RANTES (regulated on activation, normal T-cell expressed and secreted) is a T-helper type 1 (Th1) chemokine that promotes T-cell activation and proliferation. RANTES is genetically associated with asthma, sarcoidosis and multiple sclerosis. The concentration of RANTES is increased at inflammation sites in different autoimmune diseases. Type 1 diabetes (T1D) is a Th1-mediated disease with complex genetic predisposition. We tested RANTES as a candidate gene for association with T1D using three single-nucleotide polymorphism (SNP) variants (rs4251719, rs2306630 and rs2107538) to capture haplotype information. The minor alleles of all SNPs were transmitted less frequently to T1D offspring (transmission rates 37.3% (P=0.002), 38.7% (P=0.007) and 41.0% (P=0.01)) and were less frequently present in patients compared to controls (P=0.009, 0.03 and 0.04, respectively). A similar protective effect was observed for the haplotype carrying three minor alleles (transmission disequilibrium test (TDT): P=0.003; odds ratio (OR)=0.55; confidence interval (CI): 0.37–0.83; case/control: P=0.03; OR=0.74; CI: 0.55–0.98). Both patients and controls carrying the protective haplotype express significantly lower serum levels of RANTES compared to non-carriers. Subsequently, we tested a cohort of 310 celiac disease patients, but failed to detect association. RANTES SNPs are significantly associated with RANTES serum concentration and development of T1D. The rs4251719*A–rs2306630*A–rs2107538*A haplotype associated with low RANTES production confers protection from T1D. Our data imply that RANTES is associated with T1D both genetically and functionally, and contributes to diabetes-prone Th1 cytokine profile.
Type 1 diabetes (T1D) is an autoimmune disease characterized by a T-cell-mediated progressive destruction of pancreatic beta cells.1 The genetic predisposition to T1D is complex, implying that multiple susceptibility genes with different effects play a role in the development of the disease. Approximately, 50% of the genetic susceptibility to T1D is explained by four established genetic risk factors, including human leukocyte antigen class II genes, the insulin gene, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and protein tyrosine phosphatase PTPN22.2, 3, 4 These findings indicate that analyzing candidate genes is a fruitful approach in the search for T1D susceptibility genes, but that other genetic risk factors still need to be identified.
An interesting candidate gene is RANTES (‘regulated on activation, normal T-cell expressed and secreted’, CCL5). This gene has not yet been investigated in the context of T1D, although it has been shown to be associated with other autoimmune diseases, such as atopic dermatitis, asthma, sarcoidosis, rheumatoid arthritis and multiple sclerosis.5, 6, 7, 8, 9, 10, 11, 12 RANTES belongs to the family of CC chemokines, which are involved in immunoregulatory and inflammatory processes owing to their ability to recruit, activate and co-stimulate T cells and monocytes.13, 14 In addition to the trafficking effect, RANTES, like other CC chemokines, plays an important role in co-stimulation of T-cell proliferation15, 16 and activation of the T cells localized in the inflammatory lesion.17 Activation of T cells by RANTES leads to interleukin-2 (IL-2) receptor expression, cytokine release and T-cell proliferation.16 Micromolar concentrations of RANTES can induce T-cell proliferation in an antigen-independent manner that is especially important in autoimmunity, whereas the increased level of RANTES in the inflammatory sites may lead to the enhanced activation and proliferation of local T cells.17 Recent studies suggest that RANTES is also involved in the process of T-cell differentiation. Administration of RANTES and its interaction with the CCR5 receptor bias the T-helper response toward a T-helper type 1 (Th1)-associated cytokine profile.18, 19 A RANTES−/− mouse model showed decreased T-cell proliferation and impaired production of Th1 cytokines IL-2 and interferon-γ.20
RANTES is located in a cluster with several CC chemokine genes on 17q12. Three RANTES single-nucleotide polymorphisms (SNPs) in the promoter (rs2280788: −28*C/G and rs2107538: −403*G/A) and in the first intron (rs2280789: Int1.1*T/C) have been shown in different studies to modify the transcriptional activity of RANTES.7, 21, 22 However, establishing which of these SNPs has functional consequences is complicated by the high linkage disequilibrium (LD) between them.
Given the strong involvement of RANTES in the immune process, we decided to perform a genetic analysis of the RANTES gene region in T1D. To assess the functional significance of the genetic variants, we tested whether the serum level of RANTES was dependent on the underlying genotypes.
