| Title: | Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease |
| Journal: | JAMA Cardiology |
| Published: | 1 Mar 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/36723951/ |
| DOI: | https://doi.org/10.1001/jamacardio.2022.5271 |
| URL: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9996405 |
| Citations: | 10 (10 in last 2 years) as of 8 Aug 2024 |
Publication 11140
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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.</p>
Objective: To evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk.</p>
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.</p>
Exposures: PTVs in APOB and PCSK9.</p>
Main Outcomes and Measures: Estimated untreated LDL cholesterol levels and CHD.</p>
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).</p>
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.</p>
29 Authors
- Jacqueline S. Dron
- Aniruddh P. Patel
- Yiyi Zhang
- Sean J. Jurgens
- Dimitri J. Maamari
- Minxian Wang
- Eric Boerwinkle
- Alanna C. Morrison
- Paul S. de Vries
- Myriam Fornage
- Lifang Hou
- Donald M. Lloyd-Jones
- Bruce M. Psaty
- Russell P. Tracy
- Joshua C. Bis
- Ramachandran S. Vasan
- Daniel Levy
- Nancy Heard-Costa
- Stephen S. Rich
- Xiuqing Guo
- Kent D. Taylor
- Richard A. Gibbs
- Jerome I. Rotter
- Cristen J. Willer
- Elizabeth C. Oelsner
- Andrew E. Moran
- Gina M. Peloso
- Pradeep Natarajan
- Amit V. Khera
1 Application
| Application ID | Title |
|---|---|
| 7089 | Exome Sequencing of All Premature Coronary Artery Disease Participants in UK Biobank |
Enabling scientific discoveries that improve human health