Shia T Kent, Robert S Rosenson, Christy L Avery, Yii-Der I Chen, Adolfo Correa, Steven R Cummings, L Adrienne Cupples, Mary Cushman, Daniel S Evans, Vilmundur Gudnason, Tamara B Harris, George Howard, Marguerite R Irvin, Suzanne E Judd, J Wouter Jukema, Leslie Lange, Emily B Levitan, Xiaohui Li, Yongmei Liu, Wendy S Post, Iris Postmus, Bruce M Psaty, Jerome I Rotter, Monika M Safford, Colleen M Sitlani, Albert V Smith, James D Stewart, Stella Trompet, Fangui Sun, Ramachandran S Vasan, J Michael Woolley, Eric A Whitsel, Kerri L Wiggins, James G Wilson, Paul Muntner
{"title":"PCSK9功能丧失变异、低密度脂蛋白胆固醇与冠心病和中风风险:来自黑人和白人的9项研究数据","authors":"Shia T Kent, Robert S Rosenson, Christy L Avery, Yii-Der I Chen, Adolfo Correa, Steven R Cummings, L Adrienne Cupples, Mary Cushman, Daniel S Evans, Vilmundur Gudnason, Tamara B Harris, George Howard, Marguerite R Irvin, Suzanne E Judd, J Wouter Jukema, Leslie Lange, Emily B Levitan, Xiaohui Li, Yongmei Liu, Wendy S Post, Iris Postmus, Bruce M Psaty, Jerome I Rotter, Monika M Safford, Colleen M Sitlani, Albert V Smith, James D Stewart, Stella Trompet, Fangui Sun, Ramachandran S Vasan, J Michael Woolley, Eric A Whitsel, Kerri L Wiggins, James G Wilson, Paul Muntner","doi":"10.1161/CIRCGENETICS.116.001632","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong><i>PCSK9</i> loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of <i>PCSK9</i> LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy.</p><p><strong>Methods and results: </strong>These 9 studies together included 17 459 blacks with 403 (2.3%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1%) having at least 1 R46L variant. Unadjusted odds ratios for associations between <i>PCSK9</i> LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, <i>PCSK9</i> LOF variants were associated with 35 mg/dL (95% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95% CI, 11-16) lower LDL-C in whites. <i>PCSK9</i> LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95% CI, 0.28-0.92) in blacks and 0.82 (95% CI, 0.63-1.06) in whites. <i>PCSK9</i> LOF variants were not associated with incident stroke (odds ratio, 0.84; 95% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95% CI, 0.80-1.41 in whites).</p><p><strong>Conclusions: </strong><i>PCSK9</i> LOF variants were associated with lower LDL-C and coronary heart disease incidence. <i>PCSK9</i> LOF variants were not associated with stroke risk.</p>","PeriodicalId":10277,"journal":{"name":"Circulation: Cardiovascular Genetics","volume":"10 4","pages":"e001632"},"PeriodicalIF":0.0000,"publicationDate":"2017-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729040/pdf/nihms889818.pdf","citationCount":"0","resultStr":"{\"title\":\"<i>PCSK9</i> Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites.\",\"authors\":\"Shia T Kent, Robert S Rosenson, Christy L Avery, Yii-Der I Chen, Adolfo Correa, Steven R Cummings, L Adrienne Cupples, Mary Cushman, Daniel S Evans, Vilmundur Gudnason, Tamara B Harris, George Howard, Marguerite R Irvin, Suzanne E Judd, J Wouter Jukema, Leslie Lange, Emily B Levitan, Xiaohui Li, Yongmei Liu, Wendy S Post, Iris Postmus, Bruce M Psaty, Jerome I Rotter, Monika M Safford, Colleen M Sitlani, Albert V Smith, James D Stewart, Stella Trompet, Fangui Sun, Ramachandran S Vasan, J Michael Woolley, Eric A Whitsel, Kerri L Wiggins, James G Wilson, Paul Muntner\",\"doi\":\"10.1161/CIRCGENETICS.116.001632\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong><i>PCSK9</i> loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of <i>PCSK9</i> LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy.</p><p><strong>Methods and results: </strong>These 9 studies together included 17 459 blacks with 403 (2.3%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1%) having at least 1 R46L variant. Unadjusted odds ratios for associations between <i>PCSK9</i> LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, <i>PCSK9</i> LOF variants were associated with 35 mg/dL (95% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95% CI, 11-16) lower LDL-C in whites. <i>PCSK9</i> LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95% CI, 0.28-0.92) in blacks and 0.82 (95% CI, 0.63-1.06) in whites. <i>PCSK9</i> LOF variants were not associated with incident stroke (odds ratio, 0.84; 95% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95% CI, 0.80-1.41 in whites).