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

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

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

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. PostIris 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

School of Medicine

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

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.

Original language	English (US)
Article number	e001632
Journal	Circulation: Cardiovascular Genetics
Volume	10
Issue number	4
DOIs	https://doi.org/10.1161/CIRCGENETICS.116.001632
State	Published - Aug 1 2017

Keywords

goals
incidence
lipoproteins, LDL
meta-analysis
myocardial infarction
polymorphism, single nucleotide
stroke

ASJC Scopus subject areas

Genetics
Cardiology and Cardiovascular Medicine
Genetics(clinical)

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10.1161/CIRCGENETICS.116.001632

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Kent, S. T., Rosenson, R. S., Avery, C. L., Chen, Y. D. I., Correa, A., Cummings, S. R., Cupples, L. A., Cushman, M., Evans, D. S., Gudnason, V., Harris, T. B., Howard, G., Irvin, M. R., Judd, S. E., Jukema, J. W., Lange, L., Levitan, E. B., Li, X., Liu, Y., ... Muntner, P. (2017). 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. Circulation: Cardiovascular Genetics, 10(4), Article e001632. https://doi.org/10.1161/CIRCGENETICS.116.001632

Kent, ST, Rosenson, RS, Avery, CL, Chen, YDI, Correa, A, Cummings, SR, Cupples, LA, Cushman, M, Evans, DS, Gudnason, V, Harris, TB, Howard, G, Irvin, MR, Judd, SE, Jukema, JW, Lange, L, Levitan, EB, Li, X, Liu, Y, Post, WS, Postmus, I, Psaty, BM, Rotter, JI, Safford, MM, Sitlani, CM, Smith, AV, Stewart, JD, Trompet, S, Sun, F, Vasan, RS, Woolley, JM, Whitsel, EA, Wiggins, KL, Wilson, JG & Muntner, P 2017, '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', Circulation: Cardiovascular Genetics, vol. 10, no. 4, e001632. https://doi.org/10.1161/CIRCGENETICS.116.001632

@article{1dcbba5b556849d9b7a4bb00957a27f5,

title = "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",

abstract = "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.",

keywords = "goals, incidence, lipoproteins, LDL, meta-analysis, myocardial infarction, polymorphism, single nucleotide, stroke",

author = "Kent, {Shia T.} and Rosenson, {Robert S.} and Avery, {Christy L.} and Chen, {Yii Der I.} and Adolfo Correa and Cummings, {Steven R.} and Cupples, {L. Adrienne} and Mary Cushman and Evans, {Daniel S.} and Vilmundur Gudnason and Harris, {Tamara B.} and George Howard and Irvin, {Marguerite R.} and Judd, {Suzanne E.} and Jukema, {J. Wouter} and Leslie Lange and Levitan, {Emily B.} and Xiaohui Li and Yongmei Liu and Post, {Wendy S.} and Iris Postmus and Psaty, {Bruce M.} and Rotter, {Jerome I.} and Safford, {Monika M.} and Sitlani, {Colleen M.} and Smith, {Albert V.} and Stewart, {James D.} and Stella Trompet and Fangui Sun and Vasan, {Ramachandran S.} and Woolley, {J. Michael} and Whitsel, {Eric A.} and Wiggins, {Kerri L.} and Wilson, {James G.} and Paul Muntner",

note = "Funding Information: AGES Study (Age, Gene, Environment, Susceptibility - Reykjavik): This study has been funded by the National Institutes of Health (NIH) contracts N01-AG-1-2100 and HHSN27120120022C, the National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee (VSN 00-063). The researchers are indebted to the participants for their willingness to participate in the study. ARIC Study (Atherosclerosis Risk in Communities): The Atherosclerosis Risk in Communities Study is performed as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100 009C, HHSN268201100010C, HHSN268201100011C, and HHSN26 8201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. Cardiovascular Health Study: This Cardiovascular Health Study research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC850 80, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and NHLBI grants R01HL085251, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL130114, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from the NIA. A full list of principal Cardiovascular Health Study investigators and institutions can be found at Cardiovascular Health Study-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, Clinical and Translational Science Institute grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. FHS (Framingham Heart Study): This research was conducted in part using data and resources from the FHS of the NHLBI and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the FHS investigators participating in the SHARe project (SNP Health Association Resource). This work was partially supported by the NHLBI{\textquoteright}s FHS (contract no. N01-HC-25195 and HHSN268201500001I) and an NHLBI contract with Affymetrix, Inc, for genotyping services (contract no. N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Additional support for these analyses was provided by R01HL103612 (PI Dr Psaty, subcontract PI Dr Vasan). Health Aging and Body Composition (Health ABC) study: The Health ABC study was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences, and genotyping services were provided by the Center for Inherited Disease Research. Center for Inherited Disease Research is fully funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, NIA. JHS (Jackson Heart Study): The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268 201300050C from the NHLBI and the National Institute on Minority Health and Health Disparities. Multi-Ethnic Study of Atherosclerosis (MESA): MESA is supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and by grants UL1-TR-000040 and UL1-TR-001079 from the National Center for Research Resources/National Center for Advancing Translational Sciences. UL1-RR-024156. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, Clinical and Translational Science Institute grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http:// www.mesa-nhlbi.org and http://www.mesa-nhlbi.org/. PROSPER (Prospective Study of Pravastatin in the Elderly at Risk for Vascular Disease): PROSPER was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Prof Dr Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh frame-work program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). REGARDS study (Reasons for Geographic and Racial Differences in Stroke): The REGARDS study is supported by a cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Service. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health. Additional REGARDS study funding was provided by grants R01-HL80477 and K24-HL111154 from the National, Heart, Lung and Blood Institute to Dr Safford. We thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS study investigators and institutions can be found at http://www.regardsstudy.org. The genotyping of PCSK9 variants in the REGARDS study was funded by an academic/industry collaboration between UAB, Mount Sinai School of Medicine, and Amgen, Inc. Publisher Copyright: {\textcopyright} 2017 American Heart Association, Inc.",

