Xiangfeng Lu

Genome-wide association study in Han Chinese identifies four new susceptibility loci for coronary artery disease.

We performed a meta-analysis of 2 genome-wide association studies of coronary artery disease comprising 1,515 cases and 5,019 controls followed by replication studies in 15,460 cases and 11,472 controls, all of Chinese Han ancestry. We identify four new loci for coronary artery disease that reached the threshold of genome-wide significance (P < 5 × 10−8). These loci mapped in or near TTC32-WDR35, GUCY1A3, C6orf10-BTNL2 and ATP2B1. We also replicated four loci previously identified in European populations (in or near PHACTR1, TCF21, CDKN2A-CDKN2B and C12orf51). These findings provide new insights into pathways contributing to the susceptibility for coronary artery disease in the Chinese Han population.

Effect of omega-3 fatty acids supplementation on endothelial function: a meta-analysis of randomized controlled trials.

OBJECTIVE Inverse association was reported between omega-3 fatty acids (FAs) supplementation and the risk of cardiovascular disease. Identifying the effect of omega-3 FAs on endothelial function may contribute to explain the association. We conducted a meta-analysis to assess the effect of omega-3 FAs supplementation on endothelial function, as measured by flow-mediated dilation (FMD) and endothelium-independent vasodilation (EIV). METHODS Randomized placebo-controlled trials (RCTs) were identified from the databases of PubMed, EMBASE and Cochrane library by two investigators and the pooled effects were measured by weighted mean difference (WMD), together with 95% confidence intervals (CIs). Subgroup and meta-regression analyses were used to explore the source of between-study heterogeneity. RESULTS Totally 16 eligible studies involving 901 participants were finally included in meta-analysis. Compared with placebo, omega-3 FAs supplementation significantly increased FMD by 2.30% (95% CI: 0.89-3.72%, P = 0.001), at a dose ranging from 0.45 to 4.5 g/d over a median of 56 days. Subgroup analyses suggested that the effect of omega-3 FAs on FMD might be modified by the health status of the participants or the dose of supplementation. Sensitivity analyses indicated that the protective effect of omega-3 on endothelial function was robust. No significant change in EIV was observed after omega-3 FAs supplementation (WMD: 0.57%; 95% CI: -0.88 to 2.01%; P = 0.442). CONCLUSION Supplementation of omega-3 fatty acids significantly improves the endothelial function without affecting endothelium-independent dilation.

Genome-wide association study in Chinese identifies novel loci for blood pressure and hypertension

Hypertension is a common disorder and the leading risk factor for cardiovascular disease and premature deaths worldwide. Genome-wide association studies (GWASs) in the European population have identified multiple chromosomal regions associated with blood pressure, and the identified loci altogether explain only a small fraction of the variance for blood pressure. The differences in environmental exposures and genetic background between Chinese and European populations might suggest potential different pathways of blood pressure regulation. To identify novel genetic variants affecting blood pressure variation, we conducted a meta-analysis of GWASs of blood pressure and hypertension in 11 816 subjects followed by replication studies including 69 146 additional individuals. We identified genome-wide significant (P < 5.0 × 10(-8)) associations with blood pressure, which included variants at three new loci (CACNA1D, CYP21A2, and MED13L) and a newly discovered variant near SLC4A7. We also replicated 14 previously reported loci, 8 (CASZ1, MOV10, FGF5, CYP17A1, SOX6, ATP2B1, ALDH2, and JAG1) at genome-wide significance, and 6 (FIGN, ULK4, GUCY1A3, HFE, TBX3-TBX5, and TBX3) at a suggestive level of P = 1.81 × 10(-3) to 5.16 × 10(-8). These findings provide new mechanistic insights into the regulation of blood pressure and potential targets for treatments.

