IL2RA genetic heterogeneity in multiple sclerosis and type 1 diabetes susceptibility and soluble interleukin-2 receptor production

Abstract

Multiple sclerosis (MS) and type 1 diabetes (T1D) are organ-specific autoimmune disorders with significant heritability, part of which is conferred by shared alleles. For decades, the Human Leukocyte Antigen (HLA) complex was the only known susceptibility locus for both T1D and MS, but loci outside the HLA complex harboring risk alleles have been discovered and fully replicated. A genome-wide association scan for MS risk genes and candidate gene association studies have previously described the IL2RA gene region as a shared autoimmune locus. In order to investigate whether autoimmunity risk at IL2RA was due to distinct or shared alleles, we performed a genetic association study of three IL2RA variants in a DNA collection of up to 9,407 healthy controls, 2,420 MS, and 6,425 T1D subjects as well as 1,303 MS parent/child trios. Here, we report "allelic heterogeneity" at the IL2RA region between MS and T1D. We observe an allele associated with susceptibility to one disease and risk to the other, an allele that confers susceptibility to both diseases, and an allele that may only confer susceptibility to T1D. In addition, we tested the levels of soluble interleukin-2 receptor (sIL-2RA) in the serum from up to 69 healthy control subjects, 285 MS, and 1,317 T1D subjects. We demonstrate that multiple variants independently correlate with sIL-2RA levels.

Figure 1. Association of IL2RA SNPs with multiple sclerosis and type 1 diabetes.

(A) Linkage disequilibrium (r ² values) between the SNPs in this study. r ² values are based on 6,317 control subjects from Great Britain. (B) Disease associations (Odds Ratios of minor allele) with MS and T1D are shown for the three SNPs in this study. (C) The SNPs that are perfect proxies (r ² = 1) for the SNPs studied are shown. These perfect proxy SNPs are based on the analysis of 32 CEPH individuals. MS, multiple sclerosis. T1D, type 1 diabetes.