A second major histocompatibility complex susceptibility locus for multiple sclerosis

Abstract

ObjectiveVariation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRB1 gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed.MethodsUsing a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DRB1*1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects.ResultsScreening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 × 10−5).InterpretationVariation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene. Ann Neurol 2007

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

“…However, when stratifying the results separately for all DRB1 alleles, Cw*05 conferred a significant protection for MS in the subgroup of individuals negative for DRB1*03. This is partially in line with the data reported by Yeo et al 11 who observed a protective effect of Cw*05 in the whole sample as well as in individuals negative for DRB1*03 and other MS-associated DRB1 alleles (DRB1*15, DRB1*0103). Conversely, in DRB1*03-positive individuals, and in the absence of A*02, Cw*05 was a risk marker and conferred a risk similar to DRB1*15 (OR ¼ 3.89, P ¼ 0.0006).…”

“…(characterizing the 44.1 ancestral haplotype) was significantly decreased in the study of Yeo et al 11 However, the association with the A*02-B*44-Cw*05 haplotypic combination was not investigated by the authors. On the other hand, evidence reported in this study and from work undertaken using an experimental animal model 17 points to a direct role of A*02.…”

“…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. In a panel of 1124 Italian MS patients and 1136 controls, we found a significant association with the missense variant V142L (rs2857766) in the gene encoding the Myelin Oligodendrocyte Glycoprotein (MOG) mapping in the HLA-class I region, telomeric to HLA-A (0.3 Mb) and HLA-C (1.6 Mb).…”

Anti-inflammatory genes associated with multiple sclerosis: A gene expression study

“…The strongest susceptibility signal maps to the HLA-DRB1 gene in the class II region of the major histocompatibility complex (MHC) (Barcellos et al, 2006;Yeo et al, 2007). Recently, the two largest genome-wide association studies (GWAS) of MS genetics confirmed HLA as the major MS susceptibility locus and provided unequivocal evidence for the association of additional 110 non-MHC "candidate" genetic variants conferring susceptibility to the disease (IMSGC, 2011;IMSGC, 2013).…”

Multiple sclerosis associates with LILRA3 deletion in Spanish patients

“…22,25 Best known among pathogens that tamper major histocompatibility complex class I expression are herpesviruses, which can alter T-and natural killer-lymphocyte function by subverting the expression of host major histocompatibility complex molecules, or by encoding viral homologues of these. [26][27][28][29][30][31] As all of the polymorphisms of the LRC in chromosome 19, natural killer cells, herpesviruses and HLA class I molecules have been implicated in the susceptibility or pathogenesis of MS, 8,[32][33][34][35][36][37][38][39] it is also of interest to determine whether the genotypic diversity of KIR is associated with MS and whether such an association could explain, by linkage disequilibrium (LD), the reported relationship between MS and deletion of LILRA3.…”