@article{700bdd8ff20a4bd2a7fe6a951f12d0f8,
title = "Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease",
abstract = "IMPORTANCE: Protein-truncating variants (PTVs) in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with significantly lower low-density lipoprotein (LDL) cholesterol concentrations. The association of these PTVs with coronary heart disease (CHD) warrants further characterization in large, multiracial prospective cohort studies.OBJECTIVE: To evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk.DESIGN, SETTING, AND PARTICIPANTS: This studied included participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies and the UK Biobank. NHLBI study participants aged 5 to 84 years were recruited between 1971 and 2002 across the US and underwent whole-genome sequencing. UK Biobank participants aged 40 to 69 years were recruited between 2006 and 2010 in the UK and underwent whole-exome sequencing. Data were analyzed from June 2021 to October 2022.EXPOSURES: PTVs in APOB and PCSK9.MAIN OUTCOMES AND MEASURES: Estimated untreated LDL cholesterol levels and CHD.RESULTS: Among 19 073 NHLBI participants (10 598 [55.6%] female; mean [SD] age, 52 [17] years), 139 (0.7%) carried an APOB or PCSK9 PTV, which was associated with 49 mg/dL (95% CI, 43-56) lower estimated untreated LDL cholesterol level. Over a median (IQR) follow-up of 21.5 (13.9-29.4) years, incident CHD was observed in 12 of 139 carriers (8.6%) vs 3029 of 18 934 noncarriers (16.0%), corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.28-0.89; P = .02). Among 190 464 UK Biobank participants (104 831 [55.0%] female; mean [SD] age, 57 [8] years), 662 (0.4%) carried a PTV, which was associated with 45 mg/dL (95% CI, 42-47) lower estimated untreated LDL cholesterol level. Estimated CHD risk by age 75 years was 3.7% (95% CI, 2.0-5.3) in carriers vs 7.0% (95% CI, 6.9-7.2) in noncarriers, corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.32-0.81; P = .004).CONCLUSIONS AND RELEVANCE: Among 209 537 individuals in this study, 0.4% carried an APOB or PCSK9 PTV that was associated with less exposure to LDL cholesterol and a 49% lower risk of CHD.",
keywords = "Adult, Aged, Apolipoproteins B/genetics, Cholesterol, LDL, Coronary Disease/epidemiology, DNA, Female, Humans, Male, Middle Aged, Proprotein Convertase 9/genetics, Prospective Studies",
author = "Dron, {Jacqueline S} and Patel, {Aniruddh P} and Yiyi Zhang and Jurgens, {Sean J} and Maamari, {Dimitri J} and Minxian Wang and Eric Boerwinkle and Morrison, {Alanna C} and {de Vries}, {Paul S} and Myriam Fornage and Lifang Hou and Lloyd-Jones, {Donald M} and Psaty, {Bruce M} and Tracy, {Russell P} and Bis, {Joshua C} and Vasan, {Ramachandran S} and Daniel Levy and Nancy Heard-Costa and Rich, {Stephen S} and Xiuqing Guo and Taylor, {Kent D} and Gibbs, {Richard A} and Rotter, {Jerome I} and Willer, {Cristen J} and Oelsner, {Elizabeth C} and Moran, {Andrew E} and Peloso, {Gina M} and Pradeep Natarajan and Khera, {Amit V}",
note = "Funding Information: Conflict of Interest Disclosures: Dr Patel has received grants from National Human Genome Research Institute and Harvard Catalyst during the conduct of the study. Dr Lloyd-Jones has received grants from the National Institutes of Health during the conduct of the study. Dr Psaty has received grants from the National Institutes of Health during the conduct of the study and serves on the steering committee of the Yale Open Data Access Project. Dr Tracy has received grants from the National Institutes of Health during the conduct of the study. Dr Ramachandran has received grants from the National Institutes of Health during the conduct of the study. Dr Rotter has received grants from the National Institutes of Health during the conduct of the study. Dr Willer and spouse are both employed by Regeneron Pharmaceuticals. Dr Oelsner has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Moran has received grants from the National Heart, Lung, and Blood Institute during the conduct of the study. Dr Peloso has received grants from the National Institutes of Health during the conduct of the study. Dr Natarajan has received grants from Amgen, Apple, Boston Scientific, Novartis, and AstraZeneca; personal fees from Apple, AstraZeneca, Novartis, Genentech/Roche, Allelica, Foresite Labs, and Blackstone Life Sciences; serves on the scientific advisory board for Esperion Therapeutics, geneXwell, and TenSixteen Bio; and Dr Natarajan{\textquoteright}s spouse is an employee and has equity at Vertex outside the submitted work. Dr Khera has received grants from the National Human Genome Research Institute and IBM Research as well as personal fees from Verve Therapeutics, Amgen, and Novartis during the conduct of the study; personal fees from Silence Therapeutics, Sarepta Therapeutics, Maze Therapeutics, Navitor Pharmaceuticals, MedGenome, Illumina, Korro Bio, Veritas International, Color Health, Third Rock Ventures, Foresite Labs, and Ambry outside the submitted work; and is a coinventor on a patent application for the use of imaging data in assessing body fat distribution and associated cardiometabolic risk. No other disclosures were reported. Publisher Copyright: {\textcopyright} 2023 American Medical Association. All rights reserved.",
year = "2023",
month = mar,
day = "8",
doi = "https://doi.org/10.1001/jamacardio.2022.5271",
language = "English",
volume = "8",
pages = "258--267",
journal = "JAMA Cardiology",
issn = "2380-6591",
publisher = "American Medical Association",
number = "3",
}