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

Correspondence: Dr S Schmidt, Center for Human Genetics, Duke University Medical Center, Box 3445, Durham, NC 27710, USA. E-mail: silke.schmidt@duke.edu

Received 28 March 2006; Revised 25 April 2006; Accepted 26 April 2006; Published online 1 June 2006.

Abstract

Discrepant findings have been reported regarding an association of the apolipoprotein E (APOE) gene with the clinical course of multiple sclerosis (MS). To resolve these discrepancies, we examined common sequence variation in six candidate genes residing in a 380-kb genomic region surrounding and including the APOE locus for an association with MS severity. We genotyped at least three polymorphisms in each of six candidate genes in 1540 Caucasian MS families (729 single-case and multiple-case families from the United States, 811 single-case families from the UK). By applying the quantitative transmission/disequilibrium test to a recently proposed MS severity score, the only statistically significant (P=0.003) association with MS severity was found for an intronic variant in the Herpes Virus Entry Mediator-B Gene (PVRL2). Additional genotyping extended the association to a 16.6 kb block spanning intron 1 to intron 2 of the gene. Sequencing of PVRL2 failed to identify variants with an obvious functional role. In conclusion, the analysis of a very large data set suggests that genetic polymorphisms in PVRL2 may influence MS severity and supports the possibility that viral factors may contribute to the clinical course of MS, consistent with previous reports.