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

• Type of Material: Article
• Authors: Aeron M. Small, Corporal Michael J Crescenz VA Medical Center; Jennifer E. Huffman, VA Boston Healthcare System; Derek Klarin, Boston VA Healthcare System; Julie A. Lynch, Salt Lake City Health Care System; Themistocles Assimes, VA Palo Alto Health Care System; Scott DuVall, Salt Lake City Health Care System; Yan Sun, Emory University; Labiba Shere, VA Palo Alto Health Care System; Pradeep Natarajan, Boston VA Healthcare System; Michael Gaziano, Boston VA Healthcare System; Daniel J. Rader, University of Pennsylvania; Peter Wilson, Emory University; Philip S. Tsao, VA Palo Alto Health Care System; Kyong-Mi Chang, Corporal Michael J Crescenz VA Medical Center; Kelly Cho, Boston VA Healthcare System; Christopher J. O'Donnell, Boston VA Healthcare System; Juan P. Casas, Boston VA Healthcare System; Scott M. Damrauer, Corporal Michael J Crescenz VA Medical Center
• Language: English
• Date: 2020-11-09
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose
• License: Creative Commons Universal : Public Domain Dedication
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0239752
• Title of Journal or Parent Work: PLOS ONE
• Volume: 15
• Issue: 11
• Start Page: e0239752
• End Page: e0239752
• Grant/Funding Information: This work was supported by funding from the Department of Veterans Affairs (VA) Office of Research and Development for the Million Veteran Program Grant #MVP000 and three additional awards (I01-01BX03340 [Cho/Wilson], I01-BX003362 [Tsao/Chang], and I01-CX001025 [Wilson]). Dr. Damrauer is supported by the VA Clinical Sciences Research and Development Career Development Award [IK2-CX001780].
• Keywords: RISK; Science & Technology - Other Topics; EVOLOCUMAB; ASSOCIATION; VARIANTS; CHOLESTEROL; Multidisciplinary Sciences; Science & Technology; ABDOMINAL AORTIC-ANEURYSM
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Background Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized. Methods 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. Results 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). Conclusions Genetically reduced PCSK9 function results in a reduction in risk of several important extracoronary 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.