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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Kent, Shia T.; Rosenson, Robert S.; Avery, Christy L.; Chen, Yii-Der Ida; Correa, Adolfo; Cummings, Steven R.; Cupples, L. Adrienne; Cushman, Mary; Evans, Daniel S.; & Gudnason, Vilmundur G., et al. (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), e001632. PMCID: PMC5729040

Abstract

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.

URL

http://dx.doi.org/10.1161/circgenetics.116.001632

Reference Type

Journal Article

Year Published

2017

Journal Title

Circulation: Cardiovascular Genetics

Author(s)

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

PMCID

PMC5729040

ORCiD

Avery - 0000-0002-1044-8162