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The causal effects of moderate alcohol consumption on cardiovascular diseases (CVDs) are continuously debated, especially on coronary artery disease (CAD).We aimed to explore the causal associations of alcohol consumption with CVDs and all-cause mortality among Chinese males.A prospective cohort study was conducted in 40,386 Chinese males, with 17,676 being genotyped for the rs671 variant in the aldehyde dehydrogenase 2 (ALDH2) gene. A Cox proportional hazards model was conducted to estimate the effects of self-reported alcohol consumption. Mendelian randomization (MR) analysis was performed to explore the causality using rs671 as an instrumental variable.During the follow-up of 303,353 person-years, 2406 incident CVDs and 3195 all-cause mortalities were identified. J-shaped associations of self-reported alcohol consumption with incident CVD and all-cause mortality were observed, showing decreased risks for light (≤25 g/d) and moderate drinkers (25-≤60 g/d). However, MR analyses revealed a linear association of genetically predicted alcohol consumption with the incident CVD (P-trend = 0.02), including both CAD (P-trend = 0.03) and stroke (P-trend = 0.02). The HRs (95% CIs) for incident CVD across increasing tertiles of genetically predicted alcohol consumption were 1 (reference), 1.18 (1.01, 1.38), and 1.22 (1.03, 1.46). After excluding heavy drinkers, the risk of incident CVD and all-cause mortality was increased by 27% and 20% per standard drink increment of genetically predicted alcohol consumption, respectively.Our analyses extend the evidence of the harmful effect of alcohol consumption to total CVD (including CAD) and all-cause mortality, highlighting the potential health benefits of lowering alcohol consumption, even among light-to-moderate male drinkers.

Aims LDL cholesterol (LDL-C) is a well-established risk factor for coronary artery disease (CAD). However, the optimal LDL-C level with regard to efficacy and safety remains unclear. We aimed to investigate the causal relationships between LDL-C and efficacy and safety outcomes. Methods and results We analyzed 353 232 British from the UK Biobank and 41 271 Chinese from the China-PAR project. Linear and non-linear Mendelian randomization (MR) analyses were performed to evaluate the causal relation between genetically proxied LDL-C and CAD, all-cause mortality, and safety outcomes (including haemorrhagic stroke, diabetes mellitus, overall cancer, non-cardiovascular death, and dementia). No significant non-linear associations were observed for CAD, all-cause mortality, and safety outcomes (Cochran Q P > 0.25 in British and Chinese) with LDL-C levels above the minimum values of 50 and 20 mg/dL in British and Chinese, respectively. Linear MR analyses demonstrated a positive association of LDL-C with CAD [British: odds ratio (OR) per unit mmol/L increase, 1.75, P = 7.57 × 10−52; Chinese: OR, 2.06, P = 9.10 × 10−3]. Furthermore, stratified analyses restricted to individuals with LDL-C levels less than the guideline-recommended 70 mg/dL demonstrated lower LDL-C levels were associated with a higher risk of adverse events, including haemorrhagic stroke (British: OR, 0.72, P = 0.03) and dementia (British: OR, 0.75, P = 0.03). Conclusion In British and Chinese populations, we confirmed a linear dose–response relationship of LDL-C with CAD and found potential safety concerns at low LDL-C levels, providing recommendations for monitoring adverse events in people with low LDL-C in the prevention of cardiovascular disease.

ObjectiveTo construct a polygenic risk score (PRS) for stroke and evaluate its utility in risk stratification and primary prevention for stroke.MethodsUsing a meta-analytic approach and large genome-wide association results for stroke and stroke-related traits in East Asians, we generated a combined PRS (metaPRS) by incorporating 534 genetic variants in a training set of 2,872 patients with stroke and 2,494 controls. We then validated its association with incident stroke using Cox regression models in large Chinese population-based prospective cohorts comprising 41,006 individuals.ResultsDuring a total of 367,750 person-years (mean follow-up 9.0 years), 1,227 participants developed stroke before age 80 years. Individuals with high polygenic risk had an about 2-fold higher risk of incident stroke compared with those with low polygenic risk (hazard ratio [HR] 1.99, 95% confidence interval [CI] 1.66–2.38), with the lifetime risk of stroke being 25.2% (95% CI 22.5%–27.7%) and 13.6% (95% CI 11.6%–15.5%), respectively. Individuals with both high polygenic risk and family history displayed lifetime risk as high as 41.1% (95% CI 31.4%–49.5%). Individuals with high polygenic risk achieved greater benefits in terms of absolute risk reductions from adherence to ideal fasting blood glucose and total cholesterol than those with low polygenic risk. Maintaining favorable cardiovascular health (CVH) profile could substantially mitigate the increased risk conferred by high polygenic risk to the level of low polygenic risk (from 34.6% to 13.2%).ConclusionsOur metaPRS has great potential for risk stratification of stroke and identification of individuals who may benefit more from maintaining ideal CVH.Classification of EvidenceThis study provides Class I evidence that metaPRS is predictive of stroke risk.

Several studies reported temperature exposure was associated with altered cardiac automatic function, while this effect of temperature on hourly heart rate variability (HRV) among populations with cardiovascular risks was seldom addressed.We conducted this panel study in four Chinese cities with three repeated visits among 296 participants at intermediate to high-risk of cardiovascular disease (CVD). Real-time temperature level and 24-h ambulatory electrocardiogram were monitored during each seasonal visit. Linear mixed-effects models were used to investigate associations between individual temperature and HRV parameters, and the seasonal effects and circadian effect were also evaluated.We found the overall downward trend of hourly HRV associated with acute exposure to higher temperature. For each 1 °C increment in temperature of 1-3 h prior to HRV measurements (lag 1-3 h), hourly standard deviation of normal-to-normal intervals (SDNN) decreased by 0.38 % (95 % confidence interval [CI]: 0.22, 0.54), 0.28 % (95 % CI: 0.12, 0.44), and 0.20 % (95 % CI: 0.04, 0.36), respectively. Similar inverse associations between temperature and HRV were observed in stratified analyses by temperature level. Inverse associations for cold and warm seasons were also observed, despite some effects gradually decreased and reversed in the warm season as lag times extended. Moreover, HRV showed a more significant reduction with increased temperature during daytime than nighttime. Percent change of hourly SDNN was -0.41 % (95 % CI: -0.62, -0.21) with 1 °C increment of lag 1 h during daytime, while few obvious changes were revealed during nighttime.Generally, increasing temperature was significantly associated with reduced HRV. Inverse relationships for cold and warm seasons were also observed. Associations during daytime were much more prominent than nighttime. Our findings clarified the relationship of temperature with HRV and provided evidence for prevention approaches to alleviate cardiac automatic dysfunction among populations at intermediate to high-risk of CVD.

