Hongfan Li

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.

Renalase gene is a novel susceptibility gene for essential hypertension: a two-stage association study in northern Han Chinese population.

Renalase, a novel flavin adenine dinucleotide-dependent amine oxidase, is secreted by the kidney, degrades circulating catecholamines, and modulates cardiac function and systemic blood pressure (BP). Its discovery may provide novel insights into the mechanisms of BP regulation and the pathogenesis of essential hypertension (EH). We designed a two-stage case-control study to investigate whether the renalase gene harbored any genetic variants associated with EH in the northern Han Chinese population. From the International Collaborative Study of Cardiovascular Disease in Asia (InterASIA in China), 1,317 hypertensive cases and 1,269 normotensive controls were recruited. These total 2,586 subjects were taken as the main study population in this study. In stage 1, all the eight selected single nucleotide polymorphisms (SNPs) of the renalase gene were genotyped and tested within a subsample (503 cases and 490 controls) of the main study population. By single locus analyses, three SNPs, rs2576178, rs2296545, and rs2114406, showed significant associations with EH (P < 0.05). In stage 2, these three SNPs were genotyped on the remaining individuals and analyzed using all the individuals. After Bonferroni correction for multiple comparisons, the associations of rs2576178 and rs2296545 with EH were still significant in stage 2. The cases had higher frequencies of rs2576178 G allele and rs2296545 C allele than the controls (0.55 versus 0.49, P < 0.0001; 0.61 versus 0.55, P < 0.0001). Particularly, under the codominant model, the adjusted odds ratios for rs2576178 GG genotype and rs2296545 CC genotype were 1.58 (95% CI, 1.25 to 2.00; P = 0.0002) and 1.61 (95% CI, 1.26 to 2.04; P = 0.0002), respectively. We also found risk-associated haplotypes and diplotypes, which further confirmed the significant association between the renalase gene and EH. These findings may provide novel genetic susceptibility markers for EH and lead to a better understanding of EH pathophysiology. In addition, further replications in other populations and functional studies would be warranted.

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.

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.

Association Study of G Protein‐Coupled Receptor Kinase 4 Gene Variants with Essential Hypertension in Northern Han Chinese

To investigate the association between polymorphisms in the G protein‐coupled receptor kinase 4 gene (GRK4) (R65L, A142V and A486V) and essential hypertension in northern Han Chinese, we conducted a case‐control study consisting of 503 individuals with essential hypertension (HT) and 490 age‐, gender‐, and area‐matched normotensive (NT) controls. The three GRK4 variants were genotyped by PCR‐RFLP analysis. Both haplotype and single locus analysis were used to process the genotyping data. The A486 allele showed a significant association with HT (P < 0.001). A total of 6 haplotypes were observed in the entire population, with the haplotypes L‐V‐A and R‐A‐A being found to be significantly related to hypertension (P= 0.001).

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.

Common variants at 12q24 are associated with drinking behavior in Han Chinese.

BACKGROUND Alcohol consumption is heritable, but genetic susceptibility to drinking behavior has not been investigated widely in genome-wide association studies. OBJECTIVE We aimed to identify susceptibility loci for drinking behavior (drinkers compared with nondrinkers) in Han Chinese. DESIGN We performed 2 genome-wide association studies including 1420 drinkers and 3590 nondrinkers in discovery, followed by a de novo replication analysis comprising 4896 drinkers and 13,293 nondrinkers. DNA samples of the subjects were collected for genotyping. RESULTS The association results of drinking behavior (drinkers or nondrinkers) showed a cluster of single nucleotide polymorphisms at 12q24 in discovery (P < 5 × 10(-8)), with the strongest association for rs11066280 near C12orf51 (P-combined = 3.26 × 10(-215)). Moreover, we observed the association with drinking behavior for a functional variant in ALDH2 at 12q24 (rs671, P-discovery = 5.17 × 10(-35)). We also identified the association between rs11066280 and daily alcohol intake among drinkers (P-combined = 4.01 × 10(-21)). CONCLUSION Our data indicate that common variants at 12q24 may contribute to the susceptibility of drinking behavior in Han Chinese.

PLA2G7 gene polymorphisms and coronary heart disease risk: A meta-analysis

INTRODUCTION Variants of PLA2G7 gene have been reported to be associated with coronary heart disease (CHD) since ten years ago, but the available data on this relationship are inconsistent. A meta-analysis was conducted to assess the effect of PLA2G7 gene on CHD. MATERIALS AND METHODS Association studies were identified from the databases of PubMed, EMbase, Chinese National Knowledge Infrastructure (CNKI) and Wanfang by two investigators and pooled effects (odds ratio (OR), together with 95% confidence interval (CI)) were calculated. RESULTS 14 association studies focusing on three polymorphisms (A379V, V279F and R92H) in PLA2G7 gene and risk of CHD were included in meta-analysis, covering a total of 8,280 cases and 5,656 controls. Concerning R92H, a significantly increased CHD risk was observed in recessive model, with an OR of 1.31(1.02, 1.68). Nevertheless, combined analyses of studies of the A379V and V279F variants showed no significant overall association with CHD, yielding ORs of 0.99(0.85, 1.15) and 1.09(0.88, 1.35) in allelic analysis, with strong evidence of heterogeneity. Similar results were also obtained in dominant and recessive models. CONCLUSIONS The results indicate 92H allele had probably increased the risk of CHD, while the hypothesized effects of A379V and V279F polymorphisms on CHD cannot be confirmed in present data. However, given the limited number of studies and the potential biases, the influence of these polymorphisms on CHD risk needs further investigation.