IL2RA/CD25 Gene Polymorphisms: Uneven Association with Multiple Sclerosis (MS) and Type 1 Diabetes (T1D)

Abstract

BackgroundIL-2 receptor (IL2R) alpha is the specific component of the high affinity IL2R system involved in the immune response and in the control of autoimmunity.Methods and ResultsHere we perform a replication and fine mapping of the IL2RA gene region analyzing 3 SNPs previously associated with multiple sclerosis (MS) and 5 SNPs associated with type 1 diabetes (T1D) in a collection of 798 MS patients and 927 matched Caucasian controls from the south of Spain. We observed association with MS in 6 of 8 SNPs. The rs1570538, at the 3′- UTR extreme of the gene, previously reported to have a weak association with MS, is replicated here (P = 0.032). The most associated T1D SNP (rs41295061) was not associated with MS in the present study. However, the rs35285258, belonging to another independent group of SNPs associated with T1D, showed the maximal association in this study but different risk allele. We replicated the association of only one (rs2104286) of the two IL2RA SNPs identified in the recently performed genome-wide association study of MS.ConclusionsThese findings confirm and extend the association of this gene with MS and reveal a genetic heterogeneity of the associated polymorphisms and risk alleles between MS and T1D suggesting different immunopathological roles of IL2RA in these two diseases.

The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis

“…9 In families with systemic lupus erythematosus (SLE), other autoimmune diseases, such as MS and RA, occur more frequently than in the general population. 10 Such observations suggest the presence of shared genes and involvement of common disease pathways, and are supported by a number of reports on genes that are associated with more than one autoimmune disease, such as PTPN22 in RA and SLE, 11 IRF5 in MS, 12 RA 13 and SLE, 14 and more recently IL2RA/CD25 in T1D 15 and MS, 16 though with a different risk allele.…”

Association of the AFF3 gene and IL2/IL21 gene region with juvenile idiopathic arthritis

“…24,25 There is also emerging data suggesting that one of the associated SNPs at the IL2RA locus confers differing risk and protective effects for T1D and multiple sclerosis. 26,27 JIA is a phenotypically heterogeneous disease and can be classified into more clinically homogeneous diseases using the ILAR classification criteria (Supplementary Table 1). 28 However, comparing each of the ILAR subtypes separately against controls would result in a large number of hypothesis tests.…”

Determination of the real effect of genes identified in GWAS: the example of IL2RA in multiple sclerosis

“…41 This SNP is also in strong LD with rs10795791 and rs4147359 (HapMap r 2 ¼0.93 and 0.72, respectively), which were shown to be associated both with MS and T1D. 12 Regarding rs2256774, it was found associated to higher levels of rubella antibody 42 and is in strong LD (HapMap r 2 ¼0.63) with rs11594656, which was shown to be correlated with IL2RA expression. 13,15 These studies only considered single-SNP effect and did not take into account the genetic complexity of IL2RA effect.…”

“…12,13 Moreover, functional studies showed that rs2104286 was associated with differences in surface expression of level proteins, 13 and in levels of a soluble form of IL-2 receptors. 14,15 However, when an association signal has been obtained on a SNP, there is still a long way before identifying the causal variants, and deciphering their mode of action and their connection with the other pieces of the pathway.…”