Genome-Wide Association Study Identifies 8 Novel Loci Associated With Blood Pressure Responses to Interventions in Han Chinese

Background—Blood pressure (BP) responses to dietary sodium and potassium intervention and cold pressor test vary considerably among individuals. We aimed to identify novel genetic variants influencing individuals’ BP responses to dietary intervention and cold pressor test. Methods and Results—We conducted a genome-wide association study of BP responses in 1881 Han Chinese and de novo genotyped top findings in 698 Han Chinese. Diet-feeding study included a 7-day low-sodium (51.3 mmol/d), a 7-day high-sodium (307.8 mmol/d), and a 7-day high-sodium plus potassium supplementation (60 mmol/d). Nine BP measurements were obtained during baseline observation and each intervention period. The meta-analyses identified 8 novel loci for BP phenotypes, which physically mapped in or near PRMT6 (P=7.29×10–9), CDCA7 (P=3.57×10–8), PIBF1 (P=1.78×10–9), ARL4C (P=1.86×10–8), IRAK1BP1 (P=1.44×10−10), SALL1 (P=7.01×10–13), TRPM8 (P=2.68×10–8), and FBXL13 (P=3.74×10–9). There was a strong dose–response relationship between the number of risk alleles of these independent single-nucleotide polymorphisms and the risk of developing hypertension during the 7.5-year follow-up in the study participants. Compared with those in the lowest quartile of risk alleles, odds ratios (95% confidence intervals) for those in the second, third, and fourth quartiles were 1.39 (0.97, 1.99), 1.72 (1.19, 2.47), and 1.84 (1.29, 2.62), respectively (P=0.0003 for trend). Conclusions—Our study identified 8 novel loci for BP responses to dietary sodium and potassium intervention and cold pressor test. The effect size of these novel loci on BP phenotypes is much larger than those reported by the previously published studies. Furthermore, these variants predict the risk of developing hypertension among individuals with normal BP at baseline.

Adiponectin Levels and Risk of Coronary Heart Disease: A Meta-analysis of Prospective Studies

Background:Adiponectin is the most abundant circulating protein secreted by adipocytes. There is uncertainty about the association between adiponectin levels and risk of coronary heart disease (CHD). We conducted this meta-analysis to summarize the effect of adiponectin on the risk of CHD. Methods:A comprehensive search was performed to identify all prospective studies on the association of adiponectin levels and risk of CHD. The quality of the eligible studies was evaluated by the Newcastle-Ottawa Scale. The fixed- or random-effects model was selected to pool the relative risk (RR) and 95% confidence interval (CI). Heterogeneity among studies was evaluated using Q test and the I2 statistic. Publication bias was estimated using modified Eggers linear regression test. Results:Twelve prospective studies comprising 8 nested case-control studies and 4 cohort studies were included in the meta-analysis. A total of 14,960 participants were enrolled and 4,132 incident CHD events were observed. The pooled RR for CHD was 0.83 (95% CI, 0.69–0.98, P = 0.031). Subgroup analyses showed that the pooled RRs (95% CIs) for CHD risk were 0.78 (0.66–0.92) and 0.75 (0.59–0.94) for men and women, respectively. For studies with mean age less than 65 years, the pooled RR (95% CI) for CHD risk was 0.72 (0.59–0.87). For studies with 100 or more CHD cases, the pooled RR was marginally significant (RR = 0.83, 95% CI, 0.69–1.00; P = 0.051). No publication bias was found in our study (P = 0.911). Conclusions:This meta-analysis showed that higher levels of adiponectin were associated with a low risk of CHD. The protective effect was consistently existed in men and women and in the middle-aged populations.

Interactions among genetic variants from contractile pathway of vascular smooth muscle cell in essential hypertension susceptibility of Chinese Han population.

