A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis

Abstract

Genetic susceptibility to multiple sclerosis is associated with genes of the major histocompatibility complex (MHC), particularly HLA-DRB1 and HLA-DQB1 (ref. 1). Both locus and allelic heterogeneity have been reported in this genomic region. To clarify whether HLA-DRB1 itself, nearby genes in the region encoding the MHC or combinations of these loci underlie susceptibility to multiple sclerosis, we genotyped 1,185 Canadian and Finnish families with multiple sclerosis (n = 4,203 individuals) with a high-density SNP panel spanning the genes encoding the MHC and flanking genomic regions. Strong associations in Canadian and Finnish samples were observed with blocks in the HLA class II genomic region (P < 4.9 x 10(-13) and P < 2.0 x 10(-16), respectively), but the strongest association was with HLA-DRB1 (P < 4.4 x 10(-17)). Conditioning on either HLA-DRB1 or the most significant HLA class II haplotype block found no additional block or SNP association independent of the HLA class II genomic region. This study therefore indicates that MHC-associated susceptibility to multiple sclerosis is determined by HLA class II alleles, their interactions and closely neighboring variants.

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

“…Conversely, Chao et al 7 failed to observe a transmission distortion of the HLA-A*02 allele in a large family sample from Canada and no SNPs in the HLA-A region showed association with MS independently of HLA-class II loci in Canadian and Finnish families. 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.…”

“…Moreover, none of the 1068 single-nucleotide-polymorphisms (SNPs) from a highdensity panel spanning the entire HLA genomic region showed additional association in 1185 Canadian and Finnish families after conditioning for HLA-DRB1. 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 ).…”

Genetic variation in nitric oxide synthase 2A (NOS2A) and risk for multiple sclerosis

“…Variation in the MHC, specifically the HLA-DRB1*15 haplotype, is the strongest known genetic factor for MS, and results from multiple studies support this association. 32,33 The complex contribution from this region, however, is estimated to account for only a portion of the risk for the disease. On the basis of these results, it is clear that common (frequency 45 to 10%) non-MHC MS susceptibility alleles confer quite modest risk (odd ratios o2), and are difficult to detect using linkage studies.…”

Mapping candidate non-MHC susceptibility regions to multiple sclerosis

“…This agrees with the evidence of strong association in the MHC class II region between markers G511525 and D6S2444. 36,37 In addition, the analyses predicted at least 38 potential non-MHC susceptibility regions (Figure 1). Of these, 17 regions have been reported in the linkage and/or GAMES studies in five or more different populations, such as chromosomes 7q21, 2,4,7,14,15,20 17q23, 5,9,14 19q13, 2,9,15,20 and 20p12, 4,14,15 and appear to account for several linkage and association reports in each population.…”