HLA‐DR, ‐DQA1 and ‐DQB1 associations in Australian multiple sclerosis patients

Abstract

Molecular genotyping for the major histocompatibility complex (MHC) class II loci, HLA-DRB1, -DQB1 and -DQA1, in 100 patients with relapsing/remitting multiple sclerosis (MS) demonstrated an association with the HLA-DR2, DQw6-associated alleles DRB1*1501, DQB1*0602 and DQA1*0102, thereby extending this finding among MS patients in several countries to an Australian population. Analysis by the relative predispositional effect (RPE) method provided no evidence for a second susceptibility allele at either DQA1 or DQB1. However, our data and that of others suggest a negative association with DQA1*0101. Associations were found with DQB1 alleles sharing sequence homology with DQB1*0602, with DQB1 alleles encoding leucine at residue 26 (Leu 26), with DQA1 alleles encoding glutamine at residue 34 (Gln 34) and with Leu 26 plus Gln 34 alleles, but each was shown by two-loci linkage analysis to be secondary to the DRB1*1501, DQB1*0602, DQA1*0102 association. The recently reported negative association with DQA1 alleles encoding phenylalanine at amino acid 25, leucine at amino acid 69 and arginine at amino acid 52 was not found in this study, although there was a trend towards reduced phenylalanine at amino acid 25. The determination at a molecular level of an explanation for the world-wide association with these alleles remains elusive despite major advances in MHC typing.

A genome screen for linkage in Australian sibling-pairs with multiple sclerosis

“…18 Since Australian MS linkage screen M Ban et al 16p was not identified in the two screens in Southern European populations, 14,15 this observation emphasises that alternate combinations of genes may determine susceptibility to multiple sclerosis in different populations (allelic and locus heterogeneity). Despite the wellestablished association of the MHC region with susceptibility to multiple sclerosis in several populations including Australia, 19,20 we only found modest evidence for linkage in this region. While this result is intriguing as greater than 90% of our subjects were of Northern European origin, it reflects the limited statistical power of the linkage approach in small samples of affected family members.…”

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

“…Among haplotypes simultaneously HLA-DRB1*15-positive and HLA-DQB1*0602-negative, it became apparent that the single haplotype accounting for overtransmission contained the closelyrelated HLA-DQB1*0603, reportedly overtransmitted in MS (29) and similarly protective against type I diabetes (30). Among HLA-DRB1*15-positive, HLA-DQB1*0602/*0603-negative haplotypes, transmission was neutral (T/NT ϭ 14/13).…”

An investigation of NOS2A promoter polymorphisms in Australian multiple sclerosis patients

“…While the HLA-DRB1*1501, DQA1*0102, DQB1*0602 haplotype has consistently been found to associate with MS, 4,5 this cannot account for all of the heritability of the disease. A number of other, non-MHC genes are each likely to make small contributions to MS susceptibility; the detection of such genes may uncover major pathways involved in pathogenesis and hence targets for drug development.…”

“…2,3 The only robust genetic association that has been found is with the HLA-DRB1*1501, DQA1*0102, DQB1*0602 haplotype in Caucasian populations. 4,5 A large number of genome wide screens have been conducted in recent years; most recently the GAMES collaboration (Genetic Analysis of Multiple sclerosis in EuropeanS), which pooled the collective resources of 16 European countries and Australia (migrant European), in screens for linkage disequilibrium (LD). 6 While no region consistently reached the level of significance attained for the HLA region, multiple regions showed potential association at a level of probability greater than that expected by chance alone.…”