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* Department of Neurology, University of California, San Francisco, CA 94143;
Division of Epidemiology, School of Public Health, University of California, Berkeley, CA 94720;
Division of Laboratory Medicine, University of Texas, Cancer Center, Houston, TX 77030;
Department of Neurology, Wayne State Medical School, Detroit, MI 48201;
¶ Maryland Center for Multiple Sclerosis Treatment and Research, University of Maryland School of Medicine, Baltimore, MD 21201
Genetic susceptibility to multiple sclerosis (MS) is associated with the MHC located on chromosome 6p21. This signal maps primarily to a 1-Mb region encompassing the HLA class II loci, and it segregates often with the HLA-DQB1*0602, -DQA1*0102, -DRB1*1501, -DRB5*0101 haplotype. However, the identification of the true predisposing gene or genes within the susceptibility haplotype has been handicapped by the strong linkage disequilibrium across the locus. African Americans have greater MHC haplotypic diversity and distinct patterns of linkage disequilibrium, which make this population particularly informative for fine mapping efforts. The purpose of this study was to establish the telomeric boundary of the HLA class II region affecting susceptibility to MS by assessing genetic association with the neighboring HLA-DRB5 gene as well as seven telomeric single nucleotide polymorphisms in a large, well-characterized African American dataset. Rare DRB5*null individuals were previously described in African populations. Although significant associations with both HLA-DRB1 and HLA-DRB5 loci were present, HLA-DRB1*1503 was associated with MS in the absence of HLA-DRB5, providing evidence for HLA-DRB1 as the primary susceptibility gene. Interestingly, the HLA-DRB5*null subjects appear to be at increased risk for developing secondary progressive MS. Thus, HLA-DRB5 attenuates MS severity, a finding consistent with HLA-DRB5’s proposed role as a modifier in experimental autoimmune encephalomyelitis. Additionally, conditional haplotype analysis revealed a susceptibility signal at the class III AGER locus independent of DRB1. The data underscore the power of the African American MS dataset to identify disease genes by association in a region of high linkage disequilibrium.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was funded by grants from the National Institutes of Health (RO1 NS046297, U19AI067152, K23 NS048869-01, and R01NS049510) and the National Multiple Sclerosis Society (RG3060C8).
2 Address correspondence and reprint requests to Dr. Jorge R. Oksenberg, Department of Neurology, University of California, San Francisco, 513 Parnassus Avenue, Medical Science Building, Room S-256, San Francisco, CA 94143-0435. E-mail address: jorge.oksenberg{at}ucsf.edu
3 Abbreviations used in this paper: MS, multiple sclerosis; AGE, advanced glycation end product; CHM, conditional haplotype method; EAE, experimental autoimmune encephalomyelitis; LD, linkage disequilibrium; MBP, myelin basic protein; OR, odds ratio; SNP, single nucleotide polymorphisms.
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