Circulation-Cardiovascular Genetics最新文献

{"title":"Calcium Signaling Pathway Genes RUNX2 and CACNA1C Are Associated With Calcific Aortic Valve Disease","authors":"Sandra Guauque-Olarte, D. Messika‐Zeitoun, A. Droit, M. Lamontagne, Joël Tremblay-Marchand, Emilie Lavoie-Charland, N. Gaudreault, B. Arsenault, M. Dubé, J. Tardif, S. Body, J. Seidman, C. Boileau, P. Mathieu, P. Pibarot, Y. Bossé","doi":"10.1161/CIRCGENETICS.115.001145","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001145","url":null,"abstract":"Background—Calcific aortic valve stenosis (AS) is a life-threatening disease with no medical therapy. The genetic architecture of AS remains elusive. This study combines genome-wide association studies, gene expression, and expression quantitative trait loci mapping in human valve tissues to identify susceptibility genes of AS. Methods and Results—A meta-analysis was performed combining the results of 2 genome-wide association studies in 474 and 486 cases from Quebec City (Canada) and Paris (France), respectively. Corresponding controls consisted of 2988 and 1864 individuals with European ancestry from the database of genotypes and phenotypes. mRNA expression levels were evaluated in 9 calcified and 8 normal aortic valves by RNA sequencing. The results were integrated with valve expression quantitative trait loci data obtained from 22 AS patients. Twenty-five single-nucleotide polymorphisms had P<5×10−6 in the genome-wide association studies meta-analysis. The calcium signaling pathway was the top gene set enriched for genes mapped to moderately AS-associated single-nucleotide polymorphisms. Genes in this pathway were found differentially expressed in valves with and without AS. Two single-nucleotide polymorphisms located in RUNX2 (runt-related transcription factor 2), encoding an osteogenic transcription factor, demonstrated some association with AS (genome-wide association studies P=5.33×10−5). The mRNA expression levels of RUNX2 were upregulated in calcified valves and associated with eQTL-SNPs. CACNA1C encoding a subunit of a voltage-dependent calcium channel was upregulated in calcified valves. The eQTL-SNP with the most significant association with AS located in CACNA1C was associated with higher expression of the gene. Conclusions—This integrative genomic study confirmed the role of RUNX2 as a potential driver of AS and identified a new AS susceptibility gene, CACNA1C, belonging to the calcium signaling pathway.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001145","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64397024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Smoking on Blood Pressure and Resting Heart RateCLINICAL PERSPECTIVE","authors":"A. Linneberg, R. Jacobsen, T. Skaaby, Amy E Taylor, M. Fluharty, J. Jeppesen, J. Bjørngaard, B. Åsvold, M. Gabrielsen, A. Campbell, R. Marioni, M. Kumari, P. Marques-Vidal, M. Kaakinen, A. Cavadino, I. Postmus, T. Ahluwalia, S. Wannamethee, J. Lahti, K. Räikkönen, A. Palotie, A. Wong, C. Dalgård, I. Ford, Y. Ben-Shlomo, L. Christiansen, K. Kyvik, D. Kuh, J. Eriksson, P. Whincup, H. Mbarek, E. D. Geus, J. Vink, D. Boomsma, G. Smith, D. Lawlor, A. Kisialiou, A. McConnachie, S. Padmanabhan, J. Jukema, C. Power, E. Hyppönen, M. Preisig, G. Waeber, P. Vollenweider, T. Korhonen, T. Laatikainen, V. Salomaa, J. Kaprio, M. Kivimäki, Blair H. Smith, C. Hayward, T. Sørensen, B. Thuesen, N. Sattar, R. Morris, P. Romundstad, M. Munafo, M. Järvelin, L. Husemoen","doi":"10.1161/CIRCGENETICS.115.001225","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001225","url":null,"abstract":"Background— Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood.\u0000\u0000Methods and Results— Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day.\u0000\u0000Conclusions— This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lifestyle Intervention for Weight Loss and Cardiometabolic Changes in the Setting of Glucokinase Regulatory Protein Inhibition: Glucokinase Regulatory Protein-Leu446Pro Variant in Look AHEAD","authors":"W. Jeffery, C. Thorson, J. Bantle, J. Redmon, R. Crow, S. Crow, S. Raatz, K. Brelje, Elizabeth Hoelscher, Jennifer Patricio, S. Schwartz, G. Foster, R. Berkowitz, Henry A. Glick","doi":"10.1161/CIRCGENETICS.115.001192","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.115.001192","url":null,"abstract":"Background—Glucokinase regulatory protein (GCKR) inhibitors offer a novel treatment approach for glucose control in diabetes mellitus; however, their cardiometabolic effects, particularly in relation to increased triglycerides and C-reactive protein (CRP) levels, are of concern. GCKR Leu446Pro is a common variant associated with reduced GCKR function, increased triglycerides, and CRP. Methods