Previous studies indicated that long-term exposure to high level of fine particulate matter (PM

Aim ATP-binding cassette (ABC) transporters and endonuclease-exonuclease-phosphatase family domain containing 1 (EEPD1) are reported to regulate cellular cholesterol efflux in macrophages. Bioinformatics analysis has revealed that ABCG1 and EEPD1 might be potential targets of microRNA (miR)-320b. This study aimed to elucidate the roles of miR-320b in cholesterol efflux from macrophages and the pathogenesis of atherosclerosis. Methods Microarray was conducted to profile microRNA (miRNA) expression, and quantitative real-time PCR (qPCR) was used to validate the differentially expressed miRNAs in peripheral blood mononuclear cells of coronary artery disease (CAD) patients and healthy controls. Luciferase assay was conducted to evaluate the activity of reporter construct containing the 3´-untranslated region (3´-UTR) of target genes. Besides, NBD-cholesterol efflux induced by high-density lipoprotein (HDL) and lipid-free apolipoprotein A1 (apoA1) was detected using fluorescence intensity, respectively. Apoe－/－ mice were injected with adeno-associated virus (AAV)2-miR-320b or control via tail vein, thereafter fed with 14 week atherogenic diet to study the roles of miR-320b in vivo. Results MiR-320b was highly expressed in CAD patients compared with that in the healthy controls in both the microarray analysis and qPCR analysis. In vitro study showed that miR-320b decreased HDL- and apoA1- mediated cholesterol efflux from macrophages partly by directly targeting ABCG1 and EEPD1 genes and partly via suppressing the LXRα-ABCA1/G1 pathway. Consistently, in vivo administration of AAV2-miR-320b into Apoe－/－ mice attenuated cholesterol efflux from peritoneal macrophages, which showed reduced expression of ABCA1/G1 and EEPD1, and increased lipid LDL-C level, with a down-regulation of hepatic LDLR and ABCA1. AAV2-miR-320b treatment also increased atherosclerotic plaque size and lesional macrophage content and enhanced pro-inflammatory cytokines levels through the elevated phosphorylation level of nuclear factor-κB p65 in macrophages. Conclusion We identify miR-320b as a novel modulator of macrophage cholesterol efflux and that it might be a promising therapeutic target for atherosclerosis treatment.

MiR-520b belongs to the miR-373/520 family, is expressed only in human and nonhuman primates. Previous reports indicated that the expression of miR-520b was repressed in human atherosclerotic plaque tissue compared with healthy vessels. However, the role of miR-520b in coronary artery disease still remains to be uncovered. In this study, we demonstrated that endothelial cells (ECs) in human atherosclerotic plaques expressed miR-520b and aimed to elucidate the impact of miR-520b on EC activation and inflammatory response. To determine the potential targets of miR-520b, we performed RNA-seq analysis by transfecting miR-520b mimics in ECs. The quantitative real-time PCR (qPCR) validation suggested that miR-520b over-expression reduced pro-inflammatory gene expression (e.g. ICAM1, VCAM1, SELE) while the inhibition of miR-520b induced their expression. By combining bioinformatics prediction and functional assays, we identified that RELA (Nuclear Factor-κB (NF-κB) Transcription Factor P65) was a direct target of miR-520b. Moreover, miR-520b mimics attenuated monocyte adhesion and monocyte trans-endothelial migration (the initial steps of atherosclerotic formation) in response to lipopolysaccharides (LPS) stimulation. Re-expression of a non-miR-targetable version of p65 could rescue the reduced monocyte cell attachment, suggesting that this process is NF-κB p65 dependent. MiR-520b reduced the abundance of NF-κB p65 in cytoplasmic fractions without corresponding increase in nuclear fractions, indicating that this regulation is independent of p65 translocation process. MiR-520b mimics attenuated the activity of VCAM-1 promoter, whereas miR-520b inhibitor activated its activity. However, miR-520b inhibitor had no effect on promoter activity containing the mutated NF-κB p65 binding sites, strongly demonstrating that the impact of miR-520b on VCAM1 gene is mediated by NF-κB p65. Thus, we concluded that miR-520b suppressed EC inflammation and the cross-talk between monocytes and ECs by down-regulating NF-κB p65-ICAM1/VCAM1 axis and might serve as a potential therapeutic target for EC dysfunction and atherosclerosis.

