type 1 diabetes Eur J Hum Genet 2000 8: 145–148

    CAS  PubMed  Google Scholar 

  216. 216

    Inoue H, Tanizawa Y, Wasson J et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome) Nat Genet 1998 20: 143–148

    CAS  Google Scholar 

  217. 217

    Strom T, Hörtnagel K, Hofmann S et al. Diabetes insipidus, diabetes mellitus, optic athrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein Hum Mol Genet 1998 7: 2021–2028

    CAS  Google Scholar 

  218. 218

    Hardy C, Khanim F, Torres R et al. Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1 Am J Hum Genet 1999 65: 1279–1290

    CAS  PubMed  PubMed Central  Google Scholar 

  219. 219

    Cucca F, Goy J, Kawaguchi Y et al. A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients Nat Genet 1998 19: 301–302

    CAS  PubMed  Google Scholar 

  220. 220

    Anonymous. Vitamin D supplement in early childhood and risk for Type I (insulin-dependent) diabetes mellitus. The EURODIAB Substudy 2 Study Group Diabetologia 1999 42: 51–54

    PubMed  Google Scholar 

  221. 221

    Stene LC, Ulriksen J, Magnus P, Joner G . Use of cod liver oil during pregnancy associated with lower risk of Type I diabetes in the offspring Diabetologia 2000 43: 1093–1098

    CAS  Google Scholar 

  222. 222

    Hypponen E, Laara E, Reunanen A, Jarvelin MR, Virtanen SM . Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study Lancet 2001 358: 1500–1503

    CAS  Google Scholar 

  223. 223

    Lemire JM . Immunomodulatory role of 1,25-dihydroxyvitamin D3 J Cell Biochem 1992 49: 26–31

    CAS  PubMed  Google Scholar 

  224. 224

    Hitman GA, Mannan N, McDermott MF et al. Vitamin D receptor gene polymorphisms influence insulin secretion in Bangladeshi Asians Diabetes 1998 47: 688–690

    CAS  PubMed  Google Scholar 

  225. 225

    Ogunkolade BW, Boucher BJ, Prahl JM et al. Vitamin D receptor mRNA and VDR protein levels in relation to vitamin D status, insulin secretory capacity and VDR genotype in Bangladeshi Asians Diabetes (in press)

  226. 226

    Zmuda JM, Cauley JA, Ferrell RE . Molecular epidemiology of vitamin D receptor gene variants Epidemiol Rev 2000 22: 203–217

    CAS  PubMed  Google Scholar 

  227. 227

    McDermott MF, Ramachandran A, Ogunkolade BW et al. Allelic variation in the vitamin D receptor influences susceptibility to IDDM in Indian Asians Diabetologia 1997 40: 971–975

    CAS  PubMed  Google Scholar 

  228. 228

    Pani MA, Knapp M, Donner H et al. Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans Diabetes 2000 49: 504–507

    CAS  PubMed  Google Scholar 

  229. 229

    Chang TJ, Lei HH, Yeh JI et al. Vitamin D receptor gene polymorphisms influence susceptibility to type 1 diabetes mellitus in the Taiwanese population Clin Endocrinol (Oxf) 2000 52: 575–580

    CAS  Google Scholar 

  230. 230

    Schork NJ . Extended multipoint identity-by-descent analysis of human quantitative traits—efficiency, power, and modeling considerations Am J Hum Genet 1993 53: 1306–1319

    CAS  PubMed  PubMed Central  Google Scholar 

  231. 231

    Tiwari HK, Elston RC . Linkage of multilocus components of variance to polymorphic markers Ann Hum Genet 1997 61: 253–261

    CAS  PubMed  Google Scholar 

  232. 232

    Zeng ZB . Theoretical basis for separation of multiple linked gene effects in mapping quantitative trait loci Proc Nat Acad Sci USA 1993 90: 10972–10976

    CAS  PubMed  Google Scholar 

  233. 233

    Zeng ZB . Precision mapping of quantitative trait loci Genetics 1994 136: 1457–1468

    CAS  PubMed  PubMed Central  Google Scholar 

  234. 234

    Dupuis J, Brown PO, Siegmund D . Statistical-methods for linkage analysis of complex traits from high-resolution maps of identity by descent Genetics 1995 140: 843–856

    CAS  PubMed  PubMed Central  Google Scholar 

  235. 235

    Buhler J, Owerbach D, Schaffer AA, Kimmel M, Gabbay KH . Linkage analyses in type-i diabetes-mellitus using caspar, a software and statistical program for conditional analysis of polygenic diseases Hum Hered 1997 47: 211–222

    CAS  Google Scholar 

  236. 236

    Farrall M . Affected sibpair linkage tests for multiple linked susceptibility genes Genet Epidemiol 1997 14: 103–115

    CAS  PubMed  Google Scholar 

  237. 237

    Cox NJ, Frigge M, Nicolae DL et al. Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans Nat Genet 1999 21: 213–215

