OAS1: a multiple sclerosis susceptibility gene that influences disease severity.
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.
O'Brien
M
M
Education & Research Centre, St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland. margaretobrien@physicians.ie
Lonergan
R
R
Costelloe
L
L
O'Rourke
K
K
Fletcher
J M
JM
Kinsella
K
K
Sweeney
C
C
Antonelli
G
G
Mills
K H
KH
O'Farrelly
C
C
Hutchinson
M
M
Tubridy
N
N
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D016899:Interferon-beta / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000235:genetics*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D055815:Young Adult
D007155:Immunologic Factors; D016899:Interferon-beta; C475085:OAS1 protein, human; D015088:2',5'-Oligoadenylate Synthetase