Background and aims Dysregulation of long non-coding RNAs (lncRNAs) has been proven to be involved in the pathogenesis of coronary artery disease (CAD). However, it remains to be extensively explored. Thus, the present study aims to study expression patterns, biological functions, and diagnostic value of lncRNAs in CAD. Methods Using microarray, we performed the transcriptome-wide lncRNA and mRNAs expression profile of peripheral blood mononuclear cells (PBMCs) of 93 CAD patients and 48 healthy controls. Gene Ontology (GO) and pathway analysis for differentially expressed mRNAs were used to investigate underlying biological associations of differentially expressed lncRNAs, and path-net was created to depict interactions of significant pathways. qRT-PCR was used to validate selected lncRNAs in 412 CAD patients and 295 healthy controls. Receiver operating characteristic (ROC) curve analysis was performed to evaluate whether lncRNAs could be used in the diagnosis of CAD patients. Finally, the functional significance of validated lncRNAs was determined in THP-1-derived macrophages. Results We identified 1210 lncRNAs and 890 mRNAs differentially expressed from the expression profile and validated 7 lncRNAs. Two novel lncRNA biomarkers, ENST00000444488.1 and uc010yfd.1, together with CAD risk factors, had the better performance for discrimination of CAD patients from healthy controls, and ENST00000444488.1 could diagnose acute myocardial infarction (AMI) patients. The knockdown of 20 ENST00000444488.1, uc010yfd.1, ASO3973 and ENST00000602558.1 affected the expression of inflammation-related genes and their nearby genes in THP-1-derived macrophages, respectively. Conclusions We offered a transcriptome-wide overview of aberrantly expressed lncRNAs in CAD patients, and identified two novel lncRNA biomarkers for diagnosing CAD. Loss of validated lncRNAs regulated the expression of inflammation-related genes and their nearby genes.

BACKGROUND The mammalian cyclic guanosine monophosphate (cGMP)-dependent protein kinases type II (PKG II) plays critical physiological or pathological functions in different tissues. However, the biological effects of PKG II are dependent on cGMP. Published data indicated that L-arginine (L-Arg) promoted NO production, NO can activate soluble guanylate cyclase (sGC), and catalyzes guanosine triphosphate (GTP) into cGMP, which suggested L-Arg could activate PKG II. Therefore, the present work was performed to address: (i) whether L-Arg could be a potential alternative in PKG II activation, and (ii) whether L-Arg also contributes to PKG II against cancer. MATERIAL AND METHODS Nude BALB/c mice were inoculated with human MCF-7, HepG2, and SW480 cell lines via subcutaneous (s.c.) injecting. After 7 days of inoculation, Ad-PKG II was injected into the cancer tissues every 4 days, and the next day 10 μmol/mouse L-Arg was administered. Western blotting and immunohistochemistry were used to assess protein expression. RESULTS Our results demonstrated that L-Arg significantly activated PKG II and effectively ameliorated xenograft tumor development through inhibiting cancer growth, angiogenesis, and metastasis, which was partially dependent on blocking of epidermal growth factor receptor (EGFR) activity, as well as downstream signaling pathways such as Erk1/2. CONCLUSIONS Our results provide an exciting new insight: L-Arg is a potential alternative to PKG II activation.

Previous studies have indicated that reactive oxygen species produced by NADPH oxidase (Nox) are important risk factors of hypertension. The current study aims to examine the associations of Nox-related genes with longitudinal blood pressure (BP) changes and the risk of incident hypertension in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) follow-up study. A total of 1,768 participants from 633 families were included in our analysis. Nine BP measurements were obtained in the morning at baseline and during two follow-up visits. The mixed-effect models were used to investigate the associations of 52 tagged single-nucleotide polymorphisms in 11 Nox-related genes with BP changes and incident hypertension. Gene-based analyses were performed by truncated product method (TPM) and Versatile Gene-based Association Study (VEGAS). Over the 7.2 years of follow-up, systolic BP (SBP) and diastolic BP (DBP) increased, and 32.1% (512) of participants developed hypertension. SNPs rs12094228, rs16861188 and rs12066019 in NCF2 were significantly associated with longitudinal change in SBP (Pinteraction = 1.1 × 10−3, 2.8 × 10−3 and 1.2 × 10−3, respectively). Gene-based analyses revealed that NCF2 was significantly associated with SBP (PTPM = 1.00 × 10−6, PVEGAS = 1.26 × 10−4) and DBP changes (PTPM = 5.84 × 10−4, PVEGAS = 1.04 × 10−3). These findings suggested that NCF2 may play an important role in BP changes over time in the Han Chinese population.

Decamethonium diiodide is reported to perform the chemo- and regioselective encapsulation of para-dihalobenzenes through the competitive formation of halogen-bonded cocrystals starting from solutions that also contain ortho and meta isomers. Selective caging in the solid occurs even when an excess ortho or meta isomers, or even a mixture of them, is present in the solution. A prime matching between the size and shape of the dication and the formed dianions plays a key role in enabling the selective self-assembly, as proven by successful encapsulation of halogen-bond donors as weak as 1,4-dichlorobenzene and by the results of cocrystallization trials involving mismatching tectons. Encapsulated para-dihalobenzenes guest molecules can be removed quantitatively by heating the cocrystals under reduced pressure and be recovered as pure materials. The residual decamethonium diiodide can be recycled with no reduction in selectivity.

Despite advances in chemotherapy, ovarian cancer (OC) is still the most lethal gynecologic malignancy. So, it is imperative to explore its mechanism and find novel targets to improve the outcome. Type II cyclic guanosine 3′,5′-monophosphate (cGMP)-dependent protein kinase (PKG II) has been recently reported to inhibit proliferation and metastasis in several tumors. The present study is to clarify the effect of PKG II combined with l-arginine (l-Arg) on OC cells. SKOV3 and A2780 cells were infected with adenovirus coding cDNA of PKG II to increase PKG II expression and l-Arg was applied to activate this kinase. CCK8 assay, Transwell migration and TUNEL assay were applied to detect the proliferation, migration and apoptosis of the OC cells, respectively. Western blotting was used to detect the level of total and phosphorylated proteins. Our results showed that co-treatment with PKG II and l-Arg inhibited EGF-induced proliferation and the expression of Proliferating Cell Nuclear Antigen (PCNA), Cyclin E and N-Cadherin, whereas up-regulated the expression of E-Cadherin, abolished the anti-apoptotic effect of EGF, prevented the process of epithelial-to-mesenchymal transition (EMT) as well as blocked EGF-triggered Raf-MEK and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways. Our results suggested that PKG II activated by l-Arg could inhibit proliferation and migration and promote the apoptosis of OC cells. Based on the above results and our previous data, it is speculated that PKG II is an inhibitor of cancer with extensive effects.

