Genetic variation in nitric oxide synthase 2A (NOS2A) and risk for multiple sclerosis.
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.
Barcellos
L F
LF
Division of Epidemiology, School of Public Health, University of California, Berkeley, CA 94720-7356, USA. barcello@genepi.berkeley.edu
Ramsay
P P
PP
Caillier
S J
SJ
Sawcer
S
S
Haines
J
J
Schmidt
S
S
Pericak-Vance
M
M
Compston
D A S
DA
Gabatto
P
P
Hauser
S L
SL
Oksenberg
J R
JR
D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II