Haplotype structure of the RANTES region
To comprehensively test RANTES for association with T1D, we first investigated the LD structure of the RANTES gene (www.hapmap.org).23 We observed that RANTES is located in an extended block of strong LD and that two SNPs from the block is sufficient to tag all the haplotype information (data not shown; available at http://humgen.med.uu.nl/publications/zhernakova2006_1.html).
Next, we assessed whether the haplotype structure in a Dutch population is similar to the CEHP families included in HAPMAP. In 90 healthy controls that were picked at random from the whole control group, we determined that SNPs rs2306630 and rs3817655 were mutually redundant, meaning that only one of this pair needed to be used for testing. Thus, only three SNPs – rs4251719, rs2306630 and rs2107538 – are informative for the RANTES gene region. Although the infrequent rs2280788 SNP did not differ between haplotypes, we included this SNP in our study owing to its possible functionality. Consequently, four SNPs (rs4251719, rs2306630, rs2280788 and rs2107538) were tested in further studies.
All four SNPs were tested for association with transmission disequilibrium test (TDT) in our cohort of 218 families. We observed a significant decrease in transmission of the minor alleles of rs4251719*A (OR=0.55; 95% CI: 0.37–0.81; P=0.002); rs2306630*A (OR=0.59; 95% CI: 0.40–0.87; P=0.007) and rs2107538*A (OR=0.64; 95% CI: 0.45–0.91; P=0.01) to affected children (Table 1). The transmission of the rare rs2280788*G allele was also decreased, but failed to reach significance (Table 1). To confirm our findings, we tested the same SNPs in a case–control design using 350 T1D cases and 540 controls. We observed a significant decrease in frequency of rs4251719*A (OR=0.70; 95% CI: 0.53–0.92; P=0.009), rs2306630*A (OR=0.74; 95% CI: 0.56–0.98; P=0.03) and rs2107538*A (OR=0.79; 95% CI: 0.63–0.99; P=0.04) in T1D cases compared to controls (Table 2).
We then tested whether any particular RANTES haplotype was associated with T1D. Three frequent haplotypes were observed in both cases and controls that together comprise 97% of all haplotypes. As all three haplotypes contained the rs2280788*C allele, the rs2280788 SNP was omitted from the haplotype analysis. Transmission of the rs4251719*A–rs2306630*A–rs2107538*A haplotype (further referred to as haplotype A–A–A) to T1D offspring was decreased (OR=0.55; 95% CI: 0.37–0.83; P=0.003). The frequency of this A–A–A haplotype was also decreased in T1D cases compared to controls (OR=0.74; 95% CI: 0.55–0.98; P=0.03; Table 4). The frequency of the rs4251719*G–rs2306630*G–rs2107538*A haplotype (G–G–A) was similar in cases and controls and transmission of this haplotype was not distorted (Tables 3 and 4). The overall haplotype association was also significant (P=0.01 and P=0.02 in TDT and the case–control study, respectively; Tables 3 and 4).
Association with celiac disease
The positive association found in T1D prompted us to investigate these RANTES polymorphism in another autoimmune disease, celiac disease (CD). We therefore genotyped RANTES SNPs rs2306630, rs2280788 and rs2107538 in a group of 310 CD patients and compared them with controls. The allele distribution of all three SNPs in celiac patients was not significantly different from that in controls (Supplementary Table 1, also available online at http://humgen.med.uu.nl/publications/zhernakova2006_1.html).
Relation to RANTES serum level
To investigate the functional relevance of the RANTES genotype, we tested for correlation between serum level and genotypes in an independent cohort of 15 recent onset T1D patients and 14 age-matched controls. The patients and controls were genotyped for the SNPs rs2280788, rs2107538 and rs2306630. Only three patients and one control were heterozygous for the rs2280788*G allele. This SNP was excluded from the analysis because of its low frequency.
Carriers of the T1D-associated alleles, rs2107538*A and rs2306630*A (A–A haplotype), had lower levels of RANTES compared to non-carriers (Figure 1). The mean level of RANTES was significantly lower in control carriers for the A–A haplotype (mean 25456.3±2841.1 pg/ml) than in non-carriers (44274.6±2617.4 pg/ml) (P=0.01). In patient carriers and non-carriers of the A–A haplotype, the RANTES serum concentrations were 27 129.8±3044.1 and 35 591.9±3369.2 pg/ml, respectively (P=0.09). When patients and controls were combined, the difference in RANTES serum level between carriers and non-carriers of the protective haplotype reached significance (P=0.003), suggesting that carriers of the protective A–A haplotype have a lower RANTES serum level than non-carriers.