Purpose: The aim of this study was to investigate the relationship between stressful life events and sleep quality and to probe the role of rumination and resilience in the relationship. Method: The Adolescent Self-Rating Life Events Checklist, Ruminative Responses Scale, Connor-Davidson Resilience Scale, and Pittsburgh Sleep Quality Index were used among 1,065 college students. Statistical Product and Service Solutions (SPSS) 20.0 and the SPSS macro Process, which were specifically developed for assessing complex models including both mediators and moderators, were used to analyze the data. Results: High scores of stressful life events predicted worse sleep quality. Rumination partially mediated the relations between stressful life events and sleep quality. Resilience moderated the direct and indirect paths leading from stressful life events to sleep quality. Conclusions: The results demonstrate that stressful life events can directly affect the sleep quality of college students and indirectly through rumination. Additionally, increasing psychological resilience could decrease both the direct effect and the indirect effect of stressful life events affecting sleep quality. The results of this study may contribute to a better understanding of the effects, as well as the paths and conditions, of stressful life events on sleep quality in college students. Moreover, these findings can provide constructive suggestions for improving college students' sleep quality.

BACKGROUND The large-scale meta-analysis of genome-wide association study (GWAS) recently identified a genomic locus where the genetic variant at rs820430 was strongly associated with hypertension in Chinese Han population, with its T allele conferred increased risks. However, the biological and disease-relevant mechanisms for this association remain elusive. METHODS A group of 275 participants from rural district of Shandong Province were enrolled, rs820430 was genotyped using genomic DNA with the fluorogenic 5'-nuclease TaqMan allelic discrimination assay system (Applied Biosystems, CA). In vitro experiments were performed in this study, such as luciferase reporter assays, gel mobility shift assays (electrophoretic mobility shift assay), and chromatin immunoprecipitation. RESULTS We found the risk T allele of rs820430 was associated with higher SLC4A7 mRNA level in cohort population. Furthermore, we characterized a cis-regulatory mechanism that the T allele of rs820430 distinctively increased c-Fos transcription factor binding, by which leading to increased SLC4A7 expression. CONCLUSIONS The present study indicated that the disease-associated T allele of a new hypertension risk variant rs820430 linked increased hypertension risk through higher SLC4A7 expression, and rs820430 functioned as an enhancer of SLC4A7 transcription by allele distinctively increased c-Fos transcription factor binding.

Background— Multiple genetic loci associated with lipid levels have been identified predominantly in Europeans, and the issue of to what extent these genetic loci can predict blood lipid levels increases over time and the incidence of future hyperlipidemia remains largely unknown. Methods and Results— We conducted a meta-analysis of genome-wide association studies of lipid levels in 8344 subjects followed by replication studies including 14 739 additional individuals. We replicated 17 previously reported loci. We also newly identified 3 Chinese-specific variants in previous regions ( HLA-C , LIPG , and LDLR ) with genome-wide significance. Almost all the variants contributed to lipid levels change and incident hyperlipidemia >8.1-year follow-up among 6428 individuals of a prospective cohort study. The strongest associations for lipid levels change were detected at LPL , TRIB1 , APOA1-C3-A4-A5 , LIPC , CETP , and LDLR ( P range from 4.84×10 −4 to 4.62×10 −18 ), whereas LPL , TRIB1 , ABCA1 , APOA1-C3-A4-A5 , CETP , and APOE displayed significant strongest associations for incident hyperlipidemia ( P range from 1.20×10 −3 to 4.67×10 −16 ). The 4 lipids genetic risk scores were independently associated with linear increases in their corresponding lipid levels and risk of incident hyperlipidemia. A C -statistics analysis showed significant improvement in the prediction of incident hyperlipidemia on top of traditional risk factors including the baseline lipid levels. Conclusions— These findings identified some evidence for allelic heterogeneity in Chinese when compared with Europeans in relation to lipid associations. The individual variants and those cumulative effects were independent risk factors for lipids increase and incident hyperlipidemia.

Aim: Silent mating type information regulator 2 homolog 1 (SIRT1) functions as an atheroprotective factor in vascular biology, and genetic variations in SIRT1 are associated with coronary artery calcification and type 2 diabetes in several populations. In this study, we investigated the relationship between the mRNA expression levels of the SIRT1 gene and single nucleotide polymorphisms (SNPs) in the context of acute coronary syndrome (ACS).Methods: Whole-genome expression microarray and real-time PCR techniques were used to detect the gene expression levels, and Western blotting was performed to determine the protein expression level. The four selected SNPs were genotyped in a Taqman genotyping platform.Results: Compared with that observed in the controls, the mRNA expression levels of the SIRT1 gene in the microarray study were significantly lower in the acute myocardial infarction (AMI), unstable angina (UA) and overall ACS patients. These results were replicated in another independent cohort with respect to the mRNA (AMI, p＜0.001; UA, p＜0.001; ACS, p＜0.001) and protein (p＜0.05) levels. Furthermore, the relationship between the SIRT1 mRNA expression and the genotypes of four possible functional SNPs (rs12778366, rs3758391, rs2273773 and rs4746720) was tested, the results of which showed significant differences in the SIRT1 mRNA expression among the allelic genes of rs3758391 (p＜0.01) in the healthy participants.Conclusions: The present results confirm that the SIRT1 gene plays a protective role against ACS and that the rs3758391 SNP affects the mRNA expression in healthy participants, providing new insight into the processes regulating the genetic control of the SIRT1 gene with respect to the pathogenesis of ACS.

