Epistasis amongHLA-DRB1, HLA-DQA1,andHLA-DQB1loci determines multiple sclerosis susceptibility

Abstract

Multiple sclerosis (MS), a common central nervous system inflammatory disease, has a major heritable component. Susceptibility is associated with the MHC class II region, especially HLA-DRB5*0101-HLA-DRB1*1501-HLA-DQA1*0102-HLA-DQB1*0602 haplotypes (hereafter DR2), which dominate genetic contribution to MS risk. Marked linkage disequilibrium (LD) among these loci makes identification of a specific locus difficult. The once-leading candidate, HLA-DRB1*15, localizes to risk, neutral, and protective haplotypes. HLA-DRB1*15 and HLA-DQB1*0602, nearly always located together on a small ancestral chromosome segment, are strongly MS-associated. One intervening allele on this haplotype, viz. HLA-DQA1*0102, shows no primary MS association. Two Canadian cohorts (n ‫؍‬ 830 and n ‫؍‬ 438 trios) genotyped for HLA-DRB1, HLA-DQA1 and HLA-DQB1 alleles were tested for association using TDT. To evaluate epistasis involving HLA-DRB1*15, transmissions from HLA-DRB1*15-negative parents were stratified by the presence/absence of HLA-DRB1*15 in affected offspring. All 3 alleles contribute to MS susceptibility through novel epistatic interactions. HLA-DQA1*0102 increased disease risk when combined with HLA-DRB1*1501 in trans, thereby unambiguously implicating HLA-DQ in MS susceptibility. Three-locus haplotypes demonstrated that HLA-DRB1*1501 and HLA-DQB1*0602 each influence risk. Transmissions of rare morcellated DR2 haplotypes showed no interaction with HLA-DQA1*0102. Incomplete haplotypes bearing only HLA-DRB1*1501 or HLA-DQB1*0602 did not predispose to MS. Balanced reciprocal transmission distortion can mask epistatic allelic association. These findings implicate epistasis among HLA class II alleles in human immune responses generally, provide partial explanation for intense linkage disequilibrium in the MHC, have relevance to animal models, and demonstrate key roles for DR2-specific interactions in MS susceptibility. MHC disease associations may be more generally haplotypic or diplotypic.genetics ͉ MHC ͉ linkage disequilibrium

Risk HLA-DQA1 and PLA2R1 Alleles in Idiopathic Membranous Nephropathy

“…Thirty-five different alleles in HLA-DQA1 have been documented (www.ebi.ac.uk/imgt/hla) and associated with various immune-related diseases, but so far, none have been linked to idiopathic membranous nephropathy. 31 However, a report on a previous study, in which a traditional method was used (restriction-fragment-length polymorphism analysis), pointed out that HLA-DQA1 alleles could be involved in idiopathic membranous nephropathy. 24 HLA-DQA1 is part of a heterodimer consisting of an alpha chain (DQA) and a beta chain (DQB), both anchored in the membrane and forming the antigen-presenting groove.…”

STAT3 locus in inflammatory bowel disease and multiple sclerosis susceptibility

“…33 Coordinated impairment of some other component of the STAT3 pathway seems a plausible hypothesis and further studies are warranted to ensue the correct ascertainment of the genetic determinants in MS. Strategies that include epistatic interactions are beginning to yield interesting leads in MS and in other complex diseases. 34,35 Genetic studies stand out as approaches to define pathogenic pathways and ultimately, the integration of genetic together with functional data will promote a clearer understanding of the clinical forms of autoimmunity.…”

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

“…Epistasis among HLA-DRB1, HLA-DQA1 and HLA-DQB1 loci has been shown to influence MS risk. [94][95][96][97][98]179 Narcolepsy HLA-DQB1*0602 HLA-DQB1*06011associated with protection [180][181][182] Rheumatoid arthritis Figure 1 Genes and genetic diversity in the MHC class II region. The classical MHC class I, class III and class II regions are shown together with a higher resolution plot showing the location of genes within the MHC class II region chr6:32 250 000-33 300 000 (hg18 build 36.1).…”