Pub Date : 2015-12-01DOI: 10.1161/CIRCGENETICS.115.001225
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
Background— Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood. Methods 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. Conclusions— 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.
吸烟是一个重要的心血管疾病危险因素，但吸烟与血压之间的联系机制尚不清楚。方法和结果:来自23项基于人群的研究的14317名参与者(62666名从不吸烟者，40669名戒烟者，37982名目前吸烟者)的数据被纳入观察性和孟德尔随机化荟萃分析，研究吸烟状况和吸烟严重程度与收缩压和舒张压、高血压和静息心率的关系。在孟德尔随机化分析中，基因变异rs16969968/rs1051730被用作当前吸烟者吸烟严重程度的代表。在观察性分析中，与从不吸烟相比，吸烟与较低的收缩压和舒张压以及较低的高血压风险相关，但与较高的静息心率相关。在当前吸烟者的观察性分析中，每天1支烟的吸烟严重程度与更高的(0.21 bpm;95%置信区间0.19;0.24)静息心率和稍高的舒张压(0.05 mm Hg;95%置信区间0.02;0.08 mm Hg)和收缩压(0.08 mm Hg;95%置信区间0.03;0.13)。然而，在目前吸烟者的孟德尔随机分析中，尽管rs16969968/rs1051730的每个吸烟增加等位基因都与较高的静息心率相关(0.36 bpm/等位基因;95%置信区间0.18;0.54)，与舒张压、收缩压或高血压无强相关性。这意味着每天抽20支烟的人心率要高出7 bpm。结论:这项孟德尔随机荟萃分析支持重度吸烟与较高静息心率水平的因果关系，但与血压无关。这些发现表明，吸烟的部分心血管风险可能是通过增加静息心率来实现的。
{"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":"8 1","pages":"832-841"},"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}
Pub Date : 2015-11-17DOI: 10.1161/CIRCGENETICS.115.001192
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
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.
{"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":"9 1","pages":"71–78"},"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}
Pub Date : 2015-02-01DOI: 10.1161/CIRCGENETICS.113.000442
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
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.
{"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":"8 1","pages":"64–73"},"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}
Pub Date : 2012-06-01DOI: 10.1161/CIRCGENETICS.112.963611
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.
{"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":"5 1","pages":"e15–e26"},"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}
Pub Date : 2012-04-01DOI: 10.1161/CIRCGENETICS.112.963074
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.
{"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":"5 1","pages":"e7–e12"},"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}
Pub Date : 2012-02-01DOI: 10.1161/CIRCGENETICS.112.962779
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.
{"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":"40 1","pages":"e1–e6"},"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}
Pub Date : 2011-10-01DOI: 10.1161/CIRCGENETICS.111.961524
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.
{"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":"4 1","pages":"e13–e19"},"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}
Pub Date : 2008-12-01DOI: 10.1161/CIRCGENETICS.109.874875
W. Lieb, R. Vasan
Received April 21, 2009; accepted April 21, 2009. 1. 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. ### Study Hypothesis Interindividual 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. ### How Was the Hypothesis Tested? Within 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 …
2009年4月21日收稿;2009年4月21日接受。1. 国际华法林药物遗传学协会;Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA。根据临床和药理学资料估计华法林的剂量。中华医学杂志。2009;36(1):753 - 764。PMID: 19228618。研究假设对华法林治疗反应的个体间差异部分是由遗传因素决定的。具体而言，已知CYP2C9(编码细胞色素P450，家族2，亚家族C和多肽9)和VKORC1(编码维生素K环氧化物还原酶复合物亚基-1)这两个基因的变异会影响华法林剂量需求。可以想象，一种除临床信息外还包括遗传预测因子的算法比仅基于临床数据的算法逐步改善华法林剂量估计。这个假设是如何检验的?在国际华法林药物遗传学联合会中，选择5052名参与者进行分析，目标国际标准化比例为2比3。在符合条件的患者中，随机选择80% (n=4043)为“衍生队列”，剩余20% (n=1009)为“验证队列”。在对不同的统计模型进行评估后，最小二乘线性回归模型(以华法林剂量的平方根为因变量)最适合数据，并用于进一步分析。我们比较了三种模型预测华法林治疗剂量(定义为稳定抗凝水平的稳态剂量)的能力:临床模型(包括年龄、身高、体重、种族、酶诱诱剂状态和胺碘酮使用状态等信息)、固定剂量模型(每天5mg)和药药学模型(除上述临床协变量外，还包括CYP2C9和VKORC1基因型信息)。此外，根据华法林周剂量≤21 mg、≤21 mg和<49 mg、≥49 mg /周3个亚组对3种算法的性能进行评估。为了评估模型的预测准确性，…
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