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Human Molecular Genetics Advance Access published online on December 1, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi436
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© The Author 2005. Published by Oxford University Press. All rights reserved The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oupjournals.org
Received October 21, 2005
Accepted November 23, 2005

Article

Association of the truncating splice site mutation in BTNL2 with multiple sclerosis is secondary to HLA-DRB1*15

James A. Traherne 1, Lisa F. Barcellos 2, Stephen J. Sawcer 3, D. Alastair S. Compston 3, Patricia P. Ramsay 4, Stephen L. Hauser 5, Jorge R. Oksenberg 5, and John Trowsdale 1 *

1 Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge, CB2 2XY, UK
2 Division of Epidemiology, School of Public Health, University of California, Berkeley, CA 94720-7360, USA; Department of Neurology and Human Genetics Program, School of Medicine, University of California, San Francisco, CA 94143-0435, USA; Division of Research, Kaiser Permanente, Oakland, CA 94612, USA
3 Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK
4 Division of Epidemiology, School of Public Health, University of California, Berkeley, CA 94720-7360, USA
5 Department of Neurology and Human Genetics Program, School of Medicine, University of California, San Francisco, CA 94143-0435, USA

* To whom correspondence should be addressed.
John Trowsdale, E-mail: jt233{at}cam.ac.uk


  Abstract

The major histocompatibility complex HLA-DRB1*15 (DR2) haplotype is strongly associated with risk of multiple sclerosis. The primary susceptibility has been localised to only a ~200 kb region encompassing the HLA-DR and -DQ loci. Further dissection of disease association with this region is demanding because of the high levels of linkage disequilibrium (LD). Recently, evidence was obtained for the involvement of a gene, potentially encoding an immune co-receptor, in another DR2-associated autoimmune condition, sarcoidosis. The implicated gene, BTNL2, is adjacent to DR and is in strong LD with HLA-DRB1. This fact, combined with a sequence relationship between BTNL2 and MOG, an auto-antigen associated with MS, makes the gene an attractive candidate. To determine whether BTNL2 contributes to multiple sclerosis we genotyped 1,136 well-characterized multiple sclerosis families from the United Kingdom and United States as well as an African American case-control dataset, making this among the largest genetic studies in multiple sclerosis. Family-based and case-control association studies were performed for the BTNL2 and HLA-DRB1 loci. In all family datasets, the protein-truncating allele of BTNL2, implicated in sarcoidosis, was significantly over-transmitted to cases (combined datasets: global p = 2.4 x 10-11). Given that the protein-truncating allele of BTNL2 virtually always occurred with DRB1*15, an effect could only be tested in DRB1*15 negative individuals or pedigrees. However, despite adequate power to detect an independent association, no difference in transmission of BTNL2 alleles or genotypes were observed in DRB1*15 negative individuals with MS. Conditional logistic regression modeling also strongly supported the conclusion that BTNL2 does not confer additional disease risk. The association of BTNL2 with multiple sclerosis observed in the African American dataset was also secondary to the primary DRB1*15 association.


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