Background and objective Recent study supports the hypothesis that the abnormalities of vascular smooth muscle cell (VSMC) that alter the intrinsic contractile state of the cell can directly cause abnormal vascular tone and disorders of blood pressure regulation, including hypertension. This study aimed to explore the individual and interactive effects of five genes from the contractile pathway of VSMC (KCNMB1, RGS2, PRKG, ROCK2, and MYLK) on the risk of essential hypertension. Methods Potential functional polymorphisms of the five genes were analyzed in a large, representative Chinese Han sample of 4759 individuals, including 2411 hypertensive patients and 2348 age-matched and sex-matched healthy controls. Results Single locus analyses showed significant association of the alleles of RGS2-rs34717272 with hypertension (original P of χ2 test=0.005; P value of permutation=0.019). After the adjustment for covariates, the carriers of minor D allele of RGS2-rs34717272 had an increased hypertension risk (DD+ID vs. II; odds ratio=1.19; 95% confidence interval, 1.04–1.35; P value after the Bonferroni correction=0.009×5=0.045). We also found that the carriers of minor T allele of KCNMB1-rs11739136 had a significantly decreased risk for hypertension (TT+CT vs. CC; odds ratio=0.83; 95% confidence interval, 0.72–0.95; P value after the Bonferroni correction=0.008×5=0.040). Final interaction models were selected and evaluated by permutation test and/or cross-validation test. Both the multifactor-dimensionality reduction and classification and regression trees methods showed a high-order gene–gene interaction among KCNMB1, RGS2, PRKG, and MYLK genes (P value of permutation in multifactor-dimensionality reduction=0.012). Conclusion The overall results supported that the genetic variants in the contractile pathway of VSMC could contribute to hypertension risk independently or in an interactive manner.

Caffeine Intake and Atrial Fibrillation Incidence: Dose Response Meta-analysis of Prospective Cohort Studies

BACKGROUND The association between habitual caffeine intake with incident atrial fibrillation (AF) was unknown. We conducted a meta-analysis to investigate the association between chronic exposure of caffeine and the risk of AF and to evaluate the potential dose-response relation. METHODS We searched PubMed, EMBASE, and the Cochrane Library up to November 2013 and references of relevant retrieved articles. Prospective cohort studies were included with relative risk (RR) or hazard ratio and 95% confidence intervals (CIs) for AF according to coffee/caffeine intake. RESULTS Six prospective cohort studies with 228,465 participants were included. In the primary meta-analysis, caffeine exposure was weakly associated with a reduced risk of AF (RR, 0.90; 95% CI, 0.81-1.01; P = 0.07; I(2) = 73%). In subgroup analyses, pooled results from studies with adjustment of potential confounders showed an 11% reduction for low doses (RR, 0.89; 95% CI, 0.80-0.99, P = 0.032; I(2) = 30.9%, P = 0.227) and 16% for high doses (RR, 0.84; 95% CI, 0.75-0.94, P = 0.002; I(2) = 24.1%, P = 0.267) of caffeine consumption in AF risk. An inverse relation was found between habitual caffeine intake and AF risk (P for overall trend = 0.015; P for nonlinearity = 0.27) in dose-response meta-analysis and the incidence of AF decreased by 6% (RR, 0.94; 95% CI, 0.90-0.99) for every 300 mg/d increment in habitual caffeine intake. CONCLUSIONS It is unlikely that caffeine consumption causes or contributes to AF. Habitual caffeine consumption might reduce AF risk.

The prognostic significance of atrial fibrillation in heart failure with a preserved and reduced left ventricular function: insights from a meta-analysis.

The prognostic significance of atrial fibrillation (AF) in patients with heart failure remains inconclusive.

Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci

Human height is associated with risk of multiple diseases and is profoundly determined by an individuals genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians.

Functional analysis of the C-reactive protein (CRP) gene -717A>G polymorphism associated with coronary heart disease

BackgroundAtherosclerosis underlies the major pathophysiological mechanisms of coronary heart disease (CHD), and inflammation contributes to all phases of atherosclerosis. C-reactive protein (CRP), a sensitive, but nonspecific marker of inflammation has been shown to play proatherogenic roles in the process of atherosclerosis. Our previous report showed that rs2794521 (-717A>G), located in the promoter of the CRP gene, was independently associated with CHD in Chinese subjects. In the present study, we tried to investigate the biological significance of this genetic variation in vitro.MethodsThe influence of G to A substitution at the site of rs2794521 on the transcriptional activity of the promoter of the CRP gene was assessed by luciferase reporter assay, and protein binding to the site of rs2794521 was detected by EMSA assay.ResultsThe G to A exchange at the site of rs2794521 resulted in an increased transcriptional activity of the promoter of CRP gene, and glucocorticoid receptor (GR) protein factor bound drastically differently to the A and G alleles at the site of rs2794521.ConclusionThese results provided functional evidence supporting the association of the SNP rs2794521 of the CRP gene with CHD probably through regulating the expression level of CRP by different variations of rs2794521.