Human Molecular Genetics Advance Access originally published online on August 11, 2006
Human Molecular Genetics 2006 15(18):2813-2824; doi:10.1093/hmg/ddl223
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Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis
1 Division of Epidemiology, 140 Warren Hall MC No. 7360, School of Public Health, University of California, Berkeley, CA 94720, USA, 2 Department of Neurology, University of California, San Francisco, CA 94143, USA, 3 Kaiser Permanente Northern California, Division of Research, 2000 Broadway, Oakland, CA 94612, USA, 4 Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, BOX 165 Cambridge, CB2 2QQ, UK, 5 Department of Integrative Biology, University of California, Berkeley, CA 94720, USA, 6 Celera Diagnostics, Alameda, CA 94502, USA, 7 Department of Neurology, University of Navarra, Pamplona, Spain, 8 Neuroimmunology Unit, Hospital Vall d'Hebron, Barcelona, Spain, 9 Department of Neurology, University of Genova, Genova, Italy, 10 Department of Neurology, Ophthalmology, Otolaryngology and Psychiatry, University of Palermo, Palermo, Italy, 11 Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN 37232, USA and 12 Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA
* To whom correspondence should be addressed at. Tel: +1 5106427814; Fax: +1 5106435163; Email: barcello{at}genepi.berkeley.edu
Received May 30, 2006; Accepted August 3, 2006
Variation in major histocompatibility complex genes on chromosome 6p21.3, specifically the human leukocyte antigen HLA-DR2 or DRB1*1501-DQB1*0602 extended haplotype, confers risk for multiple sclerosis (MS). Previous studies of DRB1 variation and both MS susceptibility and phenotypic expression have lacked statistical power to detect modest genotypic influences, and have demonstrated conflicting results. Results derived from analyses of 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner. DRB1*15 was strongly associated in families (P=7.8x10–31), and a dominant DRB1*15 dose effect was confirmed (OR=7.5, 95% CI=4.4–13.0, P<0.0001). A modest dose effect was also detected for DRB1*03; however, in contrast to DRB1*15, this risk was recessive (OR=1.8, 95% CI=1.1–2.9, P=0.03). Strong evidence for under-transmission of DRB1*14 (P=5.7x10–6) even after accounting for DRB1*15 (P=0.03) was present, confirming a protective effect. In addition, a high risk DRB1*15 genotype bearing DRB1*08 was identified (OR=7.7, 95% CI=4.1–14.4, P<0.0001), providing additional evidence for trans DRB1 allelic interactions in MS. Further, a significant DRB1*15 association observed in primary progressive MS families (P=0.0004), similar to relapsing-remitting MS families, suggests that DRB1-related mechanisms are contributing to both phenotypes. In contrast, results obtained from 2201 MS cases argue convincingly that DRB1*15 genotypes do not modulate age of onset, or significantly influence disease severity measured using expanded disease disability score and disease duration. These results contribute substantially to our understanding of the DRB1 locus and MS, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype–phenotype relationships.
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