year = "2017",

month = aug,

day = "1",

doi = "10.1161/CIRCGENETICS.116.001632",

language = "English (US)",

volume = "10",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams and Wilkins Ltd.",

number = "4",

}

TY - JOUR

T1 - PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke

T2 - Data from 9 Studies of Blacks and Whites

AU - Kent, Shia T.

AU - Rosenson, Robert S.

AU - Avery, Christy L.

AU - Chen, Yii Der I.

AU - Correa, Adolfo

AU - Cummings, Steven R.

AU - Cupples, L. Adrienne

AU - Cushman, Mary

AU - Evans, Daniel S.

AU - Gudnason, Vilmundur

AU - Harris, Tamara B.

AU - Howard, George

AU - Irvin, Marguerite R.

AU - Judd, Suzanne E.

AU - Jukema, J. Wouter

AU - Lange, Leslie

AU - Levitan, Emily B.

AU - Li, Xiaohui

AU - Liu, Yongmei

AU - Post, Wendy S.

AU - Postmus, Iris

AU - Psaty, Bruce M.

AU - Rotter, Jerome I.

AU - Safford, Monika M.

AU - Sitlani, Colleen M.

AU - Smith, Albert V.

AU - Stewart, James D.

AU - Trompet, Stella

AU - Sun, Fangui

AU - Vasan, Ramachandran S.

AU - Woolley, J. Michael

AU - Whitsel, Eric A.

AU - Wiggins, Kerri L.

AU - Wilson, James G.

AU - Muntner, Paul

N1 - Funding Information: AGES Study (Age, Gene, Environment, Susceptibility - Reykjavik): This study has been funded by the National Institutes of Health (NIH) contracts N01-AG-1-2100 and HHSN27120120022C, the National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee (VSN 00-063). The researchers are indebted to the participants for their willingness to participate in the study. ARIC Study (Atherosclerosis Risk in Communities): The Atherosclerosis Risk in Communities Study is performed as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100 009C, HHSN268201100010C, HHSN268201100011C, and HHSN26 8201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. Cardiovascular Health Study: This Cardiovascular Health Study research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC850 80, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and NHLBI grants R01HL085251, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL130114, and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01AG023629 from the NIA. A full list of principal Cardiovascular Health Study investigators and institutions can be found at Cardiovascular Health Study-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, Clinical and Translational Science Institute grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. FHS (Framingham Heart Study): This research was conducted in part using data and resources from the FHS of the NHLBI and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the FHS investigators participating in the SHARe project (SNP Health Association Resource). This work was partially supported by the NHLBI’s FHS (contract no. N01-HC-25195 and HHSN268201500001I) and an NHLBI contract with Affymetrix, Inc, for genotyping services (contract no. N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Additional support for these analyses was provided by R01HL103612 (PI Dr Psaty, subcontract PI Dr Vasan). Health Aging and Body Composition (Health ABC) study: The Health ABC study was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences, and genotyping services were provided by the Center for Inherited Disease Research. Center for Inherited Disease Research is fully funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, NIA. JHS (Jackson Heart Study): The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, and HHSN268 201300050C from the NHLBI and the National Institute on Minority Health and Health Disparities. Multi-Ethnic Study of Atherosclerosis (MESA): MESA is supported by the NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and by grants UL1-TR-000040 and UL1-TR-001079 from the National Center for Research Resources/National Center for Advancing Translational Sciences. UL1-RR-024156. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, Clinical and Translational Science Institute grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http:// www.mesa-nhlbi.org and http://www.mesa-nhlbi.org/. PROSPER (Prospective Study of Pravastatin in the Elderly at Risk for Vascular Disease): PROSPER was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Prof Dr Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh frame-work program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). REGARDS study (Reasons for Geographic and Racial Differences in Stroke): The REGARDS study is supported by a cooperative agreement U01 NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Service. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health. Additional REGARDS study funding was provided by grants R01-HL80477 and K24-HL111154 from the National, Heart, Lung and Blood Institute to Dr Safford. We thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS study investigators and institutions can be found at http://www.regardsstudy.org. The genotyping of PCSK9 variants in the REGARDS study was funded by an academic/industry collaboration between UAB, Mount Sinai School of Medicine, and Amgen, Inc. Publisher Copyright: © 2017 American Heart Association, Inc.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

KW - goals

KW - incidence

KW - lipoproteins, LDL

KW - meta-analysis

KW - myocardial infarction

KW - polymorphism, single nucleotide

KW - stroke

UR - http://www.scopus.com/inward/record.url?scp=85028950463&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85028950463&partnerID=8YFLogxK

U2 - 10.1161/CIRCGENETICS.116.001632

DO - 10.1161/CIRCGENETICS.116.001632

M3 - Article

C2 - 28768753

AN - SCOPUS:85028950463

SN - 1942-325X

VL - 10

JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

IS - 4

M1 - e001632

ER -

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

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