MSH5 is not a genetic predisposing factor for immunoglobulin A deficiency but marks the HLA-DRB1*0102 subgroup...

The etiology of selective IgA deficiency (IgAD) is clearly influenced by human leukocyte antigen (HLA) genetic composition, although the susceptibility observed has not been ascribed to any specific gene/s. A possible role of the MSH5 gene, mapping on this chromosomal region, has been proposed based on its function and on the association of some MSH5 polymorphisms (L85F/P786S and rs3131378) with the disease. However, the extensive linkage disequilibrium in the HLA region makes mandatory additional analyses. We aimed at evaluating the role of those MSH5 polymorphisms on IgAD susceptibility considering their linkage with other classically associated HLA markers, specifically DRB1*0102 and B*08-DRB1*03. We studied 146 trios composed by IgAD patient and parents to unambiguously establish the gametic phase. Association of those MSH5 variants with IgAD is observed but stratified analyses considering other HLA alleles rule out the role of MSH5 per se as a predisposing factor. However, the minor allele of one of the studied polymorphisms, 85F, defines the subgroup of DRB1*0102 haplotypes carrying susceptibility. The causal factor present on this haplotype (MSH5 85F-DRB1*0102) seems to be at the telomeric end of HLA class II or in Class I or III, as the allele composition in more centromeric markers is shared by all the haplotypes containing DRB1*0102.