</p><p><strong>Conclusions: </strong><i>PCSK9</i> LOF variants were associated with lower LDL-C and coronary heart disease incidence. <i>PCSK9</i> LOF variants were not associated with stroke risk.</p>\",\"PeriodicalId\":10277,\"journal\":{\"name\":\"Circulation: Cardiovascular Genetics\",\"volume\":\"10 4\",\"pages\":\"e001632\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2017-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729040/pdf/nihms889818.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation: Cardiovascular Genetics\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCGENETICS.116.001632\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation: Cardiovascular Genetics","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1161/CIRCGENETICS.116.001632","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites.
Background: PCSK9 loss-of-function (LOF) variants allow for the examination of the effects of lifetime reduced low-density lipoprotein cholesterol (LDL-C) on cardiovascular events. We examined the association of PCSK9 LOF variants with LDL-C and incident coronary heart disease and stroke through a meta-analysis of data from 8 observational cohorts and 1 randomized trial of statin therapy.
Methods and results: These 9 studies together included 17 459 blacks with 403 (2.3%) having at least 1 Y142X or C679X variant and 31 306 whites with 955 (3.1%) having at least 1 R46L variant. Unadjusted odds ratios for associations between PCSK9 LOF variants and incident coronary heart disease (851 events in blacks and 2662 events in whites) and stroke (523 events in blacks and 1660 events in whites) were calculated using pooled Mantel-Haenszel estimates with continuity correction factors. Pooling results across studies using fixed-effects inverse-variance-weighted models, PCSK9 LOF variants were associated with 35 mg/dL (95% confidence interval [CI], 32-39) lower LDL-C in blacks and 13 mg/dL (95% CI, 11-16) lower LDL-C in whites. PCSK9 LOF variants were associated with a pooled odds ratio for coronary heart disease of 0.51 (95% CI, 0.28-0.92) in blacks and 0.82 (95% CI, 0.63-1.06) in whites. PCSK9 LOF variants were not associated with incident stroke (odds ratio, 0.84; 95% CI, 0.48-1.47 in blacks and odds ratio, 1.06; 95% CI, 0.80-1.41 in whites).
Conclusions: PCSK9 LOF variants were associated with lower LDL-C and coronary heart disease incidence. PCSK9 LOF variants were not associated with stroke risk.
期刊介绍：
Circulation: Genomic and Precision Medicine considers all types of original research articles, including studies conducted in human subjects, laboratory animals, in vitro, and in silico. Articles may include investigations of: clinical genetics as applied to the diagnosis and management of monogenic or oligogenic cardiovascular disorders; the molecular basis of complex cardiovascular disorders, including genome-wide association studies, exome and genome sequencing-based association studies, coding variant association studies, genetic linkage studies, epigenomics, transcriptomics, proteomics, metabolomics, and metagenomics; integration of electronic health record data or patient-generated data with any of the aforementioned approaches, including phenome-wide association studies, or with environmental or lifestyle factors; pharmacogenomics; regulation of gene expression; gene therapy and therapeutic genomic editing; systems biology approaches to the diagnosis and management of cardiovascular disorders; novel methods to perform any of the aforementioned studies; and novel applications of precision medicine. Above all, we seek studies with relevance to human cardiovascular biology and disease.
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