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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Article numbere001632
JournalCirculation: Cardiovascular Genetics
Volume10
Issue number4
DOIs
StatePublished - Aug 1 2017

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LDL Cholesterol
Coronary Disease
Stroke
Confidence Intervals
Odds Ratio
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Meta-Analysis
hydroquinone
Incidence

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Cite this

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

In: Circulation: Cardiovascular Genetics, Vol. 10, No. 4, e001632, 01.08.2017.

Research output: Contribution to journalArticle

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
Kent, Shia T. ; Rosenson, Robert S. ; Avery, Christy L. ; Chen, Yii Der I. ; Correa, Adolfo ; Cummings, Steven R. ; Cupples, L. Adrienne ; Cushman, Mary ; Evans, Daniel S. ; Gudnason, Vilmundur ; Harris, Tamara B. ; Howard, George ; Irvin, Marguerite R. ; Judd, Suzanne E. ; Jukema, J. Wouter ; Lange, Leslie ; Levitan, Emily B. ; Li, Xiaohui ; Liu, Yongmei ; Post, Wendy S. ; Postmus, Iris ; Psaty, Bruce M. ; Rotter, Jerome I. ; Safford, Monika M. ; Sitlani, Colleen M. ; Smith, Albert V. ; Stewart, James D. ; Trompet, Stella ; Sun, Fangui ; Vasan, Ramachandran S. ; Woolley, J. Michael ; Whitsel, Eric A. ; Wiggins, Kerri L. ; Wilson, James G. ; Muntner, Paul. / 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. In: Circulation: Cardiovascular Genetics. 2017 ; Vol. 10, No. 4.
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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",
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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

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

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U2 - 10.1161/CIRCGENETICS.116.001632

DO - 10.1161/CIRCGENETICS.116.001632

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AN - SCOPUS:85028950463

VL - 10

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

SN - 1942-325X

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