    CAS  Google Scholar 

  238. 238

    Lucek P, Hanke J, Reich J, Solla SA, Ott J . Multilocus nonparametric linkage analysis of complex trait loci with neural networks Human Hered 1998 48: 275–284

    CAS  Google Scholar 

  239. 239

    Kruglyak L, Lander ES . Complete multipoint sib-pair analysis of qualitative and quantitative traits Am J Hum Genet 1995 57: 439–454

    CAS  PubMed  PubMed Central  Google Scholar 

  240. 240

    Kruglyak L, Daly MJ, Reevedaly MP, Lander ES . Parametric and nonparametric linkage analysis—a unified multipoint approach Am J Hum Genet 1996 58: 1347–1363

    CAS  PubMed  PubMed Central  Google Scholar 

  241. 241

    Atkinson MA, Leiter EH . The NOD mouse model of type 1 diabetes: as good as it gets? Nat Med 1999 5: 601–604

    CAS  PubMed  Google Scholar 

  242. 242

    Mordes JP, Bortell R, Groen H, Guberski DL, Rossini AA, Greiner DL . Autoimmune diabetes mellitus in the BB rat In: Sima AAF, Shafrir E (eds) Animal Models of Diabetes: a primer Harwood Academic: Amsterdam 2001 pp. 1–41

    Google Scholar 

  243. 243

    Becker K, Simon R, Bailey-Wilson J et al. Clustering of non-major histocompatibility complex susceptibility candidate loci in human autoimmune diseases Proc Natl Acad Sci USA 1998 95: 9979–9984

    CAS  PubMed  PubMed Central  Google Scholar 

  244. 244

    Becker KG . Comparative genetics of type 1 diabetes and autoimmune disease—Common loci, common pathways? Diabetes 1999 48: 1353–1358

    CAS  PubMed  Google Scholar 

  245. 245

    Cordell HJ, Todd JA, Bennett ST, Kawaguchi Y, Farrall M . Two-locus maximum lod score analysis of a multifactorial trait: joint consideration of IDDM2 and IDDM4 with IDDM1 in type 1 diabetes Am J Hum Genet 1995 57: 920–934

    CAS  PubMed  PubMed Central  Google Scholar 

  246. 246

    Coraddu F, Sawcer S, D’Alfonso S et al. A genome screen for multiple sclerosis in Sardinian multiplex families Eur J Hum Genet 2001 9: 621–626

    CAS  PubMed  Google Scholar 

  247. 247

    Susi M, Holopainen P, Mustalahti K, Maki M, Partanen J . Candidate gene region 15q26 and genetic susceptibility to coeliac disease in Finnish families Scand J Gastroenterol 2001 36: 372–374

    CAS  PubMed  Google Scholar 

  248. 248

    Myerscough A, John S, Barrett JH, Ollier WER, Worthington J . Linkage of rheumatoid arthritis to insulin-dependent diabetes mellitus loci—Evidence supporting a hypothesis for the existence of common autoimmune susceptibility loci Arthritis Rheum 2000 43: 2771–2775

    CAS  Google Scholar 

  249. 249

    Cornelis F, Faure S, Martinez M et al. New susceptibility locus for rheumatoid-arthritis suggested by a genome-wide linkage study Proc Natl Acad Sci USA 1998 95: 10746–10750

    CAS  Google Scholar 

  250. 250

    Vaidya B, Imrie H, Perros P et al. Evidence for a new Graves disease susceptibility locus at chromosome 18q21 Am J Hum Genet 2000 66: 1710–1714

    CAS  PubMed  PubMed Central  Google Scholar 

  251. 251

    Nair RP, Henseler T, Jenisch S et al. Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan Hum Mol Genet 1997 6: 1349–1356

    CAS  Google Scholar 

  252. 252

    Ober C, Tsalenko A, Parry R, Cox NJ . A second-generationgenomewide screen for asthma-susceptibility alleles in a founder population Am J Hum Genet 2000 67: 1154–1162

    CAS  PubMed  PubMed Central  Google Scholar 

  253. 253

    King AL, Yiannakou JY, Brett PM et al. A genome-wide family-based linkage study of coeliac disease Ann Hum Genet 2000 64: 479–490

    CAS  Google Scholar 

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Correspondence to F Pociot.

Additional information

This work was in part supported by the EU BioMed 2 Programme (grant no. BMH4–CT97–2311), Novo Nordisk A/S, The Danish Diabetes Association, and the DANDY Foundation. Support from the Juvenile Diabetes Foundation International is also acknowledged.

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Pociot, F., McDermott, M. Genetics of type 1 diabetes mellitus. Genes Immun 3, 235–249 (2002).

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  • type 1 diabetes mellitus
  • T1DM
  • genetic susceptibility
  • human leukocyte antigen
  • genome scan

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