Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency

Abstract

To understand the genetic predisposition to selective immunoglobulin A deficiency (IgAD), we performed a genome-wide association study in 430 affected individuals (cases) from Sweden and Iceland and 1,090 ethnically matched controls, and we performed replication studies in two independent European cohorts. In addition to the known association of HLA with IgAD, we identified association with a nonsynonymous variant in IFIH1 (rs1990760G>A, P = 7.3 x 10(-10)) which was previously associated with type 1 diabetes and systemic lupus erythematosus. Variants in CLEC16A, another known autoimmunity locus, showed suggestive evidence for association (rs6498142C>G, P = 1.8 x 10(-7)), and 29 additional loci were identified with P < 5 x 10(-5). A survey in IgAD of 118 validated non-HLA autoimmunity loci indicated a significant enrichment for association with autoimmunity loci as compared to non-autoimmunity loci (P = 9.0 x 10(-4)) or random SNPs across the genome (P < 0.0001). These findings support the hypothesis that autoimmune mechanisms may contribute to the pathogenesis of IgAD.

Selective IgA Deficiency in Autoimmune Diseases

“…CD, on the other hand, does not appear to be associated with rs1990760 (74). In 2010, we performed a GWAS on a large cohort of patients with IgAD (13) and identified an association with rs1990760 in the IFIH1 gene. Taken together, there is thus ample evidence for the implication of IFIH1 both in IgAD and in several autoimmune disorders, although the mechanism involved remains elusive.…”

“…Other haplotypes, including HLA-DR7, DQ2 and DR1, DQ5 are also associated with IgAD (11). In contrast, the DR15, DQ6 haplotype has been shown to confer an almost complete protection against the disorder (12)(13)(14). Polymorphisms in the non-MHC genes interferoninduced helicase 1 (IFIH1) and c-type lectin domain family 16, member A (CLEC16A) genes have also been shown to be associated with IgAD in a recent genome-wide association study (GWAS) (13).…”

Update on immunoglobulin A nephropathy, Part I: Pathophysiology

“…The same region had been previously associated with several autoimmune diseases [20][21][22][23][24][25][26][27] . Another MHC locus has been found in the region that includes the HLA-DPA1, BPB1 and DPB2 genes.…”

Preclinical and Predictive Algorithms in Monitoring Patients with Autoimmune Diseases and Their Relatives-at-Risks

“…IFIH1 disturbs cell-mediated and humoral immunity by initiating selective deficiency of IgA. (Ferreira et al, 2010) IL2RA (interleukin 2 receptor, alpha, also known as CD25, T1D0, TGGFR) represents, along with IL2RB and the -chain IL2RG, a fragment of the high-affinity receptor IL-2 (homodimerization of -chains yields low-affinity receptors, while homodimerization ofchains gives receptors with medium affinity). By virtue of its structural and functional peculiarities, IL2RA makes the greatest contribution to the progression of T1D.…”