Published online before print February 12, 2004, doi: 10.1161/01.STR.0000117238.75736.53
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2004;35:654.)
© 2004 American Heart Association, Inc.
Original Contributions |
Endothelial Nitric Oxide Gene Haplotypes and Risk of Cerebral Small-Vessel Disease
From the Department of Clinical Neurosciences, St George’s Hospital Medical School, London (A.H., K.G., M.O., H.M.); Division of Psychological Medicine, Institute of Psychiatry, London (J.K., P.S.); Centre for Clinical Pharmacology, University College, London (P.V.); and Department of Neurology, St James’ Hospital, Leeds (J.B.), UK.
Correspondence to Professor Hugh Markus, Department of Clinical Neurosciences, St. George’s Hospital Medical School, London SW17 ORE UK. E-mail h.markus{at}sghms.ac.uk
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 (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.
Key Words: endothelium • genetics • nitric oxide • nitric oxide synthase • small-vessel disease • stroke
This article has been cited by other articles:
 |
|
 |
|
  H. S. Markus Genes, endothelial function and cerebral small vessel disease in man Exp Physiol, January 1, 2008; 93(1): 121 - 127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Gonzalez-Sanchez, M. T. Martinez-Larrad, M. E. Saez, C. Zabena, M. J. Martinez-Calatrava, and M. Serrano-Rios Endothelial Nitric Oxide Synthase Haplotypes Are Associated with Features of Metabolic Syndrome Clin. Chem., January 1, 2007; 53(1): 91 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Casas, G. L. Cavalleri, L. E. Bautista, L. Smeeth, S. E. Humphries, and A. D. Hingorani Endothelial Nitric Oxide Synthase Gene Polymorphisms and Cardiovascular Disease: A HuGE Review Am. J. Epidemiol., November 15, 2006; 164(10): 921 - 935. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. L. Chen, P. Y. Wang, W. H. Sheu, Y. T. Chen, Y. P. Ho, H. H. Hu, and H. Y. Hsu Changes of brachial flow-mediated vasodilation in different ischemic stroke subtypes. Neurology, September 26, 2006; 67(6): 1056 - 1058. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T.-H. Lee and K.-C. Chang Editorial Comment--Are We in Another Unavoidable 'Diagnose and Adios' Era? Stroke, September 1, 2005; 36(9): 1852 - 1853. [Full Text] [PDF]
|
|
|
|
|
|
M. Dichgans and H. S. Markus Genetic Association Studies in Stroke: Methodological Issues and Proposed Standard Criteria Stroke, September 1, 2005; 36(9): 2027 - 2031. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. D. Howard, W. H. Giles, J. Xu, M. A. Wozniak, A. M. Malarcher, L. A. Lange, R. F. Macko, M. J. Basehore, D. A. Meyers, J. W. Cole, et al. Promoter Polymorphisms in the Nitric Oxide Synthase 3 Gene Are Associated With Ischemic Stroke Susceptibility in Young Black Women Stroke, September 1, 2005; 36(9): 1848 - 1851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. H.G. Henskens, A. A. Kroon, M. P.J. van Boxtel, P. A.M. Hofman, and P. W. de Leeuw Associations of the Angiotensin II Type 1 Receptor A1166C and the Endothelial NO Synthase G894T Gene Polymorphisms With Silent Subcortical White Matter Lesions in Essential Hypertension Stroke, September 1, 2005; 36(9): 1869 - 1873. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Napoli and F. Papa C-Reactive Protein and Cerebral Small-Vessel Disease: An Opportunity to Reassess Small-Vessel Disease Physiopathology? Circulation, August 9, 2005; 112(6): 781 - 785. [Full Text] [PDF]
|
|
|
|
|
|
K. Gormley, S. Bevan, A. Hassan, and H. S. Markus Polymorphisms in Genes of the Endothelin System and Cerebral Small-Vessel Disease Stroke, August 1, 2005; 36(8): 1656 - 1660. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Alberts and E. Tournier-Lasserve Update on the Genetics of Stroke and Cerebrovascular Disease 2004 Stroke, February 1, 2005; 36(2): 179 - 181. [Full Text] [PDF]
|
|
|
|
|
|
K. Gwinn-Hardy and V. Dawson Genomics-Proteomics and Stroke: Introduction Stroke, November 1, 2004; 35(11_suppl_1): 2731 - 2734. [Full Text] [PDF]
|
|