Objective Our previous study has found that circulating microRNA (miRNA, or miR) -122, -140-3p, -720, -2861, and -3149 are significantly elevated during early stage of acute coronary syndrome (ACS). This study was conducted to determine the origin of these elevated plasma miRNAs in ACS. Methods qRT-PCR was performed to detect the expression profiles of these 5 miRNAs in liver, spleen, lung, kidney, brain, skeletal muscles, and heart. To determine their origins, these miRNAs were detected in myocardium of acute myocardial infarction (AMI), and as well in platelets and peripheral blood mononuclear cells (PBMCs, including monocytes, circulating endothelial cells (CECs) and lymphocytes) of the AMI pigs and ACS patients. Results MiR-122 was specifically expressed in liver, and miR-140-3p, -720, -2861, and -3149 were highly expressed in heart. Compared with the sham pigs, miR-122 was highly expressed in the border zone of the ischemic myocardium in the AMI pigs without ventricular fibrillation (P < 0.01), miR-122 and -720 were decreased in platelets of the AMI pigs, and miR-122, -140-3p, -720, -2861, and -3149 were increased in PBMCs of the AMI pigs (all P < 0.05). Compared with the non-ACS patients, platelets miR-720 was decreased and PBMCs miR-122, -140-3p, -720, -2861, and -3149 were increased in the ACS patients (all P < 0.01). Furthermore, PBMCs miR-122, -720, and -3149 were increased in the AMI patients compared with the unstable angina (UA) patients (all P < 0.05). Further origin identification revealed that the expression levels of miR-122 in CECs and lymphocytes, miR-140-3p and -2861 in monocytes and CECs, miR-720 in monocytes, and miR-3149 in CECs were greatly up-regulated in the ACS patients compared with the non-ACS patients, and were higher as well in the AMI patients than that in the UA patients except for the miR-122 in CECs (all P < 0.05). Conclusion The elevated plasma miR-122, -140-3p, -720, -2861, and -3149 in the ACS patients were mainly originated from CECs and monocytes.

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 x 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 x 10(-3) to 5.16 x 10(-8). These findings provide new mechanistic insights into the regulation of blood pressure and potential targets for treatments.

Objective Coactivator-associated arginine methyltransferase 1 (CARM1) is essential for the activation of a subset of NF-кB-dependent genes, which code the chemokines triggering plaque vulnerability. Unstable atherosclerotic plaques lead to the onset of acute coronary syndrome (ACS). Therefore, we aimed to investigate whether CARM1 is involved in the pathogenesis of ACS and ascertain the regulatory mechanism of CARM1 expression at posttranscriptional level. Methods Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood of 19 patients with ACS and 22 subjects with risk factors for coronary heart disease. Gene expression was determined by quantitative real-time PCR and Western blot. The effects of CARM1 and miR-15a on their target genes expression were assessed by gain-of-function and loss-of-function approaches. Results PBMCs from patients with ACS showed higher levels of CARM1 mRNA and protein expression. The levels of CARM1 mRNA were positively correlated with three chemokines including interferon-inducible protein-10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), and interleukin-8 (IL-8) in PBMCs ( CARM1 and IP-10 : r = 0.55, P = 0.008; CARM1 and MCP-1 : r = 0.64, P = 0.002; CARM1 and IL-8 : r = 0.55, P = 0.008). Moreover, CARM1 regulated the transcription of these chemokines in human embryonic kidney 293T (HEK293T) cells. We also found that the levels of miR-15a were decreased by 37% in patients with ACS and miR-15a modulated CARM1 expression through targeted binding to CARM1 3′-UTR. Conclusion The present study demonstrated that CARM1 targeted by miR-15a played an important role in chemokine activation in the pathogenesis of ACS.

Fibrillin-1 (FBN1) was reported to have impact on the physiological arterial stiffness and vascular remodeling with hypertension of recent years. In the previous study we reported the association of four functional single nucleotide polymorphisms (SNPs) of FBN1 gene and hypertension. Here, we further investigate the association of four tagging SNPs (tagSNPs) which covered remain genetic variation blocks of FBN1 gene with hypertension, blood pressure and efficacy of antihypertensive in a South Han Chinese population. A case–control study including 2,012 hypertension cases and 2,116 controls age- and sex-matched controls was conducted from a community-based population and four candidate tagSNPs of the FBN1 gene were genotyped. Association analysis by multiple logistic regression was conducted for allele, genotype and haplotype and hypertension, blood pressure trait and control status with antihypertensive. General linear model was applied to compare blood pressure levels between genotypes. The association of rs17361868 and hypertension was statistically significant and that was further observed in female, ≥55 years, non-smoking and non-drinking populations (P

Human height is a complex genetic trait with high heritability but discovery efforts in Asian populations are limited. We carried out a meta-analysis of genome-wide association studies (GWAS) for height in 6,534 subjects with in silico replication of 1,881 subjects in Han Chinese. We identified three novel loci reaching the genome-wide significance threshold (P5 × 10(-8)), which mapped in or near ZNF638 (rs12612930, P = 2.02 × 10(-10)), MAML2 (rs11021504, P = 7.81 × 10(-9)), and C18orf12 (rs11082671, P = 1.87 × 10(-8)). We also confirmed two loci previously reported in European populations including CS (rs3816804, P = 2.63 × 10(-9)) and CYP19A1 (rs3751599, P = 4.80 × 10(-10)). In addition, we provided evidence supporting 35 SNPs identified by previous GWAS (P0.05). Our study provides new insights into the genetic determination of biological regulation of human height.

a b s t r a c t 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 omega3 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.

