Weili Zhang

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.

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.

Dietary Glycemic Index, Glycemic Load, and Risk of Coronary Heart Disease, Stroke, and Stroke Mortality: A Systematic Review with Meta-Analysis

Background The relationship between dietary glycemic index, glycemic load and risk of coronary heart disease (CHD), stroke, and stroke-related mortality is inconsistent. Methods We systematically searched the MEDLINE, EMBASE, and Science Citation Index Expanded databases using glycemic index, glycemic load, and cardiovascular disease and reference lists of retrieved articles up to April 30, 2012. We included prospective studies with glycemic index and glycemic load as the exposure and incidence of fatal and nonfatal CHD, stroke, and stroke-related mortality as the outcome variable. Pooled relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects models. Results Fifteen prospective studies with a total of 438,073 participants and 9,424 CHD cases, 2,123 stroke cases, and 342 deaths from stroke were included in the meta-analysis. Gender significantly modified the effects of glycemic index and glycemic load on CHD risk, and high glycemic load level was associated with higher risk of CHD in women (RR = 1.49, 95%CI 1.27−1.73), but not in men (RR = 1.08, 95%CI 0.91−1.27). Stratified meta-analysis by body mass index indicated that among overweight and obese subjects, dietary glycemic load level were associated with increased risk of CHD (RR = 1.49, 95%CI 1.27−1.76; P for interaction = 0.003). Higher dietary glycemic load, but not glycemic index, was positively associated with stroke (RR = 1.19, 95% CI 1.00−1.43). There is a linear dose-response relationship between dietary glycemic load and increased risk of CHD, with pooled RR of 1.05 (95%CI 1.02−1.08) per 50-unit increment in glycemic load level. Conclusion High dietary glycemic load is associated with a higher risk of CHD and stroke, and there is a linear dose-response relationship between glycemic load and CHD risk. Dietary glycemic index is slightly associated with risk of CHD, but not with stroke and stroke-related death. Further studies are needed to verify the effects of gender and body weight on cardiovascular diseases.

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.

Disorders of Orthostatic Blood Pressure Response Are Associated With Cardiovascular Disease and Target Organ Damage in Hypertensive Patients

BACKGROUND The prevalence and clinical significance of orthostatic hypertension (OHT) remain largely undetermined in hypertensive patients. This study investigated the association of OHT and orthostatic hypotension (OH) with cardiovascular disease (CVD) and target organ damage (TOD) in hypertensive patients. METHODS A cross-sectional study was conducted in 4,711 hypertensives and 826 normotensives, aged 40-75 years. OHT was defined as an increase in systolic blood pressure (SBP) of > or =20 mm Hg, and OH was defined as either a reduction in SBP of at least 20 mm Hg or a reduction in diastolic BP (DBP) of at least 10 mm Hg during the first 3 min after standing. RESULTS Hypertension was only independently associated with a risk of OHT. After controlling for age, sex, and other confounders, OH was associated with peripheral artery disease (PAD) (odds ratio (OR) 1.49, 95% confidence interval (CI) 1.15-1.89, P < 0.01), left ventricular hypertrophy (LVH) (OR 1.48, 95% CI 1.12-1.93, P < 0.001), coronary artery disease (CAD) (OR 1.71, 95% CI 1.12-2.61, P < 0.01), and stroke (OR 1.72, 95% CI 1.19-2.34, P < 0.01), but OHT was only associated with PAD (OR 1.36, 95% CI 1.05-1.81, P < 0.05) and stroke (OR 1.76, 95% CI 1.27-2.26, P < 0.01). The adjusted OR for PAD, predicted by the quintiles of the orthostatic SBP changes, showed a J-shaped relationship in untreated hypertensive patients, as was also the case for LVH in hypertensive women. CONCLUSIONS OH is associated with CV risk; the associations of OHT with TOD and stroke in hypertensive patients still need to be confirmed in prospective studies.