and Results—We investigated whether a 1-year intensive lifestyle intervention (ILI) for weight loss would avert the unfavorable cardiometabolic effects associated with GCKR Leu446Pro when compared with a diabetes mellitus support and education arm in overweight/obese individuals with type 2 diabetes mellitus with triglyceride (n=3214) and CRP (n=1411) data participating in a randomized lifestyle intervention study for weight loss, Action for Health in Diabetes Mellitus (Look AHEAD). Once demographics, medication use and baseline adiposity, and fitness were accounted for, ILI did not modify the baseline association of GCKR-Leu446Pro with elevated triglycerides (&bgr;±SE=0.067±0.013, P=1.5×10−7 and &bgr;±SE=0.052±0.015, P=5×10−4) or with elevated CRP (&bgr;±SE=0.136±0.034, P=5.1×10−5and &bgr;±SE=0.903±0.038, P=0.015) in the overall sample and Non-Hispanic Whites, respectively. The lack of a protective effect from ILI at 1 year when compared with diabetes mellitus support and education (ILI versus diabetes mellitus support and education interaction for triglyceride and CRP change, respectively: P=0.64 and 0.37 in the overall sample; P=0.27 and 0.05 in Non-Hispanic Whites) persisted after additional adjustment for changes in adiposity and fitness. Conclusions—Moderate improvements in adiposity and fitness with ILI did not mitigate the adverse cardiometabolic effects of GCKR inhibition in overweight/obese individuals with diabetes mellitus.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.115.001192","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Common and Rare Variants in SCN10A Modulate the Risk of Atrial Fibrillation","authors":"J. Jabbari, M. Olesen, Lei Yuan, J. Nielsen, Bo Liang, Vincenzo Macrì, I. Christophersen, Nikolaj Nielsen, A. Sajadieh, P. Ellinor, M. Grunnet, S. Haunsø, A. Holst, J. Svendsen, T. Jespersen","doi":"10.1161/CIRCGENETICS.113.000442","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.113.000442","url":null,"abstract":"Background—Genome-wide association studies have shown that the common single nucleotide polymorphism rs6800541 located in SCN10A, encoding the voltage-gated Nav1.8 sodium channel, is associated with PR-interval prolongation and atrial fibrillation (AF). Single nucleotide polymorphism rs6800541 is in high linkage disequilibrium with the nonsynonymous variant in SCN10A, rs6795970 (V1073A, r2=0.933). We therefore sought to determine whether common and rare SCN10A variants are associated with early onset AF. Methods and Results—SCN10A was sequenced in 225 AF patients in whom there was no evidence of other cardiovascular disease or dysfunction (lone AF). In an association study of the rs6795970 single nucleotide polymorphism variant, we included 515 AF patients and 2 control cohorts of 730 individuals free of AF and 6161 randomly sampled individuals. Functional characterization of SCN10A variants was performed by whole-cell patch-clamping. In the lone AF cohort, 9 rare missense variants and 1 splice site donor variant were detected. Interestingly, AF patients were found to have higher G allele frequency of rs6795970, which encodes the alanine variant at position 1073 (described from here on as A1073, odds ratio =1.35 [1.16−1.54]; P=2.3×10−5). Both of the common variants, A1073 and P1092, induced a gain-of-channel function, whereas the rare missense variants, V94G and R1588Q, resulted in a loss-of-channel function. Conclusions—The common variant A1073 is associated with increased susceptibility to AF. Both rare and common variants have effect on the function of the channel, indicating that these variants influence susceptibility to AF. Hence, our study suggests that SCN10A variations are involved in the genesis of AF.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.113.000442","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heart Failure: Genetic Epidemiology, Cardiomyopathies, and Biomarkers","authors":"","doi":"10.1161/CIRCGENETICS.112.963611","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.112.963611","url":null,"abstract":"The following articles are being highlighted as part of Circulation: Cardiovascular Genetics' Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in the Circulation portfolio and Circulation: Cardiovascular Genetics, in particular. The studies included in this article represent the most read manuscripts published on the topic of heart failure in 2010 and 2011.