Extended haplotype analysis in the HLA complex reveals an increased frequency of the HFE-C282Y mutation in individuals with multiple sclerosis

Abstract

In order to resolve a multiple sclerosis (MS) susceptibility locus that we had identified in earlier work at the telomeric end of the HLA complex, we genotyped another 34 microsatellite markers (47 in total) across the class I/extended class I region in 166 Tasmanian MS case and 104 control families (D6S299-D6S265). Extended MS susceptibility haplotypes, up to 9 Mb in length, were observed in 11% of MS cases and 4% of controls. Direct comparison of the telomerically extended portion of the MS susceptibility haplotype in HFE-Cys282Tyr (C282Y)-homozygous haemochromatosis patients identified a common ancestry for this genomic segment, which translated into an increased frequency of the C282Y allele in 489 MS cases from Tasmania and Victoria (10.2%) compared with controls (6.7%). Six C282Y homozygotes (1.2%), a three-fold increased rate over the general population, and 88 heterozygotes (18%) were identified. One C282Y-homozygous female was identified who had MS and was being treated for symptoms of iron overload. Interestingly, for 71 Victorian MS cases not of north western European (NWE) ancestry, a DR15-independent reduction in the frequency of the C282Y allele was observed, supporting the theory of a NWE origin for the C282Y-variant of the DR15 ancestral haplotype (C282Y-HLA-A*0301-B*0702-DRB1*1501-DQB1*0602). The results of linkage disequilibrium (LD) and log linear modelling analyses suggest that C282Y is increased in MS cases of NWE ancestry because it is in LD with the ancestral DR15 susceptibility haplotype (7.1) and that it does not play an independent role in predisposition to MS. However, our findings provide the impetus for further investigations into the role of iron metabolism in the severity of MS.

The Big Idea: Iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis

“…5,6 A study from Australia 29 suggests that C282Y-HFE mutation is increased in MS cases of North Western European origin and supports further investigations into the role of iron metabolism in the severity of MS.…”

Replication of KIAA0350, IL2RA, RPL5 and CD58 as multiple sclerosis susceptibility genes in Australians

“…20 A combined total of 1309 healthy controls were ascertained from the Melbourne (Victoria) node of the Australian Bone Marrow Donor Registry (n ¼ 1214), which recruits donors from both Victoria and Tasmania, and through the Menzies Research Institute in Tasmania (n ¼ 95). We estimate that this study involves 20-30% of all MS cases residing in Victoria and Tasmania.…”

Detecting genome wide haplotype sharing using SNP or microsatellite haplotype data

“…One peak covers the DRB1-DQB1-G1152 markers and the other peak is at D6S2236 showing that association extended telomerically into the extended class I region for this population. This extended class I haplotype sharing has been noted previously and appears to be a phenomena of Anglo-Celtic MS cohorts (Rubio et al 2004). Again, the actual test statistic does differ between the markers and peaks at DQB1.…”

“…The first of the real haplotype datasets is the well known CF SNP haplotype dataset (Kerem et al 1989). The second is the result of microsatellite fine mapping of the HLA region of a multiple sclerosis (MS) case and control sample (Rubio et al 2002(Rubio et al , 2004.…”