HLA-A Confers an HLA-DRB1 Independent Influence on the Risk of Multiple Sclerosis

Abstract

A recent high-density linkage screen confirmed that the HLA complex contains the strongest genetic factor for the risk of multiple sclerosis (MS). In parallel, a linkage disequilibrium analysis using 650 single nucleotide polymorphisms (SNP) markers of the HLA complex mapped the entire genetic effect to the HLA-DR-DQ subregion, reflected by the well-established risk haplotype HLA-DRB1*15,DQB1*06. Contrary to this, in a cohort of 1,084 MS patients and 1,347 controls, we show that the HLA-A gene confers an HLA-DRB1 independent influence on the risk of MS (P = 8.4×10−10). This supports the opposing view, that genes in the HLA class I region indeed exert an additional influence on the risk of MS, and confirms that the class I allele HLA-A*02 is negatively associated with the risk of MS (OR = 0.63, P = 7×10−12) not explained by linkage disequilibrium with class II. The combination of HLA-A and HLA-DRB1 alleles, as represented by HLA-A*02 and HLA-DRB1*15, was found to influence the risk of MS 23-fold. These findings imply complex autoimmune mechanisms involving both the regulatory and the effector arms of the immune system in the triggering of MS.

HLA-class I markers and multiple sclerosis susceptibility in the Italian population

“…The frequency of MOG-142L and HLA-A*02-positive individuals was significantly lower in cases than in controls, confirming the previously reported protective effect, 9,10,12,13 whereas the association with Cw*05 was not significant. To eliminate the possible confounding effect of linkage disequilibrium (LD) with HLA-DRB1*15, we performed the same analysis in DRB1*15-negative individuals.…”

“…8 Conversely, other studies have detected the effect at least of one class I genetic factor independently of HLA-DRB1. Brynedal et al 9 confirmed in a Nordic cohort of 1084 MS patients and 1347 controls the results of a previous study performed in a smaller Swedish panel, 10 showing that HLA-A*02 is negatively associated with MS (OR ¼ 0.63, P ¼ 7 Â 10 À12 ). Yeo et al 11 analyzed over 1600 UK MS patients and 3600 controls and found that HLA-Cw*05 exerts an MS-protective effect (OR ¼ 0.49, 95% confidence intervals, CI ¼ 0.34-0.69, P ¼ 3.3 Â 10 À5 ) after excluding all individuals carrying DRB1 alleles associated with MS.…”

“…8 As both these studies were based on an intrafamilial association method, an obvious explanation of the discrepancy could be a stratification problem related to the case-control approach used in the present as well as the other two studies. 9,13 However, as a significant HLA-A*02 association was seen in independent studies and in three different populations, this simple explanation seems unlikely and further studies are needed to address this point.…”

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.…”