Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci 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.

Fig. 1.

Trans Epistasis between HLA-DRB1*1501 and HLADQA1*0102. (A) HLA-DQA1*0102 (blue) is overtransmitted (OR = 2.1) when HLADRB1*1501 (red) is also present in affected offspring. (B) When HLADRB1*1501 is absent, HLA-DQA1*0102 is undertransmitted (OR = 0.64).

Fig. 2.

Transmission of morcellated DR2 haplotypes reveals cis epistasis in the MHC class II region. (A) The classical MS susceptibility haplotype bearing HLA-DRB1*1501, HLA-DQA1*0102, and HLA-DQB1*0602 confers susceptibility to MS with an OR of 2.6. (B) Haplotypes bearing HLA-DRB1*1501 in the absence of HLA-DQB1*0602 confer no susceptibility (OR = 1.1). (C) Haplotypes bearing HLA-DQB1*0602 in the absence of HLA-DRB1*1501 are also neutral (OR = 1.2). (D) HLA-DQA1*0102-bearing haplotypes which lack HLA-DRB1*1501 and HLA-DQB1*0602 are protective (OR = 0.87).