Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 with Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease

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 GuoKent 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

Producción científica: Articlerevisión exhaustiva

7 Citas (Scopus)

Resumen

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 19073 NHLBI participants (10598 [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 18934 noncarriers (16.0%), corresponding to an adjusted hazard ratio of 0.51 (95% CI, 0.28-0.89; P =.02). Among 190464 UK Biobank participants (104831 [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 209537 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.

Idioma originalEnglish (US)
Páginas (desde-hasta)258-267
Número de páginas10
PublicaciónJAMA Cardiology
Volumen8
N.º3
DOI
EstadoPublished - mar 8 2023
Publicado de forma externa

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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