Rutai Hui

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.

VKORC1 Haplotypes Are Associated With Arterial Vascular Diseases (Stroke, Coronary Heart Disease, and Aortic Dissection)

Background— The haplotypes in the gene vitamin K epoxide reductase complex subunit 1 (VKORC1) have been found to affect warfarin dose response through effects on the formation of reduced-form vitamin K, a cofactor for &ggr;-carboxylation of vitamin K–dependent proteins, which is involved in the coagulation cascade and has a potential impact on atherosclerosis. We hypothesized that VKORC1-dependent effects on the coagulation cascade and atherosclerosis would contribute to susceptibility for vascular diseases. Methods and Results— To test the hypothesis, we studied the association of polymorphisms of VKORC1 with stroke (1811 patients), coronary heart disease (740 patients), and aortic dissection (253 patients) compared with matched controls (n=1811, 740, and 416, respectively). Five common noncoding single-nucleotide polymorphisms of VKORC1 were identified in a natural haplotype block with strong linkage disequilibrium (D′>0.9, r2>0.9), then single-nucleotide polymorphism (SNP) +2255 in the block was selected for the association study. We found that the presence of the C allele of the +2255 locus conferred almost twice the risk of vascular disease (odds ratio [OR] 1.95, 95% confidence interval [CI] .58 to 2.41, P<0.001 for stroke; OR 1.72, 95% CI 1.24 to 2.38, P<0.01 for coronary heart disease; and OR 1.90, 95% CI 1.04 to 3.48, P<0.05 for aortic dissection). We also observed that subjects with the CC and CT genotypes had lower levels of undercarboxylated osteocalcin (a regulator for the bone), probably vascular calcification, and lower levels of protein induced in vitamin K absence or antagonism II (PIVKA-II, a des-&ggr;-carboxy prothrombin) than those with TT genotypes. Conclusions— The haplotype of VKORC1 may serve as a novel genetic marker for the risk of stroke, coronary heart disease, and aortic dissection.

The relationship of sleep duration and insomnia to risk of hypertension incidence: a meta-analysis of prospective cohort studies

To assess whether habitual sleep duration or insomnia increase the incidence of hypertension. PubMed, EMBASE and Cochrane were searched without language restriction. Prospective cohort studies of adults with at least a 1-year follow-up duration were included. Habitual sleep duration or symptoms of insomnia were assessed as baseline exposure, and the outcome was incidence of hypertension. Subgroup, meta-regression and sensitivity analyses were conducted to assess heterogeneity, and Egger’s test was used to assess publication bias. Eleven studies (17 cohorts) were included. Short sleep duration, sleep continuity disturbance (SCD), early-morning awakening (EMA) and combined symptoms of insomnia increased the risk of hypertension incidence (the relative risks (95% confidence intervals) were 1.21 (1.05–1.40) for short sleep duration, 1.20 (1.06–1.36) for SCD, 1.14 (1.07–1.20) for EMA and 1.05 (1.01–1.08) for combined insomnia symptoms). Less evidence exists to support conclusions about the association between long sleep duration or difficulty falling asleep (DFA) and hypertension incidence. No obvious heterogeneity or publication biases were found. Our meta-analysis demonstrates that short sleep duration and single/combined symptoms of insomnia (except DFA) are associated with an increased risk of hypertension incidence. It is important to consider sleep duration and insomnia during hypertension prevention and treatment. More laboratory studies on potential mechanisms and prospective observational studies with objective measures of sleep are needed.

Combined effect of obesity and cardio-metabolic abnormality on the risk of cardiovascular disease: A meta-analysis of prospective cohort studies

BACKGROUND Cardiovascular risk is inconsistent in the normal-weight, overweight, and obese individuals due to metabolic abnormality. We aimed to investigate combined effects of obesity and metabolic abnormality on the risk of cardiovascular disease and mortality. METHODS The MEDLINE, EMBASE, Cochrane library, and references of relevant original articles prior to May 2013 were searched for prospective studies investigating cardiovascular risk and death associated with combined effects of obesity and metabolic syndrome or insulin resistance. Pooled relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects or fixed-effect models when appropriate. RESULTS Fourteen perspective studies with a total of 299,059 participants and 12,125 cases of incident CVD, 2130 cases of CVD death, and 7071 cases of all-cause death were included in the meta-analysis. Compared with healthy normal-weight individuals, metabolically healthy overweight (MHOW) and obese (MHOB) individuals showed increased risk for CVD events, which appeared much stronger during the long-term follow-up period of >15 years, with pooled RR of 1.47 (95% CI 1.37-1.58) in MHOW and 2.00 (95% CI 1.79-2.24) in MHOB. Normal-weight but metabolically abnormal individuals were at increased risk for CVD (pooled RR 1.81, 95% CI 1.56-2.10), CVD-related death (pooled RR 1.55, 95% CI 1.16-2.08), and all-cause death (pooled RR 1.27, 95% CI 1.10-1.47). Metabolically abnormal obese individuals were at the highest risk for CVD and mortality. CONCLUSION Individuals with metabolic abnormality, although at normal-weight, had an increased risk of CVD and mortality. Healthy overweight and obese persons had higher risk, which refuted the notion that metabolically healthy obese phenotype is a benign condition.

