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Article: Endothelial Nitric Oxide Gene Haplotypes and Risk of Cerebral Small-Vessel Disease

TitleEndothelial Nitric Oxide Gene Haplotypes and Risk of Cerebral Small-Vessel Disease
Authors
Issue Date2004
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://stroke.ahajournals.org
Citation
Stroke, 2004, v. 35 n. 3, p. 654-659 How to Cite?
AbstractBackground 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 (NOx) 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. NOx 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.
Persistent Identifierhttp://hdl.handle.net/10722/175909
ISSN
2015 Impact Factor: 5.787
2015 SCImago Journal Rankings: 3.671
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorHassan, Aen_US
dc.contributor.authorGormley, Ken_US
dc.contributor.authorO'sullivan, Men_US
dc.contributor.authorKnight, Jen_US
dc.contributor.authorSham, Pen_US
dc.contributor.authorVallance, Pen_US
dc.contributor.authorBamford, Jen_US
dc.contributor.authorMarkus, Hen_US
dc.date.accessioned2012-11-26T09:02:23Z-
dc.date.available2012-11-26T09:02:23Z-
dc.date.issued2004en_US
dc.identifier.citationStroke, 2004, v. 35 n. 3, p. 654-659en_US
dc.identifier.issn0039-2499en_US
dc.identifier.urihttp://hdl.handle.net/10722/175909-
dc.description.abstractBackground 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 (NOx) 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. NOx 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.en_US
dc.languageengen_US
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://stroke.ahajournals.orgen_US
dc.relation.ispartofStrokeen_US
dc.subject.meshAgeden_US
dc.subject.meshAllelesen_US
dc.subject.meshBrain - Blood Supply - Radiographyen_US
dc.subject.meshBrain Infarction - Genetics - Physiopathologyen_US
dc.subject.meshBrain Ischemia - Genetics - Physiopathologyen_US
dc.subject.meshEuropean Continental Ancestry Group - Geneticsen_US
dc.subject.meshFemaleen_US
dc.subject.meshGene Frequencyen_US
dc.subject.meshGenotypeen_US
dc.subject.meshHaplotypes - Geneticsen_US
dc.subject.meshHumansen_US
dc.subject.meshIntrons - Geneticsen_US
dc.subject.meshMaleen_US
dc.subject.meshMicrocirculation - Physiopathologyen_US
dc.subject.meshMiddle Ageden_US
dc.subject.meshNitrates - Blooden_US
dc.subject.meshNitric Oxide Synthase - Geneticsen_US
dc.subject.meshNitric Oxide Synthase Type Iiien_US
dc.subject.meshNitrites - Blooden_US
dc.subject.meshOdds Ratioen_US
dc.subject.meshPolymorphism, Genetic - Geneticsen_US
dc.subject.meshPredictive Value Of Testsen_US
dc.subject.meshRisk Assessmenten_US
dc.subject.meshRisk Factorsen_US
dc.titleEndothelial Nitric Oxide Gene Haplotypes and Risk of Cerebral Small-Vessel Diseaseen_US
dc.typeArticleen_US
dc.identifier.emailSham, P: pcsham@hku.hken_US
dc.identifier.authoritySham, P=rp00459en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1161/01.STR.0000117238.75736.53en_US
dc.identifier.pmid14963277-
dc.identifier.scopuseid_2-s2.0-1442348272en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-1442348272&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume35en_US
dc.identifier.issue3en_US
dc.identifier.spage654en_US
dc.identifier.epage659en_US
dc.identifier.isiWOS:000189243400009-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridHassan, A=7402686940en_US
dc.identifier.scopusauthoridGormley, K=6602572560en_US
dc.identifier.scopusauthoridO'Sullivan, M=7202497806en_US
dc.identifier.scopusauthoridKnight, J=13002769800en_US
dc.identifier.scopusauthoridSham, P=34573429300en_US
dc.identifier.scopusauthoridVallance, P=7103109555en_US
dc.identifier.scopusauthoridBamford, J=7102811524en_US
dc.identifier.scopusauthoridMarkus, H=7102054556en_US

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