Correlation Between Functional Genetic Variation In Hypoxia-induced VEGFA/VEGFR2 Signaling Pathway And Ischemic Cerebrovascular Diseases

Hypoxia-induced VEGFA/VEFGR2 signal pathway was involved in atherosclerosis,formation of collateral circulation,increased vascular permeability,brain edema,neuroprotection and neurogenesis and other pathophysiological processes in ischemic cerebrovascular diseases.Atherosclerosis and increased vascular permeability of small cerebral vessels were also involved in the pathogenesis of white matter lesions.However,the association between functional genetic variants in this pathway and stroke onset,stroke outcome and extent of white matter lesions has not been explored.This study was to investigate the correlation of functional variants(HIF-1a,VEGFA and VEGFR2)with stroke onset,stroke outcome and extent of white matter lesions.Part ? Functional variants of hypoxia inducible factor-1? gene confer risk to large artery atherosclerotic strokeBackground and Purpose: Hypoxia Inducible Factor-1?(HIF-1?)has been reported as a key factor,participating in the process of atherosclerosis.This study was to explore the association between functional variants in HIF-1? gene and large artery atherosclerotic stroke in Southern Han Chinese Population.Methods: A total of 1064 patients with acute large artery atherosclerotic(LAA)stroke and 1177 healthy controls from Southern China were recruited for genotyping of rs11549465 and rs11549467 in HIF-1? gene.Multivariate logistic regression analysis was used to assess the effect of the two variants on LAA stroke.The interaction analysis with conventional risk factors and bioinformatic analysis were also performed.Results: Adjusted for potential risk factors,compared with genotype GG,GA and GA/AA of rs11549467 was significantly associated with increased risk of LAA stroke(OR 1.57,95%CI 1.04-2.36,P = 0.032;OR 1.57,95%CI 1.05-2.35,P = 0.029,respectively).No significant association was found between rs11549465 variant and LAA stroke risk(P > 0.05).Haplotype analysis indicated that patients with rs11549465C-rs11549467 A haplotype had an increased risk of LAA stroke(OR 1.53,95% CI 1.04-2.25,P = 0.032),compared with those with rs11549465C-rs11549467 G haplotype.No significant interaction between HIF-1? genetic variants(rs11549465 and rs11549467)and conventional risk factors was found.Bioinformatic analysis indicated that rs11549465 and rs11549467 variants may be functional.Conclusions: Our findings demonstrated that functional variants of HIF-1? gene may confer risk to large artery atherosclerotic stroke in Southern Han Chinese Population.Part ? Association of functional genetic variation in hypoxia-induced VEGFA/VEGFR2 signaling pathway with severity and outcome of large artery atherosclerotic strokeBackground and Purpose: Collateral vessels status varies widely and is a major determinant of variation in stroke outcome.This study was to explore the association of functional variants in angiogenesis-related genes with stroke severity and outcome.Methods: A total of 1070 patients from Southern China with acute large artery atherosclerotic(LAA)stroke were recruited for genotyping of rs11549465(HIF-1?),rs11549467(HIF-1?),rs833059(upstream of VEGFA),rs1870377(VEGFR2)and rs2305948(VEGFR2).Severe stroke was defined as a National Institute of Health Stroke Scale(NIHSS)score > 8 on admission.Unfavorable outcome was defined as a modified Rankin Scale(m RS)score > 2 at three months after index event.Then,a genetic risk score(GRS)approach and bioinformatic analysis were performed.Results: Compared with GG genotype,GA and AA+GA of rs11549467 were associated with significantly decreased risk of stroke severity(OR 0.39,95%CI 0.19-0.83,P = 0.014;OR 0.39,95%CI 0.18-0.82,P = 0.013,respectively).AA genotype of rs1870377 was associated with a significantly decreased risk of unfavorable outcome in the recessive model(OR 0.67,95% CI 0.47-0.96,P = 0.031).High GRS group(? 5)was significantly associated with an increased risk of unfavorable outcome(OR 1.42,95% CI 1.03-1.98,P = 0.035).Bioinformatic analysis indicated that rs11549467 and rs1870377 variants were missense mutation resulting in amino acid substitutions.Conclusions: Our findings demonstrate that functional variants in angiogenesis-related genes are significantly associated with stroke severity on admission and 3-month outcome in patients with large artery atherosclerotic stroke.Part ? Correlation between functional genetic variation in hypoxia-induced VEGFA/VEGFR2 signaling pathway and white matter lesions in patients with LAA strokeBackground: White matter lesions(WMLs)were highly heritable and prevalent in older subjects and in stroke patients.Angiogenesis-related factors participated in various mechanisms involved in the progression of WMLs.This study was to explore the association between functional variants in hypoxia-induced VEGFA/VEGFR2 signaling pathway and WMLs in patients with large artery atherosclerosis(LAA)stroke.Methods: A total of 567 cases with LAA stroke followed the inclusion criteria.The severity of WMLs was evaluated by the Fazekas scale.Five loci of rs11549465(HIF-1?),rs11549467(HIF-1?),rs833059(upstream of VEGFA),rs1870377(VEGFR2)and rs2305948(VEGFR2)were genotyped with SNPscan.Multivariate logistic regression analysis was used to determine the effect of selected variants on the severity of WMLs including periventricular white matter lesions(PWMLs)and deep white matter lesions(DWMLs).The interaction analysis with conventional risk factors was also performed.Results: We found that age and hypertension were independent risk factors for total WMLs and PWMLs.Age was also an independent risk factor for DWMLs.For rs2305948 locus,patients with TC or TC + TT genotype had a significantly decreased risk of severe total WMLs(P=0.039,OR= 0.56,95%CI=0.32-0.97;P=0.037,OR= 0.56,95%CI=0.33-0.97)and DWMLs(P=0.018,OR= 0.51,95%CI=0.30-0.89;P=0.029,OR= 0.55,95%CI=0.32-0.94)after adjusted for potential risk factors.Interaction analysis suggested that compared with non-hypertensive patients with CC/TT genotype,hypertensive patients with CC/TT genotype significantly increased the risks of severe total WMLs and DWMLs(P = 0.042,OR = 2.36,95% CI = 1.29-4.32;P = 0.041,OR = 2.07,95% CI = 1.16-3.70,respectively).No significant association was observed between the other variants and WMLs.Conclusion: Our data suggested that the rs2305948 variant in VEGFR2 gene was significantly associated with the severity of WMLs,and may interact with hypertension in promoting the development of WMLs in patients with LAA stroke.