Support for linkage of familial combined hyperlipidemia to chromosome 1q21-q23 in Chinese and German families.

We examined familial combined hyperlipidemia (FCHL) families from nonisolated regions in Germany and China to see if we could corroborate support for a chromosome 1q FCHL locus in more general populations. We recruited 24 German families with 137 members, 92 of whom met the criteria of affected in terms of the low density lipoprotein (LDL) and triglyceride levels in excess of the 90th percentile for age and gender. In China, we recruited 12 families with a total of 81 members. All affected persons had total cholesterol concentrations> 240 mg/dl and triglyceride concentrations> 250 mg/dl. We examined the markers APOA2, D1S1677, D1S104, D1S194, D1S426, and D1S196. Two‐point linkage analysis allowing for heterogeneity gave a maximum linkage of disorder score (HLOD) of 2.60 right over D1S194, estimating the proportion of linked families at 36%. This marker is adjacent to D1S104. The evidence for linkage was roughly the same both in the German (HLOD 1.40) and Chinese families (HLOD 1.52). Marker D1S194 is close to the retinoid X receptor (RXR) gene locus, which was found to be linked to triglyceride levels in an earlier twin study from our laboratory. We interpret our observations as encouraging support for the recent findings indicating the presence of a gene for FCHL on chromosome 1q. Furthermore, since D1S194 is adjacent to the gene for the RXR, we suggest that RXR is an attractive candidate for involvement in FCHL.

Plasma Uric Acid and Hypertension in a Chinese Community: Prospective Study and Metaanalysis

BACKGROUND Hyperuricemia has been positively associated with hypertension, but whether this association is independent of adiposity and other cardiovascular risk factors remains a matter of debate. METHODS We conducted a community-based prospective cohort study comprising 7220 participants (mean age 37 years; 73.8% men) in the Qingdao Port Health and Nutrition Examination Survey in China, who were free from hypertension at study entry in 1999-2000. During 4-year follow-up, 1370 men (19.0%) and 208 women (11.0%) had developed hypertension. RESULTS After adjustment for age, body mass index, and other covariates, the relative risks (RRs) of developing hypertension comparing the highest and lowest uric acid quartiles were 1.55 (95% CI 1.10-2.19; P for trend <0.001) for men and 1.91 (1.12-3.25; P for trend <0.001) for women. After additional adjustment for abdominal obesity, the RRs comparing the participants in the highest and lowest quartiles of uric acid were 1.39 (1.16-1.68; P for trend 0.003) for men and 1.85 (1.06-3.24; P for trend 0.006) for women. In joint analysis, compared with those in the lowest uric acid quartile and without abdominal obesity, participants who were in the highest quartile and also had abdominal obesity had a 3.0- and 3.4-fold greater risk of incident hypertension (1.56-3.97 for men and 2.10-3.81 for women, respectively). CONCLUSIONS These data suggest a positive association between plasma uric acid and incidence of hypertension during short-term follow-up in a Chinese population. The association between hyperuricemia and hypertension was partly mediated by abdominal obesity.

9p21 is a shared susceptibility locus strongly for coronary artery disease and weakly for ischemic stroke in Chinese Han population.

Background—Recent studies on genome-wide association have identified common variants on chromosome 9p21 associated with coronary artery disease (CAD). Given that ischemic stroke and CAD share several aspects of etiology and pathogenesis, we investigated the association of variants on chromosome 9p21 with ischemic stroke and CAD in the Chinese Han population by capturing the majority of diversity in this locus using haplotype-tagging single-nucleotide polymorphisms. Methods and Results—We performed a shared control-cases study using 15 tagging single-nucleotide polymorphisms and 2 previously reported susceptibility single-nucleotide polymorphisms spanning 58 kb of the chromosome of 9p21 in a set of 558 patients with ischemic stroke, 510 patients with CAD, and 557 unaffected participants (controls) in the Chinese Han population. The association analyses were performed at both SNP and haplotype levels. We further verified our findings in an independent cohort of 442 ischemic stroke cases and 502 control subjects. In the first study, rs2383206, rs1004638, and rs10757278 in block 3 were significantly associated with CAD but not with ischemic stroke independent of traditional cardiovascular risk factors in additive model (P=0.002 to 0.0001, q=0.026 to 0.004). Analysis from all blocks revealed that haplotype profiles of block 3 on 9p21 were significantly different between shared control and cases of CAD (P=1.3×10−10, q=1.2×10−9) and ischemic stroke (P=1.7×10−6, q=7.7×10−6). In the expanded second case-control study, block 3 on 9p21 remained associated with ischemic stroke (P=2.6×10−4, q=6.3×10−4). Conclusions—Our results suggest for the first time that 9p21 is a shared susceptibility locus, strongly for CAD and weakly for ischemic stroke, in a Chinese Han population.

