Daowen Wang

Elevated Plasma Homocysteine Was Associated With Hemorrhagic and Ischemic Stroke, but Methylenetetrahydrofolate Reductase Gene C677T Polymorphism Was a Risk Factor for Thrombotic Stroke: A Multicenter Case-Control Study in China

BACKGROUND AND PURPOSE It is still controversial whether elevated plasma homocysteine and the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene are risk factors for stroke. The aim of the present study was to investigate the association between the 2 factors and stroke in Chinese in a large case-control study. METHODS We recruited 1823 stroke patients (807 cerebral thrombosis, 513 lacunar infarction, 503 intracerebral hemorrhage) and 1832 controls. Total plasma homocysteine was determined by high-performance liquid chromatography. C677T polymorphism was genotyped by polymerase chain reaction and HinfI digestion. RESULTS Total plasma homocysteine levels were significantly higher in cases than controls (median, 14.7 versus 12.8 micromol/L; P<0.001) and associated with an increased risk of 1.87-fold (95% confidence interval [CI], 1.58 to 2.22) for overall stroke, 1.72-fold (95% CI, 1.39 to 2.12) for cerebral thrombosis, 1.89-fold (95% CI, 1.50 to 2.40) for lacunar infarction, and 1.94-fold (95% CI, 1.48 to 2.55) for intracerebral hemorrhage. The C677T mutation of the MTHFR gene was positively correlated with plasma homocysteine levels in both controls (beta=0.250, P<0.001) and cases (beta=0.272, P<0.001) and more frequently in cases than in controls (47.0% versus 44.2%, P=0.017). The TT genotype was associated with an increased risk for overall stroke (odds ratio, 1.27; 95% CI, 1.04 to 1.56) and thrombotic stroke (odds ratio, 1.37; 95% CI, 1.06 to 1.78). CONCLUSIONS The C677T polymorphism of the MTHFR gene was associated with increased risk of cerebral thrombotic stroke in Chinese. Total plasma homocysteine was correlated with both ischemic and hemorrhagic stroke, suggesting potential initiation of homocysteine-lowering therapy in this population.

High plasma homocysteine levels contribute to the risk of stroke recurrence and all-cause mortality in a large prospective stroke population.

Plasma homocysteine concentrations have been associated with the risk of stroke, but its relevance to secondary vascular events and mortality after stroke remains unclear because of inconsistent results from clinical trials. The aim of the present study was to investigate whether plasma homocysteine levels and the MTHFR (methylenetetrahydrofolate reductase) variant C677T contributed to the risk of stroke recurrence and all-cause mortality in a large prospective cohort of stroke patients in a Chinese population. A total of 1823 stroke patients (age, 35-74 years) were recruited during 2000-2001 and prospectively followed-up for a median of 4.5 years. During the follow-up, 347 recurrent strokes and 323 deaths from all-causes were documented. After adjustment for age, gender and other cardiovascular risk factors, a high homocysteine concentration was associated with an increased risk of 1.74-fold for stroke recurrence {RR (relative risk), 1.74 [95% CI (confidence interval), 1.3-2.3]; P<0.0001} and 1.75-fold for all-cause mortality [RR, 1.75 (95% CI, 1.3-2.4); P<0.0001] when highest and lowest categories were compared. Spline regression analyses revealed a threshold level of homocysteine for stroke recurrence. By dichotomizing homocysteine concentrations, the RRs were 1.31 (95% CI, 1.10-1.61; P=0.016) for stroke recurrence and 1.47 (95% CI, 1.15-1.88; P<0.0001) for all-cause mortality in patients with homocysteine levels > or =16 micromol/l relative to those with levels <16 micromol/l. The association of elevated plasma homocysteine concentrations with all-cause mortality was mainly due to an increased risk of cardiovascular deaths. No significant association was found between MTHFR C677T and stroke recurrence or mortality. In conclusion, our findings suggest that elevated homocysteine concentrations can predict the risk of stroke recurrence and mortality in patients with stroke.

