PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort

• Published in: PloS one Vol. 15; no. 11; p. e0239752
• Main Authors: Small, Aeron M., Huffman, Jennifer E., Klarin, Derek, Lynch, Julie A., Assimes, Themistocles, DuVall, Scott, Sun, Yan V., Shere, Labiba, Natarajan, Pradeep, Gaziano, Michael, Rader, Daniel J., Wilson, Peter W. F., Tsao, Philip S., Chang, Kyong-Mi, Cho, Kelly, O’Donnell, Christopher J., Casas, Juan P., Damrauer, Scott M.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.11.2020; Public Library of Science (PLoS)
• Subjects: Aorta; Arteriosclerosis; Atherosclerosis; Biology and Life Sciences; Cardiovascular disease; Cardiovascular diseases; Cholesterol; Cholesterol, LDL - blood; Chronic obstructive pulmonary disease; Cognitive ability; Cognitive Dysfunction - genetics; Coronary artery; Coronary artery disease; Coronary Artery Disease - genetics; Coronary Artery Disease - prevention & control; Coronary heart disease; Dementia disorders; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Electronic health records; Electronic medical records; Epidemiology; Female; Genetic aspects; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study; Health aspects; Health care policy; Health risk assessment; Health risks; Heart diseases; Hispanic people; Hospitals; Humans; Informatics; Ischemia; Ischemic Stroke - genetics; Ischemic Stroke - prevention & control; Lipids; Loss of Function Mutation - genetics; Low density lipoprotein; Lung cancer; Lung diseases; Male; Medical schools; Medicine; Medicine and Health Sciences; Nucleotides; Obstructive lung disease; People and Places; Phenotypes; Physical Sciences; Polymorphism, Single Nucleotide - genetics; Proprotein Convertase 9 - genetics; Quality control; Research and Analysis Methods; Risk; Risk factors; Risk management; Signaling peptides and proteins; Single-nucleotide polymorphism; Standard deviation; Triglycerides; Vascular dementia; Vascular diseases; Veterans; United States; Atlanta Georgia; Palo Alto California; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0239752

Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized. We created a genetic risk score (GRS) for PCSK9 using four single nucleotide polymorphisms (SNPs) at or near the PCSK9 locus known to impact lower LDL-Cholesterol (LDL-C): rs11583680, rs11591147, rs2479409, and rs11206510. We then used our GRS to calculate weighted odds ratios reflecting the impact of a genetically determined 10 mg/dL decrease in LDL-C on several pre-specified phenotypes including CAD, IS, peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), type 2 diabetes, dementia, chronic obstructive pulmonary disease, and cancer. Finally, we used our weighted GRS to perform a phenome-wide association study. Genetic and electronic health record data that passed quality control was available in 312,097 individuals, (227,490 White participants, 58,907 Black participants, and 25,700 Hispanic participants). PCSK9 mediated reduction in LDL-C was associated with a reduced risk of CAD and AAA in trans-ethnic meta-analysis (CAD OR 0.83 [95% CI 0.80-0.87], p = 6.0 x 10-21; AAA OR 0.76 [95% CI 0.68-0.86], p = 2.9 x 10-06). Significant protective effects were noted for PAD in White individuals (OR 0.83 [95% CI 0.71-0.97], p = 2.3 x 10-04) but not in other genetic ancestries. Genetically reduced PCSK9 function associated with a reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86 [95% CI 0.78-0.93], p = 5.0 x 10-04). Genetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and IS, including PAD and AAA. We also highlight a novel reduction in risk of dementia, supporting a well-recognized vascular component to cognitive impairment and an opportunity for therapeutic repositioning.