Sterol regulatory element binding proteins (SREBPs), as a family of membrane-bound transcription factors, control the metabolism of cholesterol and fatty acids. We conducted a case-control study to investigate whether the common variants of genes from the SREBP2 activating-related pathway, involving SREBP2, SCAP, INSIG1 and INSIG2 genes, were associated with coronary heart disease (CHD) of Chinese Han population individually or interactively. Three, four and two single nucleotide polymorphisms (SNPs) from the INSIG1, INSIG2 and SCAP genes were chosen as haplotype-tagging SNPs (htSNPs), respectively, and one nonsynonymous coding SNP was selected from SREBP2. All of the SNPs were genotyped in 853 CHD cases and 948 unrelated control subjects. The interactions among SNPs of the four genes were evaluated with multifactor-dimensionality reduction (MDR) and logistic regression models (LRM). The results from MDR indicated that there existed the SNP-SNP interactive effect of INSIG1 gene on CHD (best prediction accuracy = 56.09%, p = 0.002 on 1000 permutations). The results from LRM also identified the 2-locus interaction model (adjusted p ≤ 0.001 for interaction) as well as the 3-locus gene–gene interaction (adjusted p = 0.026 for interaction). Single polymorphism analysis showed that the rs4822063 of SREBP2 was associated with LDL-C in the controls. The genotype CC carriers had higher LDL-C than the major allele G carriers (3.44 ± 0.90 mmol/L versus 3.17 ± 0.84 mmol/L, adjusted p = 0.038). Our results suggested that the INSIG1 gene was associated with CHD; there might be potential interactive effect on CHD among genes from SREBP2 activating-related pathway; and the SREBP2 gene might be associated with plasma lipid level.

The TH (tyrosine hydroxylase) gene encodes the rate-limiting enzyme of catecholamine biosynthesis, and is involved in the pathogenesis of hypertension, but the relationship of its variants with hypertension has not been extensively studied. We designed a case-controlled study consisting of 503 HT (hypertensive) individuals and 490 NT (normotensive) individuals matched by region, age and gender to systematically investigate the association between the TH gene and hypertension. Based on the HapMap and dbSNP (where SNP is single nucleotide polymorphism) data, four SNPs, rs6356 A>G, rs6357 G>A, rs2070762 T>C and rs1800033 A>G in the TH gene were selected for genotyping. Rs1800033 was not polymorphic in our study population. No significant differences were observed for distributions of rs6356 and rs6357 between the HT and NT groups. However, both the genotype and allele frequencies of rs2070762 showed significant differences between cases and controls (P

The human plasma kallikrein gene (KLKB1) encodes plasma kallikrein, a serine protease that catalyzes the release of kinins and other vasoactive peptides and may be involved in the pathogenesis of hypertension. In this study, we performed a haplotype-based study to assess the effect of common genetic variation in the KLKB1 gene on the risk of essential hypertension. Eight common single nucleotide polymorphisms (SNPs) were selected from the HapMap database and used to determine the pattern of linkage disequilibrium (LD) and haplotype structure within the KLKB1 gene. Four tag SNPs were then identified with over 85% power to predict both common haplotypes and remaining common SNPs, and genotyped in 1,317 cases with essential hypertension and 1,269 healthy controls. Single SNP analyses indicated that SNPs rs2304595 and rs4253325 were significantly associated with hypertension, adjusted for covariates. Compared with the most common Hap2 CAGC, Hap1 AGAC and Hap3 CGAC, which carry the susceptible rs2304595 G allele and rs4253325 A allele, were found to significantly increase the risk of essential hypertension with adjusted odds ratios equal to 1.37 and 1.17, respectively (P < 0.0001 and 0.028). A strongly significant interaction with gene-drinking was also observed. Among drinkers, the adjusted OR for Hap1 relative to Hap2 was increased to 2.50 (95% CI, 2.40 to 2.61; P < 0.0001). This was the first study to perform association analysis of the KLKB1 gene with essential hypertension. Our findings suggested that common genetic variation in the KLKB1 gene might contribute to the risk of hypertension in the 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.

Objective The GALNT3 gene encodes polypeptide N-acetylgalactosaminyl transferase 3 (GalNAc-T3), a member of the GalNAc-Ts family that transfers the N-acetylgalactosamine to the hydroxyl group of serine and threonine residue in the first step of O-linked oligosaccharide biosynthesis. Emerging evidences have linked GalNAc-Ts family to coronary artery disease (CAD). However the effect of GALNT3 in CAD is unknown. The present study investigated the function and mechanisms of GALNT3 gene in endothelial injury. Methods and results The GALNT3 mRNA level was decreased by 48.2% in CAD patients (n = 58), compared with that of controls (n = 120). Expression of GALNT3 was also decreased in human umbilical vein endothelial cells (HUVECs) treated with CAD sera and subjected to hypoxia in vitro . Knockdown of GALNT3 promoted apoptosis and up-regulated the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-14 (MMP-14). Conversely, overexpression of GALNT3 significantly inhibited HUVECs apoptosis and down-regulated the expression of MMP-2 and MMP-14 genes, in addition, overexpression of GALNT3 attenuated hypoxia-induced apoptosis and expression of MMP-2 and MMP-14. Finally, the ratio of cytosolic p-p38 MAPK/p38 MAPK expression was significantly increased with GALNT3 knockdown and lower with GALNT3 overexpression, while the p38 MAPK inhibitor SB203580 blocked the effects of GALNT3 knockdown. Conclusions Expression of GALNT3 was reduced in CAD patients, and down regulation of GALNT3 contributed to endothelial injury by promoting apoptosis and up-regulating the expression of MMP-2 and MMP-14 genes via p38 MAPK activation. GALNT3 may be a potential target for future therapeutic intervention for CAD.