Effect of soy isoflavones on blood pressure: A meta-analysis of randomized controlled trials

BACKGROUND AND AIM The effect of soy isoflavones on blood pressure is controversial. The objective of this study was to evaluate the effect of dietary soy isoflavones on blood pressure. METHODS AND RESULTS Trials were searched in PubMed, the Cochrane Library, Embase and references cited in related reviews and studies. A total of eleven trials were reviewed. Meta-analysis results showed a mean decrease of 2.5 mm Hg (95% CIs, - 5.35 to 0.34 mm Hg; P = 0.08) for systolic blood pressure and 1.5 mm Hg (95% CIs, - 3.09 to 0.17 mm Hg; P = 0.08) for diastolic blood pressure in the soy isoflavones-treated group compared to placebo. Meta-regression and subgroup analyses indicated that blood pressure status was a significant predictor of heterogeneity for the effect of soy isoflavones on blood pressure. Subgroup analysis of hypertensive subjects revealed that a greater blood pressure reduction was identified in the soy isoflavone-treated group compared to placebo (5 trials; SBP: - 5.94, 95% CIs [- 10.55, - 1.34] mm Hg, P = 0.01; DBP: - 3.35, 95% CIs [- 6.52, - 0.19] mm Hg, P = 0.04). In contrast, treatment with soy isoflavones did not lead to a significant reduction in blood pressure in normotensive subjects (6 trials; SBP: 0.29, 95% CIs [- 2.39, 2.97] mm Hg, P = 0.83; DBP: - 0.43, 95% CIs [- 1.66, 0.81] mm Hg, P = 0.50). CONCLUSION Soy isoflavones had an effect of lowering blood pressure in hypertensive subjects, but not in normotensive subjects. Larger trials need to be carried out to confirm the present findings.

A Novel Loss-of-Function DDAH1 Promoter Polymorphism Is Associated With Increased Susceptibility to Thrombosis Stroke and Coronary Heart Disease

Rationale: Asymmetrical dimethylarginine (ADMA), an endogenous arginine analogue, inhibits nitric oxide synthases and plays an important role in endothelial dysfunction. Objective: In the present study, we tested whether a novel genetic variant in dimethylarginine dimethylaminohydrolase 1 (DDAH1), an important ADMA hydrolyzing gene, was associated with stroke and coronary heart disease (CHD) susceptibility in the Chinese Han population. Methods and Results: By resequencing, we identified a novel 4-nucleotide deletion/insertion variant in the DDAH1 promoter. The insertion allele disrupted binding of metal-regulatory transcription factor 1, which resulted in significant reduction of in vitro DDAH1 transcriptional activity and in vivo DDAH1 mRNA level, and in turn, increased plasma ADMA level and the ratio of ADMA to l-arginine. We initially genotyped the polymorphism in 1388 stroke patients and 1027 controls as well as 576 CHD patients and 557 controls and then replicated our study in additional independent case-control cohorts comprising 961 stroke patients and 822 controls and 482 CHD patients and 1072 controls. We identified that the −396 4N ins allele was significantly associated with increased risk of thrombosis stroke and CHD after adjusting for environmental factors in both samples for both diseases (thrombosis stroke discovery set: odds ratio [OR]=1.35, P=0.032; replication set: OR=1.51, P= 0.006; CHD discovery set: OR=1.45, P=0.035; replication set: OR=1.47, P=0.003). Conclusions: Our results suggest that the DDAH1 loss-of-function polymorphism is associated with both increased risk of thrombosis stroke and CHD.

Polymorphisms of ACE2 Gene are Associated With Essential Hypertension and Antihypertensive Effects of Captopril in Women

ACE2 appears to counterbalance the vasopressor effect of angiotensin I converting enzyme (ACE) in the renin‐angiotensin system. We hypothesized that ACE2 polymorphisms could confer a high risk of hypertension and have an impact on the antihypertensive response to ACE inhibitors. The hypothesis was tested in two case‐control studies and a clinical trial of 3,408 untreated hypertensive patients randomized to Atenolol, Hydrochlorothiazide, Captopril, or Nifedipine treatments for 4 weeks. ACE2 rs2106809 T allele was found to confer a 1.6‐fold risk for hypertension in women (95% confidence interval (CI), 1.13–2.06), whereas when combined with the effect of the ACE DD genotype, the risk was 2.34‐fold (95% CI, 1.75–4.85) in two independent samples. The adjusted diastolic blood pressure response to Captopril was 3.3 mm Hg lower in ACE2 T allele carriers than in CC genotype carriers (P=0.019) in women. We conclude that the ACE2 T allele confers a high risk for hypertension and reduced antihypertensive response to ACE inhibitors.