Variants on Chromosome 9p21.3 Correlated With ANRIL Expression Contribute to Stroke Risk and Recurrence in a Large Prospective Stroke Population

Background and Purpose— ANRIL encodes a long antisense noncoding RNA in the INK4 locus. Although ANRIL has been proven to be associated with coronary heart disease, its roles in stroke are inconsistent, and sparse data are available regarding hemorrhagic stroke. Methods— A Chinese case-control study was conducted, comprising 1657 cases (724 atherothrombosis, 466 lacunar infarction, and 462 hemorrhagic strokes) and 1664 controls. Stroke patients were prospectively followed-up for a median of 4.5 (range, 0.1–6.0) years. Expression of ANRIL transcripts was examined in 42 human atherosclerotic plaques. Results— After adjustment for vascular risk factors and correction for multiple comparisons, subjects carrying the GG genotype of rs10757278 had 1.47-fold (95% CI, 1.11–1.89; P=0.05) and 1.60-fold (95% CI, 1.16–2.15; P=0.04) increased risk for atherothrombotic and hemorrhagic strokes, respectively. During the follow-up, 317 recurrent strokes and 301 deaths from all causes were documented. Subjects carrying rs10757278GG had higher risk for stroke recurrence (relative risk [RR],1.56; 95% CI,1.15–2.12; P=0.005) and cardiovascular mortality (RR, 2.0; 95% CI, 1.26–3.18; P=0.003), respectively. Rs10757274 was also associated with stroke risk and recurrence. Family history of stroke further increased the stroke risk by 2.37-fold (95% CI, 1.38–4.06; P=0.01) and recurrent stroke risk by 2.45-fold (95% CI, 1.56–3.86; P<0.0001) respectively, when compared with those carrying none of G-alleles and without family history. Finally, rs10757278 was associated with differential expression of the ANRIL transcripts. Conclusions— Our findings indicated that the ANRIL may serve as a novel genetic marker for the risk of atherothrombotic and hemorrhagic stroke and their recurrence.

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.

Coffee Consumption and Risk of Cardiovascular Diseases and All-Cause Mortality Among Men With Type 2 Diabetes

OBJECTIVE Coffee consumption has been linked to detrimental acute metabolic and hemodynamic effects. We investigated coffee consumption in relation to risk of CVDs and mortality in diabetic men. RESEARCH DESIGN AND METHODS We conducted a prospective cohort study including 3,497 diabetic men without CVD at baseline. RESULTS After adjustment for age, smoking, and other cardiovascular risk factors, relative risks (RRs) were 0.88 (95% CI 0.50–1.57) for CVDs (P for trend = 0.29) and 0.80 (0.41–1.54) for all-cause mortality (P for trend = 0.45) for the consumption of ≥4 cups/day of caffeinated coffee compared with those for non–coffee drinkers. Stratification by smoking and duration of diabetes yielded similar results. RRs for caffeine intake for the highest compared with the lowest quintile were 1.02 (0.70–1.47; P for trend = 0.96) for CVDs and 0.96 (0.64–1.44; P for trend = 0.69) for mortality. CONCLUSIONS These data indicate that regular coffee consumption is not associated with increased risk for CVDs or mortality in diabetic men.

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.

Association of Intergenic Polymorphism of Organic Anion Transporter 1 and 3 Genes With Hypertension and Blood Pressure Response to Hydrochlorothiazide

BACKGROUND Organic anion transporter (OAT) 1 and OAT3, encoded by a tightly linked gene pair, play a key role in renal secretion of diuretics. However, no study has yet examined the influence of OAT1 and OAT3 polymorphisms on high blood pressure (BP) and the response to thiazide diuretics. We hypothesized that intergenic polymorphisms between OAT1 and OAT3 might be associated with adult hypertension and the antihypertensive effects of hydrochlorothiazide (HCTZ). METHODS The association of an intergenic polymorphism (rs10792367) with hypertension risk was investigated in two independent case-control studies (n = 1,592 and 602), and then a combined analysis was performed for improving power (1,106 cases and 1,088 controls) with adjustment for geographic location. Two clinical trials (n = 542 and 274) were conducted in untreated hypertensive patients for the association of rs10792367 with antihypertensive responses to 4 and 8 weeks of HCTZ treatment. RESULTS No significant association was found between rs10792367 and hypertension after adjustment for conventional risk factors in either the two populations, respectively, or the combined two population. After adjustment for pretreatment BP and other confounders, HCTZ-induced reduction in systolic BP was 4.8 mm Hg (P = 0.006, first trial) and 6.1 mm Hg (P = 0.003, in second trial) lower, respectively, in C allele carriers than in GG carriers in the two clinical trials. CONCLUSIONS Intergenic polymorphism rs10792367 between OAT1 and OAT3 is not associated with hypertension, but appears to be involved in between-individual variations in antihypertensive responses to HCTZ.