Although multiple genetic markers associated with blood pressure have been identified by genome-wide association studies, their aggregate effect on risk of incident hypertension and cardiovascular disease is uncertain, particularly among East Asian who may have different genetic and environmental exposures from Europeans. We aimed to examine the association between genetic predisposition to higher blood pressure and risk of incident hypertension and cardiovascular disease in 26 262 individuals in 2 Chinese population-based prospective cohorts. A genetic risk score was calculated based on 22 established variants for blood pressure in East Asian. We found the genetic risk score was significantly and independently associated with linear increases in blood pressure and risk of incident hypertension and cardiovascular disease ( P range from 4.57×10 –3 to 3.10×10 –6 ). In analyses adjusted for traditional risk factors including blood pressure, individuals carrying most blood pressure–related risk alleles (top quintile of genetic score distribution) had 40% (95% confidence interval, 18–66) and 26% (6–45) increased risk for incident hypertension and cardiovascular disease, respectively, when compared with individuals in the bottom quintile. The genetic risk score also significantly improved discrimination for incident hypertension and cardiovascular disease and led to modest improvements in risk reclassification for cardiovascular disease (all the P

Objective We evaluated the potentiality of plasma microRNAs (miRNAs, or miRs) that were considered as novel biomarkers for acute coronary syndrome (ACS), including acute myocardial infarction (AMI) and unstable angina (UA). Methods and Results We initially identified plasma miR-122, -140-3p, -144, -720, -1225-3p, -2861, and -3149 as candidate miRNAs associated with AMI (≥2 fold and P < 0.05) by comparing expression differences of miRNAs among AMI, non-coronary heart disease (non-CHD) and stable angina (SA) groups, using miRNA microarrays (n = 8 independent arrays in each group). Those seven plasma miRNAs were further examined with qRT-PCR analyses in two replications including 111 and 428 patients separately, and the results demonstrated that plasma miR-122, -140-3p, -720, -2861, and -3149 were elevated in the ACS group vs. the non-ACS (non-CHD + SA) group (P < 0.01). The area under the receiver operating characteristic curve (AUC) of the five miRNAs for ACS classification was 0.838, 0.818, 0.865, 0.852, and 0.670, respectively (all P < 0.001), while the values reached 0.843 and 0.925 when simultaneously with miR-122 and -3149 or with miR-122, -2861, and -3149 together (all P < 0.001). In plasma of pigs after coronary ligation, miR-122 was increased from 180 min to 240 min and miR-3149 was augmented from 30 min to 240 min compared with the sham pigs (all P < 0.05). Conclusion Plasma miR-122, -140-3p, -720, -2861, and -3149 were associated with and potentially novel biomarkers for ACS.

Silent mating type information regulator 2 homolog 1 (SIRT1) functions as an atheroprotective factor in vascular biology, and genetic variations in SIRT1 are associated with coronary artery calcification and type 2 diabetes in several populations. In this study, we investigated the relationship between the mRNA expression levels of the SIRT1 gene and single nucleotide polymorphisms (SNPs) in the context of acute coronary syndrome (ACS).Whole-genome expression microarray and real-time PCR techniques were used to detect the gene expression levels, and Western blotting was performed to determine the protein expression level. The four selected SNPs were genotyped in a Taqman genotyping platform.Compared with that observed in the controls, the mRNA expression levels of the SIRT1 gene in the microarray study were significantly lower in the acute myocardial infarction (AMI), unstable angina (UA) and overall ACS patients. These results were replicated in another independent cohort with respect to the mRNA (AMI, p＜0.001; UA, p＜0.001; ACS, p＜0.001) and protein (p＜0.05) levels. Furthermore, the relationship between the SIRT1 mRNA expression and the genotypes of four possible functional SNPs (rs12778366, rs3758391, rs2273773 and rs4746720) was tested, the results of which showed significant differences in the SIRT1 mRNA expression among the allelic genes of rs3758391 (p＜0.01) in the healthy participants.The present results confirm that the SIRT1 gene plays a protective role against ACS and that the rs3758391 SNP affects the mRNA expression in healthy participants, providing new insight into the processes regulating the genetic control of the SIRT1 gene with respect to the pathogenesis of ACS.

Background— Hyperhomocysteinemia is a risk factor for cardiovascular disease. Coactivator-associated arginine methyltransferase 1 ( CARM1 ) participates in the synthesis of homocysteine, but whether the genetic variations regulate CARM1 expression and homocysteine levels remains unknown. Methods and Results— Functional analyses combined with an association study were conducted to identify the causal variant for CARM1 expression and homocysteine levels. Based on functional annotations obtained from Encyclopedia of DNA Elements, we selected 4 potentially functional single-nucleotide polymorphisms in the CARM1 gene and investigated their effect on CARM1 transcription levels in vivo. rs117569851, located in the promoter region of CARM1 , as well as rs12460421 and rs4804544, was associated with CARM1 expression levels, and the last 2 single-nucleotide polymorphisms were discovered in high linkage disequilibrium with rs117569851 ( r 2 =0.9 and 1.0) in our study sample. rs117569851 was further identified to be responsible for regulating CARM1 expression. The T allele disrupted the binding of early growth response-1, which led to the downregulation of transcriptional activity in vitro and CARM1 mRNA levels in vivo. In addition, rs117569851 was associated with plasma homocysteine levels in a Chinese population (n=406), with a 2.16 μmol/L decrease per copy of T allele. Conclusions— The present study suggests that a noncoding variant in the CARM1 -promoter functions as a regulator of gene transcription and homocysteine levels.

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.

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 3 10 28 ), with the strongest association for rs11066280 near C12orf51 (P-combined = 3.26 3 10 2215 ). Moreover, we observed the association with drinking behavior for a functional variant in ALDH2 at 12q24 (rs671, P-discovery = 5.17 3 10 235 ). We also identified the association between rs11066280 and daily alcohol intake among drinkers (P-combined = 4.01 3 10 221 ). Conclusion: Our data indicate that common variants at 12q24 may contribute to the susceptibility of drinking behavior in Han Chinese. Am J Clin Nutr doi: 10.3945/ajcn.112.046482.