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2012-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.112.963611","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stroke: Etiology, Risk Factors, Imaging, and Genetic Epidemiology","authors":"","doi":"10.1161/CIRCGENETICS.112.963074","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.112.963074","url":null,"abstract":"The following articles are being highlighted as part of Circulation: Cardiovascular Genetics' Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in the Circulation portfolio and Circulation: Cardiovascular Genetics, in particular. The studies included in this article represent the most read manuscripts published on the topic of stroke in 2010 and 2011.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2012-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.112.963074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coronary Artery Disease Etiology, Genetic Epidemiology, and Pharmacogenomics","authors":"","doi":"10.1161/CIRCGENETICS.112.962779","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.112.962779","url":null,"abstract":"The following articles are being highlighted as part of Circulation: Cardiovascular Genetics' Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in the Circulation portfolio and Circulation: Cardiovascular Genetics, in particular. The studies included in this article represent the most read manuscripts published on the topic of coronary artery disease in 2010 and 2011.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2012-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.112.962779","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulation: Cardiovascular Genetics Editors' Picks Most Read Genome-Wide and Candidate Gene Association Studies","authors":"","doi":"10.1161/CIRCGENETICS.111.961524","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.111.961524","url":null,"abstract":"The following articles are being highlighted as part of Circulation: Cardiovascular Genetics' Topic Review series. This series will summarize the most important articles, as selected by the editors, published in Circulation: Cardiovascular Genetics and the rest of the Circulation portfolio. The articles included in this report represent the most read genome-wide and candidate gene association studies published in 2009 and 2010.","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2011-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.111.961524","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Summary of Recent Articles of Interest","authors":"W. Lieb, R. Vasan","doi":"10.1161/CIRCGENETICS.109.874875","DOIUrl":"https://doi.org/10.1161/CIRCGENETICS.109.874875","url":null,"abstract":"Received April 21, 2009; accepted April 21, 2009. \u0000\u00001. International Warfarin Pharmacogenetics Consortium; Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009;360:753–764. PMID: 19228618.\u0000\u0000### Study Hypothesis\u0000\u0000Interindividual variation in the response to warfarin therapy is in part determined by genetic factors. Specifically, variation in 2 genes, CYP2C9 (encoding cytochrome P450, family 2, subfamily C, and polypeptide 9) and VKORC1 (encodes vitamin K epoxide reductase complex subunit-1), are known to affect warfarin dose requirements. It is conceivable that an algorithm including genetic predictors in addition to clinical information improves warfarin dose estimation incrementally over algorithms based on clinical data alone.\u0000\u0000### How Was the Hypothesis Tested?\u0000\u0000Within the International Warfarin Pharmacogenetics Consortium, 5052 participants with a target international normalized ratio of 2 to 3 were selected for analyses. Of the eligible patients, 80% (n=4043) were randomly selected as the “derivation cohort,” the remaining 20% (n=1009) constituted the “validation cohort.” After evaluating different statistical models, a least-squares linear regression model (with the square root of warfarin dose as the dependent variable) best fit the data and was used for further analyses. Three models were compared in their ability to predict the therapeutic warfarin dose (defined as the steady-state dose leading to stable anticoagulation levels): a clinical model (including information about age, height, weight, race, enzyme inducer status, and Amiodarone use status), a fixed-dose model (5 mg per day), and a pharmacogenetic model that included CYP2C9 and VKORC1 genotypic information in addition to the above-described clinical covariates. Furthermore, the performance of the 3 algorithms was evaluated in 3 subgroups based on the weekly warfarin dose: ≤21, >21 and <49, and ≥49 mg per week. To evaluate the models’ predictive accuracy, the …","PeriodicalId":48940,"journal":{"name":"Circulation-Cardiovascular Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2008-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1161/CIRCGENETICS.109.874875","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64396730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}