Abstract
The Type I Diabetes Genetics Consortium (T1DGC) has collected thousands of multiplex and simplex families with type I diabetes (T1D) with the goal of identifying genes involved in T1D susceptibility. These families have all been genotyped for the HLA class I and class II loci and a subset of samples has been typed for an major histocompatibility complex (MHC) single-nucleotide polymorphism (SNP) panel. In addition, the T1DGC has genotyped SNPs in candidate genes to evaluate earlier reported T1D associations. Individual SNPs and SNP haplotypes in IL4R, which encodes the α-chain of the IL4 and IL13 receptors, have been associated with T1D in some reports, but not in others. In this study, 38 SNPs in IL4R were genotyped using the Sequenom iPLEX Gold MassARRAY technology in 2042 multiplex families from nine cohorts. Association analyses (transmission-disequilibrium test and parental-disequilibrium test) were performed on individual SNPs and on three-SNP haplotypes. Analyses were also stratified on the high-risk HLA DR3/DR4-DQB1*0302 genotype. A modest T1D association in HBDI families (n=282) was confirmed in this larger collection of HBDI families (n=424). The variant alleles at the non-synonymous SNPs (rs1805011 (E400A), rs1805012 (C431R), and rs1801275 (Q576R)), which are in strong linkage disequilibrium, were negatively associated with T1D risk. These SNPs were more associated with T1D among non-DR3/DR4-DQB1*0302 genotypes than DR3/DR4-DQB1*0302 genotypes. This association was stronger, both in terms of odds ratio and P-values, than the initial report of the smaller collection of HBDI families. However, the IL4R SNPs and the three-SNP haplotype containing the variant alleles were not associated with T1D in the total data. Thus, in the overall families, these results do not show evidence for an association of SNPs in IL4R with T1D.
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References
Risch N . Assessing the role of HLA-linked and unlinked determinants of disease. Am J Hum Genet 1987; 40: 1–14.
Concannon P, Erlich HA, Julier C, Morahan G, Nerup J, Pociot F et al. Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families. Diabetes 2005; 54: 2995–3001.
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.
Erlich H, Valdes AM, Noble J, Carlson JA, Varney M, Concannon P et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 2008; 57: 1084–1092.
Nejentsev S, Howson JM, Walker NM, Szeszko J, Field SF, Stevens HE et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 2007; 450: 887–892.
Noble JA, Valdes AM, Bugawan TL, Apple RJ, Thomson G, Erlich HA . The HLA class I A locus affects susceptibility to type 1 diabetes. Hum Immunol 2002; 63: 657–664.
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.
Valdes AM, Erlich HA, Noble JA . Human leukocyte antigen class I B and C loci contribute to type 1 diabetes (T1D) susceptibility and age at T1D onset. Hum Immunol 2005; 66: 301–313.
Cucca F, Dudbridge F, Loddo M, Mulargia AP, Lampis R, Angius E 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.
Erlich HA, Rotter JI, Chang JD, Shaw SJ, Raffel LJ, Klitz W et al. Association of HLA-DPB1*0301 with IDDM in Mexican-Americans. Diabetes 1996; 45: 610–614.
Lie BA, Todd JA, Pociot F, Nerup J, Akselsen HE, Joner G 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.
Nejentsev S, Gombos Z, Laine AP, Veijola R, Knip M, Simell O 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.
Bottini N, Gloria-Bottini F, Borgiani P, Antonacci E, Lucarelli P, Bottini E . Type 2 diabetes and the genetics of signal transduction: a study of interaction between adenosine deaminase and acid phosphatase locus 1 polymorphisms. Metabolism 2004; 53: 995–1001.
Marron MP, Raffel LJ, Garchon HJ, Jacob CO, Serrano-Rios M, Martinez Larrad MT et al. Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. Hum Mol Genet 1997; 6: 1275–1282.
Smyth DJ, Cooper JD, Bailey R, Field S, Burren O, Smink LJ et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet 2006; 38: 617–619.
Rich SS, Concannon P, Erlich H, Julier C, Morahan G, Nerup J et al. The Type 1 Diabetes Genetics Consortium. Ann N Y Acad Sci 2006; 1079: 1–8.
Chatila TA . Interleukin-4 receptor signaling pathways in asthma pathogenesis. Trends Mol Med 2004; 10: 493–499.
Ivansson EL, Gustavsson IM, Magnusson JJ, Steiner LL, Magnusson PK, Erlich HA et al. Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or Fas ligand, increase risk of cervical cancer. Int J Cancer 2007; 121: 2451–2457.
Mirel DB, Valdes AM, Lazzeroni LC, Reynolds RL, Erlich HA, Noble JA . Association of IL4R haplotypes with type 1 diabetes. Diabetes 2002; 51: 3336–3341.
Bugawan TL, Klitz W, Alejandrino M, Ching J, Panelo A, Solfelix CM et al. The association of specific HLA class I and II alleles with type 1 diabetes among Filipinos. Tissue Antigens 2002; 59: 452–469.
Kruse S, Japha T, Tedner M, Sparholt SH, Forster J, Kuehr J et al. The polymorphisms S503P and Q576R in the interleukin-4 receptor alpha gene are associated with atopy and influence the signal transduction. Immunology 1999; 96: 365–371.
Reimsnider SK, Eckenrode SE, Marron MP, Muir A, She JX . IL4 and IL4Ralpha genes are not linked or associated with type 1 diabetes. Pediatr Res 2000; 47: 246–249.
Maier LM, Twells RC, Howson JM, Lam AC, Clayton DG, Smyth DJ et al. Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene. Genes Immun 2003; 4: 469–475.
Maier LM, Chapman J, Howson JM, Clayton DG, Pask R, Strachan DP et al. No evidence of association or interaction between, the IL4RA, IL4, and IL13 genes in type 1 diabetes. Am J Hum Genet 2005; 76: 517–521.
Howson JMM, Walker NM, Smyth DJ, Todd JA and the Type I Diabetes Genetics Consortium. Analysis of 19 genes for association with type I diabetes in the Type I Diabetes Genetics Consortium families. Genes Immun 2009; 10 (Suppl 1): S74–S84.
Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993; 52: 506–516.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Kazeem GR, Farrall M . Integrating case-control and TDT studies. Ann Hum Genet 2005; 69 (Pt 3): 329–335.
Purcell S, Sham P, Daly MJ . Parental phenotypes in family-based association analysis. Am J Hum Genet 2005; 76: 249–259.
Acknowledgements
We are grateful to the family members who contributed samples and to all the participating T1DGC investigators and sites listed at www.t1dgc.org. This research uses resources provided by the Type I Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. Genotyping was performed at the Broad Institute Center for Genotyping and Analysis is supported by grant U54 RR020278 from the National Center for Research Resources.
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Erlich, H., Lohman, K., Mack, S. et al. Association analysis of SNPs in the IL4R locus with type I diabetes. Genes Immun 10 (Suppl 1), S33–S41 (2009). https://doi.org/10.1038/gene.2009.89
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DOI: https://doi.org/10.1038/gene.2009.89
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