Many single-nucleotide polymorphisms (SNPs) have been reported to be associated with lipid concentrations in recent genome-wide association studies. The aim of this study was to validate the associations of rs2197089 in the lipoprotein lipase (LPL) gene with serum lipid concentrations and gene expression levels in the Chinese Han population and examine the potential interactions. A total of 9339 participants were recruited and genotyped for rs2197089. Gene expression levels of LPL in blood cells of 309 participants were evaluated by real-time PCR. We observed significant associations between rs2197089 and decreased triglycerides (TG) (P=0.0006), but not high-density lipoprotein cholesterol (HDL-C) concentration (P=0.0881). However, weak evidence of interaction between cigarette smoking and rs2197089 was detected (P=0.0362). In smokers, significant association between rs2197089 and increased HDL-C concentration was found (P=0.0068). Participants with the minor allele A had higher expression levels of LPL (P=0.0243). The results of our study indicated that rs2197089 was significantly associated with TG but it was associated with HDL-C only in smokers. This SNP seemed to have influence on the expression level of LPL.

Objective Dozens of single nucleotide polymorphisms (SNPs) in the lipoprotein lipase ( LPL ) gene have been reported to be associated with lipid concentrations. The aim of this study was to validate the association between rs1059611 in the LPL gene and serum lipid concentrations in the Chinese Han population and explore the biological relevance. Methods A total of 5664 participants were recruited and genotyped for the SNP. Gene expression levels of LPL in blood cells were evaluated by real-time PCR and western blotting analysis. The functional potential of the SNP was examined by luciferase reporter assay and electrophoretic mobility-shift assay (EMSA). Results We observed significant associations between rs1059611 and increased HDL-C ( P = 5.65 × 10 −5 ) and decreased TG concentrations ( P = 2.68 × 10 −7 ). We also found that participants with the C allele had higher mRNA expression level ( P = 0.0334) and protein expression level ( P = 0.0641) of LPL . The luciferase activity of the rs1059611 T construct was 0.69-fold of the rs1059611 C construct ( P = 0.0009). The EMSA showed that the binding of the transcription factor(s) differed for the alleles of the SNP. Conclusion The results of our study demonstrated that rs1059611 was associated with HDL-C and TG concentrations in Chinese Han population and might have a functional effect on the transcription of LPL by differential binding of transcription factors.

Genetic factors may determine an individual’s blood pressure (BP) level and risk for hypertension. This study aimed to examine the associations between genetic variants of the adrenomedullin (ADM) gene and essential hypertension, as well as BP levels, in a Chinese Han population. In this study, 2410 hypertensive patients and 2346 normal controls were recruited. Three tagging single-nucleotide polymorphisms (SNPs) based on the HapMap CHB data were selected and genotyped. No significant associations between the three SNPs of the ADM gene and hypertension status were observed. However, SNP rs4399321 was found to be associated with BP levels among the controls. GG homozygotes for this SNP had higher systolic BP (SBP) levels than carriers of the A allele (P=0.002). Particularly in non-drinkers, GG homozygotes had significantly higher SBP (116.9±0.9 vs. 113.7±0.3 mm Hg, P=0.001) and diastolic (74.0±0.7 vs. 72.6±0.2 mm Hg, P=0.046) BP levels than carriers of the A allele. Neither rs4910118 nor rs7944706 was associated with BP levels in the controls either before or after being stratified by drinking status. The results of this study showed that genetic variations in the ADM gene were not associated with the risk of hypertension in a Chinese population. However, the genotype at common variation rs4399321 may influence the BP level in normotensive subjects, especially among non-drinkers. In addition, replications in other populations and further functional studies are required to confirm and interpret the association of ADM with BP.

BACKGROUND Increased blood pressure (BP) reactivity to cold pressor test (CPT) is a risk factor for hypertension. Genetic factors may influence the variation of BP response to CPT among individuals. We explored the association of genetic variants in the apelin system genes (APLN, APLNR and ACE2) and BP response to CPT in a Chinese population. METHODS A total of 1,998 Han Chinese participants from the Genetic Epidemiology Network of Salt Sensitivity completed a CPT. The percentage changes of BP right after the end of ice-water immersion were used as the measurement of BP responses to CPT. Twenty-two single nucleotide polymorphisms (SNPs) were selected and genotyped, including both tag and potential functional SNPs of the APLN, APLNR, and ACE2 genes. A mixed-effect linear model was used to assess the association between SNPs and BP responses to CPT. RESULTS In women, three SNPs (rs1514283, rs4646176, and rs879922) of the ACE2 gene were significantly associated with the diastolic BP (DBP) response to CPT in the general and recessive genetic models after adjustment for multiple testing (all false discovery rate q < 0.05). There were no significant associations of polymorphisms in APLN and APLNR genes with BP responses to CPT. CONCLUSIONS Our study identified genetic variants in the ACE2 gene that were significantly associated with DBP responses to cold stress in the Chinese female population. Future studies are warranted to confirm these findings.

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

OBJECTIVES The purpose of this study was to examine the association between genetic variants in the renin-angiotensin system and blood pressure (BP) responses to the cold pressor test (CPT). METHODS The CPT was conducted among 1998 Han Chinese participants. BP measurements were obtained before and after the CPT using a standard sphygmomanometer according to a standard protocol. The association between SNP genotypes and BP responses to the CPT was assessed using a mixed linear model. RESULTS Of 68 SNPs genotyped in six renin-angiotensin system genes, two were strongly associated with DBP responses to CPT (P ≤ 0.001; false discovery rate q value < 0.05): rs2006765 and rs943580 in the angiotensinogen (AGT) gene. Compared to C allele carriers of rs2006765, the TT homozygotes had a significantly decreased DBP response to the CPT. For participants with the TT genotype, percentage DBP responses were 5.68% (4.25-7.10%), compared to corresponding responses of 9.17% (8.66-9.68%) among participants with the CC+CT genotype. In addition, SNP rs4681443 of the angiotensin type 1 receptor (AGTR1) gene was significantly associated with percentage SBP responses to CPT (P ≤ 0.001; q-value

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.

Background Atherosclerosis 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. Methods The 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. Results The 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. Conclusion These 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.

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 Χ 2 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 x 5 = 0.045). We also found that the carriers of minor T allele of KCNMB1-rs11739136 had a significantly decreased risk for hypertension (TT+CTvs. 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.