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Risk alleles for multiple sclerosis in multiplex families

From the Wellcome Trust Centre for Human Genetics (M.J.D., H.W., K.M.M., S.V.R., D.A.D., G.C.D., L.H., G.C.E.), Department of Clinical Neurology, University of Oxford, UK; and Department of Medical Genetics and Faculty of Medicine (A.D.S.), Division of Neurology, University of British Columbia, Vancouver, BC, Canada.

Address correspondence and reprint requests to Dr. George C. Ebers, University Department of Clinical Neurology, Level 3, West Wing, John Radcliffe Hospital, Oxford, OX3 9DU, UK george.ebers{at}clneuro.ox.ac.uk

Objective: We assessed the hypotheses that non–major histocompatibility complex multiple sclerosis (MS) susceptibility loci would be common to sporadic cases and multiplex families, that they would have larger effects in multiplex families, and that the aggregation of susceptibility loci contributes to the increased prevalence of MS in such families.

Methods: A set of 43 multiplex families comprising 732 individuals and 211 affected subjects was genotyped for 13 MS candidate genes identified by genome-wide association. A control data set of 182 healthy individuals was also genotyped to perform a case–control analysis alongside the family-based pedigree disequilibrium association test, although this may have been underpowered.

Results: An effect of the IL2RA and CD58 loci was shown in multiplex families as in sporadic MS. The aggregate of the IL2RA, IL7R, EVI5, KIAA0350, and CD58 risk genotypes in affected individuals from multiplex families was found to be notably different from controls (² = 112, p = 1 x 10^–22).

Conclusions: Although differences between individual families can only be suggested, the aggregate results in multiplex families demonstrate effect sizes that are increased as compared with those reported in previous studies for sporadic cases. In addition, they imply that concentrations of susceptibility alleles at IL2RA, IL7R, EVI5, KIAA0350, and CD58 are partly responsible for the heightened prevalence of multiple sclerosis within multiplex families.

Abbreviations: CI = confidence interval; FA = frequency of risk allele in multiple sclerosis–affected individuals; FU = frequency of risk allele in unaffected controls; GI = genetically independent; HLA = human leukocyte antigen; IMSGC = International Multiple Sclerosis Genetics Consortium; MHC = major histocompatibility complex; MS = multiple sclerosis; NA = number of multiple sclerosis–affected subjects; NC = number of control subjects; NT = not transmitted; OR = odds ratio; PDT = pedigree disequilibrium test; RA = risk allele; RAF = risk allele frequency; RG = number of risk genotypes from the HLA-DRB1, IL2RA, IL7RA, EVI5, and CD58 loci; SNP = single nucleotide polymorphism; TR = transmitted.

Supported by the Multiple Sclerosis Society of Canada Scientific Research Foundation and the Multiple Sclerosis Society of the United Kingdom. M.J.D. is funded by the Engineering and Physical Sciences Research Council.

Disclosure: Author disclosures are provided at the end of the article.

Received November 19, 2008. Accepted in final form March 5, 2009.