Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease
AU - Hassan, A. E. M.
AU - Gormley, K.
AU - O'Sullivan, Michael
AU - Knight, Jo
AU - Sham, Pak C.
AU - Vallance, P.
AU - Bamford, J.
AU - Markus, Hugh S.
PY - 2004/3
Y1 - 2004/3
N2 - BACKGROUND AND PURPOSE: Genetic influences are important in multifactorial cerebral small-vessel disease (SVD) and may act via endothelial dysfunction. Nitric oxide (NO) synthesized by endothelial nitric oxide synthase (eNOS) is a key mediator of endothelial function. We determined the role of 3 potentially functional eNOS polymorphisms (T-786C, intron 4ab, G894T) located toward the 5' flanking end of the gene as risk factors for SVD and different SVD subtypes: isolated lacunar infarction (n=137) and ischemic leukoaraiosis (n=160).METHODS: Three hundred patients with SVD and 600 community controls were studied. Genotypes were determined through polymerase chain reaction with or without restriction fragment digestion. Nitrate (NO(x)) levels were determined in a subgroup by use of a Griess method. Polymorphisms were tested individually and in combination with haplotype analysis.RESULTS: The intron 4a variant was protective against SVD. This effect was confined to isolated lacunar infarction (odds ratio, 0.55; 95% confidence interval, 0.35 to 0.86; P=0.01). Haplotypes encountered were significantly different in this subtype compared with controls (P=0.001), with the -786C promoter/intron 4a combination particularly underrepresented. NO(x) levels were associated with the T-786C locus (P=0.03) but only in the presence of the intron 4a allele (P=0.07 for interaction).CONCLUSIONS: The intron 4ab insertion/deletion genotype was associated with isolated lacunar infarction. Haplotype and functional studies suggested that the protective effect of the 4a variant could be mediated through changes in eNOS promoter activity and increased NO levels. The specific association with isolated symptomatic lacunar infarction and not ischemic leukoaraiosis may reflect different etiopathogeneses of the 2 subtypes. Lack of NO could predispose to localized microatheroma in proximal arterioles rather than diffuse arteriosclerosis affecting distal perforating vessels.
AB - BACKGROUND AND PURPOSE: Genetic influences are important in multifactorial cerebral small-vessel disease (SVD) and may act via endothelial dysfunction. Nitric oxide (NO) synthesized by endothelial nitric oxide synthase (eNOS) is a key mediator of endothelial function. We determined the role of 3 potentially functional eNOS polymorphisms (T-786C, intron 4ab, G894T) located toward the 5' flanking end of the gene as risk factors for SVD and different SVD subtypes: isolated lacunar infarction (n=137) and ischemic leukoaraiosis (n=160).METHODS: Three hundred patients with SVD and 600 community controls were studied. Genotypes were determined through polymerase chain reaction with or without restriction fragment digestion. Nitrate (NO(x)) levels were determined in a subgroup by use of a Griess method. Polymorphisms were tested individually and in combination with haplotype analysis.RESULTS: The intron 4a variant was protective against SVD. This effect was confined to isolated lacunar infarction (odds ratio, 0.55; 95% confidence interval, 0.35 to 0.86; P=0.01). Haplotypes encountered were significantly different in this subtype compared with controls (P=0.001), with the -786C promoter/intron 4a combination particularly underrepresented. NO(x) levels were associated with the T-786C locus (P=0.03) but only in the presence of the intron 4a allele (P=0.07 for interaction).CONCLUSIONS: The intron 4ab insertion/deletion genotype was associated with isolated lacunar infarction. Haplotype and functional studies suggested that the protective effect of the 4a variant could be mediated through changes in eNOS promoter activity and increased NO levels. The specific association with isolated symptomatic lacunar infarction and not ischemic leukoaraiosis may reflect different etiopathogeneses of the 2 subtypes. Lack of NO could predispose to localized microatheroma in proximal arterioles rather than diffuse arteriosclerosis affecting distal perforating vessels.
KW - Aged
KW - Alleles
KW - Brain
KW - Brain Infarction
KW - Brain Ischemia
KW - European Continental Ancestry Group
KW - Female
KW - Gene Frequency
KW - Genotype
KW - Haplotypes
KW - Humans
KW - Introns
KW - Male
KW - Microcirculation
KW - Middle Aged
KW - Nitrates
KW - Nitric Oxide Synthase
KW - Nitric Oxide Synthase Type III
KW - Nitrites
KW - Odds Ratio
KW - Polymorphism, Genetic
KW - Predictive Value of Tests
KW - Risk Assessment
KW - Risk Factors
U2 - 10.1161/01.STR.0000117238.75736.53
DO - 10.1161/01.STR.0000117238.75736.53
M3 - Journal article
C2 - 14963277
VL - 35
SP - 654
EP - 659
JO - Stroke; a journal of cerebral circulation
JF - Stroke; a journal of cerebral circulation
SN - 0039-2499
IS - 3
ER -