We demonstrate that both in families and in a case–control cohort, the minor alleles of SNPs rs4251719*A, rs2306630*A and rs2107538*A are associated with protection from T1D. We further show that these alleles are related to decreased serum protein levels. This implies that RANTES is involved in the pathogenesis of T1D, presumably owing to its key role in the process of polarization, activation and differentiation of T cells.
A number of molecular mechanisms can explain the association between the RANTES gene and T1D: (i) binding of RANTES to its receptor CCR5 leads to the activation of Janus kinases (JAK).24, 25 Remarkably, the administration of JAK3 inhibitor JANEX1 delays the onset of autoimmune diabetes in non-obese diabetic (NOD) mice.26 (ii) RANTES is one of the activation factors of Erk and p38 members of the mitogen-activated protein kinase (MAPK) family that are involved in regulating cell proliferation and differentiation.17, 25, 27, 28 Interestingly, p38 is considered to be a master switch between benign and destructive insulitis and therefore provokes the development of T1D.29 Inhibition of p38 MAPK leads to the inhibition of Th1 immunity and prevents NOD mice from developing diabetes.29 It is therefore conceivable that a decreased level of RANTES could offer protection from development of T1D via reduced activation of one of these pathways.
Genetic associations of RANTES SNPs with asthma, atopic dermatitis, sarcoidosis, multiple sclerosis and other inflammatory and autoimmune diseases have been reported.5, 6, 7, 8, 9, 10, 11, 12 Therefore, RANTES could be considered a gene generally predisposing to autoimmune disease. To test this hypothesis, we investigated RANTES SNPs rs2306630, rs2280788 and rs2107538 in a group of 310 CD patients. Although RANTES genotypes did not differ significantly between patients and controls (Supplementary Table 1), our microarray studies on intestinal biopsies indicated increased levels of RANTES in the intestinal biopsies of CD patients compared to controls (B Diosdado, personal communication). The increase in the level of RANTES correlated with the severity of the morphological changes in the intestine. Despite a lack of genetic association for RANTES in CD, the fact that the levels of RANTES are increased in patient biopsies, and in combination with the genetic association with RANTES in other autoimmune diseases, renders this gene a potentially relevant candidate biological marker for autoimmune disease.
Increased protein levels of RANTES in the primary sites of inflammation have been reported in different autoimmune diseases. RANTES levels are increased in the cerebrospinal fluid of patients suffering active attacks of multiple sclerosis.14 RANTES levels are also increased in allograft rejection,14 in patients with system lupus erythematosis,30 in the synovium of patients with rheumatoid arthritis31 and in the granulomas in Crohn's disease.32 Similarly, we here report that the RANTES alleles associated with lower serum level of the protein are associated with protection from T1D.
Investigating the functionality of RANTES SNPs is complicated by the presence of high LD in this region. The transcriptional activity of two promoter SNPs (rs2280788: −28*C/G and rs2107538: −403*G/A) and an SNP in intron 1 (rs2280789: Int1.1*T/C) has been investigated.7, 21, 22 An et al.22 showed that transcription activity was mainly regulated by the Int1.1 genotype. Int1.1*C allele strongly downregulates the transcriptional activity of RANTES, whereas the −403*G/A SNP has no effect on transcription and the −28*G allele shows a modest upregulation.22 We have investigated the SNP rs2306630, which, according to the HAPMAP data, is a perfect proxy of the Int1.1 SNP (where the Int1.1*C allele could be tagged by the rs2306630*G allele and the Int1.1*T allele corresponds to the rs2306630*A allele). We observed that the haplotype 2, which is tagged by the rs2306630*A allele, is associated with a lower protein level of RANTES. Our results therefore corroborate An et al.'s22 findings.
RANTES functions via the CC receptors, mainly CCR5, and the association of T1D with the functional variant in the CCR5 gene (CCR5Δ32) has been reported previously.33, 34 We therefore considered testing for epistasis between RANTES and CCL5 genetic variants. However, the observed frequency of the CCR5Δ32 variant in our patient cohort was too low to provide conclusive evidence for interactions between these genes.
We propose RANTES as a functional candidate gene for T1D. However, as RANTES is located in an extended block of high LD, the observed genetic association could be owing to variants in other proximal genes. The block of strong LD includes six known and predicted genes (MMP28, TAF15, FLJ32830, CCL5, LOC440427 and RAD52B). Among these, the MMP28 (the epilysin member of matrix metalloproteinase (MMP)) could serve as an alternative functional candidate for predisposition to autoimmune disease. The MMP28 gene is important for tissue remodelling and wound repair. Interestingly, the level of several MMP genes is reported to be influenced by RANTES stimulation.35, 36, 37 The CC chemokine genes located telomeric of RANTES are also in relatively strong LD with RANTES, and therefore cannot be excluded. A detailed study of this region is therefore necessary to elucidate the contribution of RANTES to the observed association.
