OAS1: a multiple sclerosis susceptibility gene that influences disease severity.
O'Brien, M Lonergan, R Costelloe, L O'Rourke, K Fletcher, J M Kinsella, K Sweeney, C Antonelli, G Mills, K H O'Farrelly, C
O'Brien, M
Lonergan, R
Costelloe, L
O'Rourke, K
Fletcher, J M
Kinsella, K
Sweeney, C
Antonelli, G
Mills, K H
O'Farrelly, C
Advisors
Editors
Other Contributors
Date
2012-02-01T10:34:25Z
Date Submitted
Keywords
Other Subjects
Subject Mesh
2',5'-Oligoadenylate Synthetase/*genetics
Adolescent
Adult
Aged
Aged, 80 and over
Child
Cohort Studies
Female
*Genetic Predisposition to Disease
Genotype
Humans
Immunologic Factors/therapeutic use
Interferon-beta/therapeutic use
Male
Middle Aged
Multiple Sclerosis/drug therapy/*genetics
Multiple Sclerosis, Relapsing-Remitting/drug therapy/*genetics
*Polymorphism, Single Nucleotide
Severity of Illness Index
Young Adult
Adolescent
Adult
Aged
Aged, 80 and over
Child
Cohort Studies
Female
*Genetic Predisposition to Disease
Genotype
Humans
Immunologic Factors/therapeutic use
Interferon-beta/therapeutic use
Male
Middle Aged
Multiple Sclerosis/drug therapy/*genetics
Multiple Sclerosis, Relapsing-Remitting/drug therapy/*genetics
*Polymorphism, Single Nucleotide
Severity of Illness Index
Young Adult
Planned Date
Start Date
Collaborators
Principal Investigators
Alternative Titles
Publisher
Abstract
BACKGROUND: Type 1 interferons upregulate oligoadenylate synthetase 1 (OAS1). A single nucleotide polymorphism (SNP) in exon 7 of OAS1 results in differential RNAseL enzyme activity, the A allele coding for a truncated form with low activity and the G conferring high activity. We hypothesized that OAS1 genotypes would influence both susceptibility to multiple sclerosis (MS) and disease activity with the AA genotype being overrepresented and the GG genotype underrepresented in relapsing-remitting MS (RRMS) with increased disease activity. METHODS: We examined OAS1 genotype distribution in 401 patients with MS, 394 healthy controls, and 178 patients with RRMS receiving interferon-beta (IFNbeta) assessed as 1) having no or minimal disease activity on IFNbeta, 2) having disease activity despite IFNbeta, and 3) 65 patients with RRMS with highly active disease. RESULTS: The OAS1 genotype distribution differed between patients with MS and controls (p = 0.000003), with lower frequency of GG homozygotes in patients with MS (6%) compared with controls (17%). In relation to disease severity, 34 (32%) patients with no or minimal disease activity on IFNbeta had the AA and 8 (8%) the GG genotype; of patients with disease activity despite IFNbeta, 27 (51%) were AA, while only 1 (2%) was GG (p = 0.03). Median time to first relapse on IFNbeta was 24 months in patients with RRMS with AA genotype and 33 months with AG or GG genotype (p = 0.04). The GG genotype was absent in 65 patients with highly active RRMS (p = 0.03). CONCLUSIONS: A functional OAS1 SNP, AA genotype, confers susceptibility to MS and the GG genotype may protect against increased disease activity.
Language
eng
Citation
ISSN
1526-632X (Electronic)
0028-3878 (Linking)
0028-3878 (Linking)
eISSN
ISBN
DOI
10.1212/WNL.0b013e3181ebdd2b
PMID
20679634