SNP mapping and candidate gene sequencing in the class I region of the HLA complex: searching for multiple sclerosis susceptibility genes in Tasmanians

Abstract

This study is an extension to previously published work that has linked variation in the human leukocyte antigen (HLA) class I region with susceptibility to multiple sclerosis (MS) in Australians from the Island State of Tasmania. Single nucleotide polymorphism (SNP) mapping was performed on an 865-kb candidate region (D6S1683-D6S265) in 166 Tasmanian MS families, and seven candidate genes [ubiquitin D (UBD), olfactory receptor 2H3 (OR2H3), gamma-aminobutyric acid B receptor 1 (GABBR1), myelin oligodendrocyte glycoprotein (MOG), HLA-F, HLA complex group 4 (HCG4) and HLA-G] were resequenced. SNPs tagging the extended MS susceptibility haplotype were genotyped in an independent sample of 356 Australian MS trios and SNPs in the MOG gene were significantly over-transmitted to MS cases. We identified significant effects on MS susceptibility of HLA-A*2 (OR: 0.51; P = 0.05) and A*3 (OR: 2.85; P = 0.005), and two coding polymorphisms in the MOG gene (V145I: P = 0.01, OR: 2.2; V142L: P = 0.04, OR: 0.45) after full conditioning on HLA-DRB1. We have therefore identified plausible candidates for the causal MS susceptibility allele, and although not conclusive at this stage, our data provide suggestive evidence for multiple class I MS susceptibility genes.

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.…”

“…12 The 142L allele (MOG-142L) conferred an OR ¼ 0.70 (95% C.I ¼ 0.60-0.82) that remained similar after accounting for HLA-DRB1*15 carrier status. 12 Burfoot et al 13 showed similar data in a small Tasmanian population. Moreover, they reported a negative association with HLA-A*02, but they did not analyze if this variation was primarily associated or was dependent on MOG-142L.…”

“…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, they reported a negative association with HLA-A*02, but they did not analyze if this variation was primarily associated or was dependent on MOG-142L. 13 The relationship among the three reported HLA-class I markers, A*02, Cw*05, MOG-142L and their association with MS has not been examined so far.…”

HLA class I-associated diseases with a suspected autoimmune etiology: HLA-B27 subtypes as a model system

“…The evidence that the alleles A*03:01 and A*11:01 are associated not only with immunological abnormalities but real autoimmune diseases is relatively persuasive: A*03:01 has been found to increase the risk for MS two-fold, independent of HLA class II alleles, with which MS is also associated ( [Fogdell-Hahn et al, 2000], [Harbo et al, 2004] and [Burfoot et al, 2008]). In addition, clear-cut evidence for an involvement of the A*03:01 antigen itself in MS has been obtained in a mouse model (Friese et al, 2008).…”