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

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.

• 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
• Journal: Circulation. Cardiovascular genetics (Circ Cardiovasc Genet) Vol. 10 Issue 4 Pg. e001632 (Aug 2017) ISSN: 1942-3268 [Electronic] United States
• PMID: 28768753 (Publication Type: Journal Article)
• Copyright: © 2017 American Heart Association, Inc.

Chemical References

• Cholesterol, LDL
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• PCSK9 protein, human
• Proprotein Convertase 9

Topics

• Aged
• Aged, 80 and over
• Black People (genetics)
• Cholesterol, LDL (blood)
• Cohort Studies
• Coronary Disease (genetics, pathology, prevention & control)
• Female
• Genetic Variation
• Genotype
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Male
• Odds Ratio
• Polymorphism, Single Nucleotide
• Proportional Hazards Models
• Proprotein Convertase 9 (genetics)
• Risk Factors
• Stroke (genetics, pathology)
• White People (genetics)