IL2RA Genetic Heterogeneity in Multiple Sclerosis and Type 1 Diabetes Susceptibility and Soluble Interleukin-2 Receptor Production

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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. Multiple sclerosis (MS) and type 1 diabetes (T1D) are common, organ-specific inflammatory disorders that continue to increase in global prevalence. The processes leading to both T1D and MS are genetically determined and are thought to involve an autoimmune mechanism. After decades of research into the genetic basis of both MS and T1D, the Human Leukocyte Antigen Complex was the only known susceptibility locus for both T1D and MS. The sequencing of the human genome followed by the generation of the haplotype map, a catalogue of common genetic variation, has allowed the elucidation of allelic variants that define disease risk. Our groups have performed genome-wide association scans and candidate gene studies in both T1D and MS; the final results have identified loci outside the HLA harboring fully replicated risk alleles. Here, we show that the IL-2RA gene encoding a critical regulator of immune responses, the alpha chain of the interleukin-2 receptor, harbors variants that differentially confer risk to MS and T1D. In addition, several independent variants correlate with levels of soluble interleukin-2 receptor in the serum. This finding has critical implications for the field of complex disease genetics as it emphasizes the caution that must be taken when interpreting results for such a complex region with multiple susceptibility alleles.