Genes in the HLA class I region may contribute to the HLA class II‐associated genetic susceptibility to multiple sclerosis

Abstract

In order to analyze whether loci in the human leukocyte antigen (HLA) class I region may contribute to the HLA class II-associated genetic susceptibility to multiple sclerosis (MS), we examined selected microsatellite markers in 177 Nordic sib-pair families, 222 British sib-pair families, 323 sporadic Norwegian MS patients and 386 Norwegian controls. All samples were, in addition, genotyped for the HLA-DR DQ haplotype, and the Norwegian case-control samples were also typed for HLA-A and -B loci. In the Norwegian sporadic MS patients association was seen with HLA-A, HLA-B, and with the D6S265 marker, located 100 kb centromeric to HLA-A. Associations with HLA-A and D6S265 loci were also suggested when restricting the analysis to HLA-DR15 haplotypes. In the sib-pair data a similar trend was seen with marker D6S265. Higher genotypic relative risk (GRR) was found for individuals who carry both HLA-DR15 and -A3 (GRR = 15), compared to those who carry only HLA-DR15 (GRR = 7), only HLA-A3 (GRR = 3) or none of these alleles (GRR = 1). The highest risk was conferred by a combination of HLA-DR15 and -A3 (odds ratio (OR) = 5.2). These results suggest that HLA-A or a gene in linkage disequilibrium with it may contribute to the HLA class II-associated genetic susceptibility to MS.

Genetic variants of the HLA-A, HLA-B and AIF1 loci show independent associations with type 1 diabetes in Norwegian families

“…Furthermore, HLA class II-independent associations with HLA-A and -B have also been reported with other AIDs. In particular, HLA-A has been implicated in multiple sclerosis [34][35][36] and juvenile idiopathic arthritis, 37,38 whereas HLA-B is a well-known risk factor in ankylosing spondylitis 39 and has been implicated in systemic lupus erythematosus. 40 This raises the possibility that these genes represent susceptibility loci that are involved in common, autoimmune processes.…”

Role of CD8 T cell subsets in the pathogenesis of multiple sclerosis

“…Recent genetic studies strongly advocate an independent association between specific major histocompatibility complex (MHC) class I alleles and MS [8]. The exact contribution of CD8 T cells in the pathogenesis of MS remains ambivalent as the HLA-AÃ0301 allele is reported to increase susceptibility [9,10], whereas the HLA-AÃ0201 allele confers protection from the disease [4,11]. This review discusses the recent advances regarding functionally distinct CD8 T cell subsets and their implication in the pathogenesis of MS.…”

HLA class I alleles tag HLA-DRB1 * 1501 haplotypes for differential risk in multiple sclerosis susceptibility

“…Dense single nucleotide polymorphism (SNP) typing localized association to the immediate region of HLA class II (9). Reports from several case-control studies suggesting an independent association with the HLA class I region (22)(23)(24) appear to be secondary to linkage disequilibrium (LD) in family-based material (25). The problems of correcting for LD and for concomitant epistatic interactions, which may be haplotype-specific, are formidable for case-control studies.…”