Abstract

BackgroundMultiple sclerosis (MS) is an immune-mediated disease of polygenic etiology. Dissection of its genetic background is a complex problem, because of the combinatorial possibilities of gene-gene interactions. As genotyping methods improve throughput, approaches that can explore multigene interactions appropriately should lead to improved understanding of MS.Methods286 unrelated patients with definite MS and 362 unrelated healthy controls of Russian descent were genotyped at polymorphic loci (including SNPs, repeat polymorphisms, and an insertion/deletion) of the DRB1, TNF, LT, TGFβ1, CCR5 and CTLA4 genes and TNFa and TNFb microsatellites. Each allele carriership in patients and controls was compared by Fisher's exact test, and disease-associated combinations of alleles in the data set were sought using a Bayesian Markov chain Monte Carlo-based method recently developed by our group.ResultsWe identified two previously unknown MS-associated tri-allelic combinations:-509TGFβ1*C, DRB1*18(3), CTLA4*G and -238TNF*B1,-308TNF*A2, CTLA4*G, which perfectly separate MS cases from controls, at least in the present sample. The previously described DRB1*15(2) allele, the microsatellite TNFa9 allele and the biallelic combination CCR5Δ32, DRB1*04 were also reidentified as MS-associated.ConclusionThese results represent an independent validation of MS association with DRB1*15(2) and TNFa9 in Russians and are the first to find the interplay of three loci in conferring susceptibility to MS. They demonstrate the efficacy of our approach for the identification of complex-disease-associated combinations of alleles.

Highlights

  • Multiple sclerosis (MS) is an immune-mediated disease of polygenic etiology

  • Individuals were genotyped at polymorphic loci at or near genes of the immune response situated at chromosomes 2, 3, 6 and 19 (Table 1)

  • It agreed with TNFa/TNFb haplotype frequencies in patients and controls, which were estimated from genotype data via the population genetics data-analyzing software Arlequin version 2.00 [34]

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Summary

Introduction

Multiple sclerosis (MS) is an immune-mediated disease of polygenic etiology. Investigation of polygenic human diseases, which arise from the combined contribution of multiple independently acting and/or interacting polymorphic genes, remains a great challenge [1,2,3]. Association testing is extensively employed in candidate-gene studies, which are usually conducted in population-based case-control studies. Other candidate genes for MS predisposition studies have been selected mainly because their encoded proteins are involved in autoimmune pathogenesis. These include genes for immunorelevant molecules such as cytokines, cytokine receptors, immunoglobulins, T-cell receptors and specific adapter protein, potential autoantigens of the myelin sheath, ICAM1, and others [12]

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