Subjects and methods
A total of 350 patients with juvenile onset T1D were included in the case–control study. T1D in all the children was diagnosed according to the International Society of Pediatric and Adolescent Diabetes (ISPAD) criteria. All these patients were diagnosed at age 17 years or younger (median 8.7 years, range 1–17 years); 159 were girls. Both parents were available for 218 of these patients, so that we could perform a family-based association study on them by means of a TDT.
The control group consisted of 540 independent Dutch individuals, comprising 180 healthy spouses of non-diabetic patients included in different (not immune-mediated) studies, and 360 healthy blood donor controls, as described previously.38 Written informed consent was obtained from all participants.
Serum levels of RANTES were measured in 15 T1D patients and 14 matched controls from the REMTrial project by double-sandwich enzyme-linked immunosorbent assay, as described previously.39 The detection level for RANTES was set at 14 pg/ml.
A total of 310 independent CD patients were studied. The diagnosis of CD was made according to the revised European Society of Paediatric Gastroenterology and Nutrition (ESPGAN) criteria.40 In addition, the intestinal biopsies on which the initial diagnoses were based were re-evaluated for all patients by one experienced pathologist. Only patients with a Marsh III lesion were included in our study. Of the 310 CD patients, 214 were female and 96 were male patients. The average age at diagnosis of CD patients was 34.3 years (range from 1 to 83 years).
The RANTES gene is located in a region of strong LD of ∼155.5 kb extent and it is limited by SNPs rs4796105 and rs9899870. We selected two SNPs (rs2306630 and rs3817655) that could tag all the frequent haplotypes in the block according to the HAPMAP data. We also included three additional SNPs (rs4251719, rs2280788 and rs2107538), two of which were located in the promoter region of RANTES (rs2280788 and rs2107538) and have previously been reported to influence the protein level of RANTES. One additional previously reported functional SNP – Int1.1 (rs2280789) – was typed in the HAPMAP project and, according to the HAPMAP data, could be replaced by rs2306630 owing to the strong LD and the identical allele frequency.
SNPs rs2306630, rs4251719, rs3817655 and rs2107538 (−403*G/A) were genotyped using Taqman assays-on-demand (Applied Biosystems, 2910 AH Nieuwerkerk a/d IJssel, The Netherlands) (assay numbers C_26924101_10, C_3143173_10, C_2957192_10 and C_15874407_10, respectively). The rs2280788 (−28*C/G) SNPs was genotyped using Taqman assay-by-design (Applied Biosystems). Assays were performed according to the manufacturer's specifications. Genotypes were analyzed using a TaqMan 7900HT (Applied Biosystems). The DNA samples were processed in 384-well plates. Each plate contained eight negative controls and 16 genotyping controls (four duplicates of four different CEPH samples).
In the controls, the frequency of all the SNPs was in Hardy–Weinberg (HW) proportions, except the rs2107538 (P=0.02), which was most likely owing to a low number of individuals homozygous for the minor allele. To exclude possible genotyping mistakes, we typed this SNP in the additional cohort of 360 healthy individuals. The allelic and genotypes distribution were in HW proportions in the total control group (P=0.35).
The haplotype structure and LD in the region was investigated using the HAPMAP data (www.hapmap.org)41 with the Haploview application.42 Allele and genotype distribution in cases and controls were compared using the COCAPHASED module of the UNPHASED statistical package.43 Association in the T1D families was tested using the TDT phase module of the same package.43 Haplotypes association were estimated using the UNPHASED package.43 HW equilibrium was tested by comparing the expected and observed genotypes in 2 × 3 χ2 table. ORs were calculated and the CIs were approximated using Woolf's method with Haldane's correction.44 The Student's t-test and analysis of variance (ANOVA) were used to compare the mean levels of serum RANTES level among the RANTES genotypes.
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We are grateful to all the patients and their families and physicians for participating in the study. We thank Jackie Senior for improving the manuscript. The study was supported by grants from the Dutch Diabetes Research Foundation (97.137), The Dutch Digestive Disease Foundation (WS 03-06), The Netherlands Organization for Health Research and Development (ZonMW 912-02-028), The Juvenile Diabetes Research Foundation International (JDRF) (2001.10.004) and the Celiac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and partially funded by the Dutch Government (BSIK03009).
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