Polymorphisms in Genes of the Endothelin System and Cerebral Small-Vessel Disease

Abstract

Background and Purpose-Endothelial dysfunction has been implicated in the pathogenesis of cerebral small-vessel disease (SVD). Endothelin (ET), released by the endothelium, plays a crucial role in vasoconstriction in the cerebral circulation and could contribute to the pathogenesis of cerebral SVD. Circulating ET levels may not reflect vascular production of endothelin-1 (ET-1), most of which is abluminal. Studying genetic associations, particularly of functional polymorphisms that alter activity of the ET system, is an attractive method of determining whether ET plays a role in SVD pathogenesis. We determined whether genetic variants in components of the ET system are a risk factor for cerebral SVD. Methods-Three hundred SVD patients and 600 community controls were genotyped. Polymorphisms in the ET-1 gene (K198N), the ET receptor type A (ET A ), (Ϫ231GϾA and ϩ1222CϾT), and the ET type B (ET B ) receptor (G57S and L277L) were genotyped. Polymorphisms were studied both individually and as haplotypes. With brain imaging, cases were subtyped into those with lacunar infarct without leukoaraiosis and those with leukoaraiosis. Results-No significant differences were observed between SVD cases and controls for any individual single-nucleotide polymorphism or the ET A haplotype. There were no differences between cases with isolated lacunar infarct or with lacunar infarct and leukoaraiosis. Conclusions-This study, in a well-phenotyped population, does not support a role for genetic variation in the ET system as a risk factor for cerebral SVD. Key Words: endothelins Ⅲ genetics Ⅲ small-vessel disease Ⅲ stroke L acunar infarction (LI), resulting from disease of the cerebral small vessels, can occur in isolation or may be accompanied by patchy or confluent changes in the periventricular white matter on CT or MRI. This appearance is referred to as leukoaraiosis (LA) and is thought to be related to small-vessel disease (SVD). The pathogenesis of this condition is incompletely understood. Hypertension is the major risk factor but fails to account for all of the risk. Recent evidence suggests genetic factors are important. A twin study that investigated high-signal lesions on MRI, which are believed to reflect asymptomatic SVD, suggested that the heritability was 71%. 1 Analysis of family history data suggests that a family history of stroke at a young age is an independent risk factor for lacunar stroke. 2 Considerable evidence suggests that endothelial dysfunction plays a crucial role in the pathogenesis of SVD. Neuropathologic studies demonstrate endothelial disruption. 3 Neuroimaging studies demonstrate reduced white-matter blood flow and autoregulatory capacity. 4,5 Nitric oxide, derived from the endothelium, is responsible for the maintenance of cerebral blood flow 6 and autoregulation. Soluble markers of endothelial activation 7,8 are elevated independent of conventional risk factors in patients with lacunar stroke and LA.Knockout mice lacking the endothelial nitric oxide synthase (eNOS) gene develop vascular lesions res...

Endothelial Dysfunction in Lacunar Stroke: A Systematic Review

“…Applying the above-mentioned criteria yielded a total of 17 articles that were suitable for further analysis [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. The main reasons for excluding papers were noncerebral disease (n = 31), silent cerebral small-vessel disease (n = 18), reviews (n = 19) and language (n = 12).…”

“…Six studies [10, 15, 19, 29, 32, 33] focused on functional gene polymorphisms known to be involved in the regulation of NO and ET activity. None of the polymorphisms of ET seem relevant to lacunar stroke [10], but two polymorphisms of the endothelial constitutive NO synthase gene – intron 4ab [19] and Glu298Asp [29] – are associated with the occurrence of lacunar stroke.…”

Genetic Determinants of White Matter Hyperintensities on Brain Scans

“…16,24,29,[37][38][39][40][41][42] Six compared numbers of subjects with upper and lower WMH grades between genotype groups (Figure 2A). 16,29,37,38,42 Random-effects meta-analysis comparing deletion-deletion (DD) with deletion-insertion/ insertion-insertion (DI/II) suggested a significant association between ACE and WMH (pooled OR, 1.95; 95% CI, 1.09 -3.48), but there was substantial heterogeneity between study results (I 2 ϭ71%). One small study analyzed WMH grade as a continuous variable.…”

“…Six studies (2702 subjects) had assessed the association between AGT Met235Thr and WMH. 38,40,42,[45][46][47] Three measured WMH grade and compared numbers of subjects with upper and lower WMH grades between genotype groups ( Figure 4A). 38 small but significant association ( Figure 4B).…”

Single-Nucleotide Polymorphisms of MMP-2 Gene in Stroke Subtypes

“…The largest genetic trial concerning SVD so far compared 300 patients to 600 controls, and studied SNP of the renin-angiotensin system, endothelial nitric oxide synthase (eNOS) and the endothelin system. Only the intron 4ab genotype of the eNOS gene was associated with isolated lacunar infarction and the AGT-20C allele may be a risk factor for leukoaraiosis [24,25,26,27]. Other studies have reported a strong association of the angiotensin-converting-enzyme genotype to lacunar stroke [28, 29] as well as a –174G/C polymorphism of interleukin 6 [30, 31] and a gene variant of α 1 -antichymotrypsin – a plasma protease inhibitor [32].…”