1. ¹Division of Epidemiology, School of Public Health, University of California, Berkeley, CA, USA
2. ²Department of Neurology, University of California, San Francisco, CA, USA
3. ³Department of Clinical Neurosciences, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
4. ⁴Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN, USA
5. ⁵Center for Human Genetics, Duke University Medical Center, Durham, NC, USA
6. ⁶Miami Institute for Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA

Correspondence: Dr LF Barcellos, B84 Hildebrand Hall-MC No. 7356, School of Public Health, University of California, Berkeley, CA 94720-7356, USA. E-mail: barcello@genepi.berkeley.edu

Received 26 February 2008; Revised 28 April 2008; Accepted 29 April 2008; Published online 26 June 2008.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component. Variation in the major histocompatibility complex on chromosome 6p21, specifically the HLA-DRB1*15 haplotype, is the strongest genetic factor for MS, yet it is estimated to account for only a portion of risk for the disease. Previous evidence has implicated the nitric oxide synthase gene (NOS2A) encoding inducible NOS on chromosome 17q11 as a potential MS susceptibility gene. To determine whether variation in the NOS2A gene contributes to MS risk, we investigated a total of 50 polymorphisms within or flanking the locus for evidence of association using a comprehensive analytical strategy. A total of 6265 members from 1858 well-characterized MS families were utilized. No evidence for overtransmission of any individual single-nucleotide polymorphism allele or haplotype to the MS-affected individuals was observed. Furthermore, different transmission rates were not observed in either DRB1*15-positive or DRB1*15-negative family subgroups, or when extreme clinical outcomes characterizing disease progression were examined. The very largest study of NOS2A variation in MS, to date, excludes even a modest role for this locus in susceptibility.