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
Highlights
Yeo, Tai Wai, Philip L De Jager, Simon G Gregory, Lisa F Barcellos, Amie Walton, An Goris, Chiara Fenoglio, et al 2007
After stringent Bonferroni correction for the number of markers tested (n ϭ 165), we found that two markers continued to show statistically significant evidence for association: human leukocyte antigen (HLA)-C and rs3132552, a synonymous coding polymorphism in the corneodesmosin gene
Using a combination of microsatellite, single nucleotide polymorphisms (SNPs), and HLA typing in family-based and case–control cohorts from two different populations, we have shown that HLA-C exerts an independent effect on susceptibility to multiple sclerosis above and beyond any effects attributable to the nearby DRB1 gene
Summary
Variation 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. Two groups have typed dense microsatellite maps of the region and both found evidence for a secondary locus maximal in a region close to HLA-A: one group identifying the marker D6S1683 just telomeric of HLA-A,11 and the second group implicating a region including HLA-A extending from MOGCA to D6S265 marker.[14] Follow-up studies in Norway found evidence implicating the D6S265 marker.[16] In another smaller study, a microsatellite marker close to HLA-C (marker C1_3_2) showed evidence for an independent effect.[15] In contrast, a systematic effort to screen the MHC and flanking regions using single nucleotide polymorphisms (SNPs) found no evidence for association beyond that attributable to DRB1*1501, this study was limited by a high genotyping failure rate (40%) and, more importantly, a distribution of markers leaving regions close to the classical loci essentially unexplored.[17] In all of these studies, statistical power has inevitably been reduced by the processes required to filter out the primary effect attributable to DRB1 and the large correction required for multiple testing. None of the published studies has used sufficient samples to compensate for these statistical penalties, and none is able to provide unequivocal evidence supporting any particular secondary locus
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