Pentanucleotide TTTTA Repeat Polymorphism of Apolipoprotein(a) Gene and Plasma Lipoprotein(a) Are Associated With Ischemic and Hemorrhagic Stroke in Chinese A Multicenter Case-Control Study in China

Background and Purpose— It is still inconclusive whether high plasma lipoprotein(a) [Lp(a)] level is a risk factor for stroke. Small sample size and different ethnic groups and methodologies might be contributors to the conflicts in study results. The purpose of the present study was to investigate the association between plasma Lp(a) levels, pentanucleotide TTTTA repeat (PNTR) polymorphism of the apolipoprotein(a) [apo(a)] gene, and Chinese stroke in a case-control study. Methods— We recruited 1825 cases with stroke (44.3% cerebral atherothrombosis, 28.3% lacunar infarction, and 27.3% intracerebral hemorrhage) and 1817 controls from 7 centers in China. Lp(a) concentrations were quantified by enzyme-linked immunosorbent assay. The PNTR polymorphism of the apo(a) gene was determined by polymerase chain reaction–polyacrylamide gel electrophoresis. Conditional multivariate logistic regression analysis was used to identify independent risk factors for stroke and its subtypes. Results— Lp(a) levels were significantly higher in cases than in controls (median, 28.5 versus 23.1 mg/dL; P <0.001), leading to a 1.97-fold (95% CI, 1.64 to 2.37) increase in risk for overall stroke, 2.0-fold (95% CI, 1.59 to 2.52) increase for atherothrombotic type, 2.05-fold increase (95% CI, 1.59 to 2.63) for lacunar type, and 1.64-fold increase (95% CI, 1.21 to 2.21) for hemorrhagic type. The number of PNTR negatively correlated with Lp(a) levels. Low-number repeats (sum of both alleles <16) of apo(a) PNTR were associated with both atherothrombotic stroke (odds ratio, 1.41; 95% CI, 1.04 to 1.91) and hemorrhagic stroke (odds ratio, 1.62; 95% CI, 1.09 to 2.37). Conclusions— Our results indicate for the first time that low numbers of apo(a) PNTR and plasma Lp(a) levels are independently associated with both ischemic and hemorrhagic stroke in Chinese.

VEGF Receptor-2 Variants Are Associated With Susceptibility to Stroke and Recurrence

Background and Purpose— Dysregulation of vessel wall formation, growth, and maintenance may confer susceptibility of stroke. Methods— We tested the hypothesis that variants in 2 genes encoding vascular endothelial growth factor and vascular endothelial growth factor receptor-2 are associated with susceptibility to stroke and its recurrence in a Chinese case–control study comprising 1849 patients with stroke and 1798 control subjects and replicated the investigation in an independent study comprising 327 cases and 327 control subjects. The correlation of variants with carotid artery intima media thickness was examined in 1123 healthy individuals. Results— Compared with their corresponding wild-type genotypes, one coding variant, rs2305948 (Val297Ile), in the vascular endothelial growth factor receptor-2 gene was associated with increased susceptibility to intracerebral hemorrhage (additive model: OR, 2.06; 95% CI, 1.64 to 2.59; P=7.6×10−10; dominant model: OR, 2.20; 95% CI, 1.70 to 2.84; P=1.5×10−9), a promoter variant rs2071559 (−604T>C) in the gene was associated with reduced susceptibility to atherothrombotic stroke (additive model: OR, 0.82; 95% CI, 0.71 to 0.93; P=0.003; dominant model: OR, 0.78; 95% CI, 0.65 to 0.92; P=0.004) and was reversely correlated with carotid artery intima media thickness (P=2.8×10−5). Replication in the second study yielded similar results. During a median 4.5 years of follow-up for the first stroke population, 355 recurrent strokes were documented. Subjects carrying 297Ile had a higher risk for stroke recurrence (relative risk, 1.40; 95% CI, 1.12 to 1.75; P=0.003), and those with −604C had a lower risk for recurrence (relative risk, 0.71; 95% CI, 0.58 to 0.89; P=0.002) than their wild-type carriers. Conclusions— The vascular endothelial growth factor receptor-2 gene variants may serve as novel genetic markers for the risk of stroke and its recurrence.

