Association of IL-2RA/CD25 with type 1 diabetes in the Belgian population Folefac Aminkeng a , Ilse Weets a , Jan E. Van Autreve a , Bobby P.C. Koeleman b , Erik Quartier a , Chris Van Schravendijk a , Frans K. Gorus a , Bart J.R. Van der Auwera a, *, and the Belgian Diabetes Registry a Diabetes Research Center, Faculty of Medicine and Pharmacy, Brussels Free University–Vrije Universiteit Brussel (VUB), Brussels, Belgium b Department of Medical Genetics, University Medical Center, Utrecht, the Netherlands ARTICLE INFO Article history: Received 10 May 2010 Accepted 9 September 2010 Available online 16 September 2010 Keywords: Type 1 diabetes Genetic association Interleukin-2 receptor  IL-2Ra CD25 Autoimmune disease Correlation ABSTRACT Our goals were to study the proposed association of IL-2RA /CD25 with type 1 diabetes in the Belgian population over a broad age range, and to explore possible correlations with disease phenotypes, immune markers, HLA-DQ, INS, and PTPN22. Patients (n = 1954), healthy controls (n = 2082), and families (n = 420) were genotyped for IL-2RA/CD25 rs41295061(CA), HLA-DQ, INS-VNTR and PTPN22. IL-2RA/CD25 was associ- ated with type 1 diabetes ( 2 = 26.8, p  0.001 for alleles and  2 = 29.6, p  0.001 for genotypes). The C allele (odds ratios [OR] = 1.59) and C/C genotype (OR = 1.56) were identified as susceptibility variants, whereas the A allele (OR = 0.63), A/A genotype (OR = 0.14), and A/C genotype (OR = 0.69) as protective variants. IL-2RA/CD25 is associated with both early-onset and late-onset type 1 diabetes, but with a larger effect size in early-onset disease. There was a nonsignificant tendency toward transmission distortion (p = 0.063). Except a tendency toward younger age at onset in carriers of the C/C genotype, no correlations with disease phenotype, immune markers, HLA-DQ, INS and PTPN22 were observed. Also, the frequency of the susceptible genotype was higher in early-onset compared with late-onset TID patients (p = 0.015). In conclusion, IL-2RA/CD25 is associated with type 1 diabetes in the Belgian population, independently of disease phenotype and other biologic markers.  2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. 1. Introduction Genome-wide association studies have identified more than 50 loci for type 1 diabetes (http://www.t1dbase.org), but the contri- bution of most of these loci to prediction is relatively small. How- ever, confirmation in various populations is needed and the corre- lation with disease phenotypes, the association with immune markers and the interaction between these loci should also be studied. This might improve prediction, prevention, stratification, and disease management, and enhance our understanding of the disease heterogeneity and pathophysiology. The interleukin-2 receptor  gene region (IL-2RA), also known as CD25 on chromosome 10p15.1, has been proposed as a shared autoimmune susceptibility locus [1]. It encodes the -chain of the high affinity heterotrimeric IL2R complex [2]. The IL-2RA/CD25 protein is highly expressed on CD4 + CD25 + regulatory T-cells and is important for their survival, proliferation and function. These reg- ulatory T-cells maintain the immune homeostasis and suppress autoimmune responses [3]. Several reports have already shown a reduction in regulatory T-cell function, not only in type 1 diabetes [4] but also in multiple sclerosis [5], thus supporting the evidence for its role in the pathophysiology of autoimmunity and autoim- mune phenotypes. Lowe et al. [6] and Maier et al. [7] had localized the IL-2RA/CD25 association with type 1 diabetes to three groups of single nucleo- tide polymorphisms (SNPs; Group I, rs41295061; Group II, rs11594656; Group III, rs2104686), located in the 5= region and intron 1 of IL-2RA/CD25. One or more SNPs from each group could represent the causal variant(s), their respective minor alleles being protective and the major alleles conferring susceptibility [6,7]. Re- cently, the Type 1 Diabetes Genetics Consortium (T1DGC) geno- typed 69 SNPs and found a 5-SNP (rs3134883, rs3118470, rs7072793, rs4749955, and rs12251307) protective haplotype (H5) that was in perfect linkage disequilibrium with the minor allele of Group I (rs41295061) with an odds ratio virtually identical to that previously reported for Group I (rs41295061). The Group II (rs11594656) SNPs showed no association in the T1DGC set, whereas the group III (rs2104286) SNPs could not be distinguished from H5 [8]. Taking all of these findings into account, the current study considered the analysis of rs41295061 for the IL-2RA/CD25 in type 1 diabetes in the Belgian population. Given the reported level of risk (1.67) in previous studies [6], our goals were to study the association of IL-2RA/CD25 with type 1 diabetes in a large representative registry-based Belgian cohort, * Corresponding author. E-mail address: bartvda@vub.ac.be (B.J.R. Van der Auwera). Human Immunology 71 (2010) 1233–1237 Contents lists available at ScienceDirect 0198-8859/10/$32.00 - see front matter  2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.humimm.2010.09.006