Genetic Variants at Newly Identified Lipid Loci Are Associated with Coronary Heart Disease in a Chinese Han Population

Background Recent genome-wide association studies (GWAS) have mapped several novel loci influencing blood lipid levels in Caucasians. We sought to explore whether the genetic variants at newly identified lipid-associated loci were associated with CHD susceptibility in a Chinese Han population. Methodology/Principal Findings We conducted a two-stage case-control study in a Chinese Han population. The first-stage, consisting of 1,376 CHD cases and 1,376 sex and age- frequency matched controls, examined 5 novel lipid-associated single-nucleotide polymorphisms (SNPs) identified from GWAS among Caucasians in relation to CHD risk in Chinese. We then validated significant SNPs in the second-stage, consisting of 1,269 cases and 2,745 controls. We also tested associations between SNPs within the five novel loci and blood lipid levels in 4,121 controls. We identified two novel SNPs (rs599839 in CELSR2-PSRC1-SORT1 and rs16996148 in NCAN-CILP2) that were significantly associated with reduced CHD risk in Chinese (odds ratios (95% confidence intervals) in the dominant model 0.76 (0.61-0.90; P = 0.001), 0.67 (0.57-0.77; P = 3.4×10−8), respectively). Multiple linear regression analyses using dominant model showed that rs599839 was significantly associated with decreased LDL levels (P = 0.022) and rs16996148 was significantly associated with increased LDL and HDL levels (P = 2.9×10−4 and 0.001, respectively). Conclusions/Significance We identified two novel SNPs (rs599839 and rs16996148) at newly identified lipid-associated loci that were significantly associated with CHD susceptibility in a Chinese Han population.

Polymorphism of HMGA1 is associated with increased risk of type 2 diabetes among Chinese individuals

Aims/hypothesisVariants of the high-mobility group A1 (HMGA1) gene have been shown to be associated with insulin resistance and type 2 diabetes in individuals of European origin. We aimed to determine whether this locus confers significant susceptibility to type 2 diabetes in the Han Chinese population, and thus cross-race susceptibility to type 2 diabetes.MethodsPolymorphisms in HMGA1 were identified by direct sequencing of genomic DNA derived from 192 Chinese participants (96 patients with type 2 diabetes and 96 controls). We then genotyped the common variant IVS5-13insC (c.136-14_136-13insC) in two other independent cohorts, including a total of 2,533 cases and 2,643 ethnically matched controls.ResultsWe confirmed the association of the HMGA1 variant IVS5-13insC (c.136-14_136-13insC) with type 2 diabetes with an OR of 1.34 (95% CI 1.15, 1.56, p = 0.0002 under a dominant model, and 95% CI 1.16, 1.55, p = 0.0002 under an additive model) in the Han Chinese population, corresponding to a population attributable risk fraction of 5.0%.Conclusions/interpretationHMGA1 is an important susceptibility locus that confers a high cross-race risk of the development of type 2 diabetes.

No evidence for association of 12p13 SNPs rs11833579 and rs12425791 within NINJ2 gene with ischemic stroke in Chinese Han population

Recent genome-wide association (GWA) studies have identified two intergenic single nucleotide polymorphisms (SNPs) (rs11833579 and rs12425791) on chromosome 12p13 and within 11 kb of the NINJ2 gene that were significantly associated with stroke in Caucasians. However, the validity of the association has remained controversial. We performed genetic association analyses in three independent cohorts, including total of 3042 cases and 2973 controls. No significant association between these two SNPs and ischemic stroke was detected by meta-analysis after adjustment for cardiovascular risk factors under the additive model. Our data does not support that the common variants on 12p13 are major contributors of ischemic stroke in the Chinese Han population.

Plasma tissue kallikrein level is negatively associated with incident and recurrent stroke: a multicenter case-control study in China.

Tissue kallikrein (TK) cleaves kininogen to produce the potent bioactive compounds kinin and bradykinin, which lower blood pressure and protect the heart, kidneys, and blood vessels. Reduction in TK levels is associated with cardiovascular disease and diabetes in animal models. In this study, we investigated the association of TK levels with event‐free survival over 5 years in Chinese first‐ever stroke patients.

Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy.

Although genetic testing has been recommended in patients with hypertrophic cardiomyopathy (HCM) in current clinical practice, its utility in prognostic prediction remains to be ascertained. We assessed the dosage effect of rare variants in sarcomere genes on the long‐term outcomes of HCM.