TY - JOUR
T1 - Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 with Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease
AU - Dron, Jacqueline S.
AU - Patel, Aniruddh P.
AU - Zhang, Yiyi
AU - Jurgens, Sean J.
AU - Maamari, Dimitri J.
AU - Wang, Minxian
AU - Boerwinkle, Eric
AU - Morrison, Alanna C.
AU - De Vries, Paul S.
AU - Fornage, Myriam
AU - Hou, Lifang
AU - Lloyd-Jones, Donald M.
AU - Psaty, Bruce M.
AU - Tracy, Russell P.
AU - Bis, Joshua C.
AU - Vasan, Ramachandran S.
AU - Levy, Daniel
AU - Heard-Costa, Nancy
AU - Rich, Stephen S.
AU - Guo, Xiuqing
AU - Taylor, Kent D.
AU - Gibbs, Richard A.
AU - Rotter, Jerome I.
AU - Willer, Cristen J.
AU - Oelsner, Elizabeth C.
AU - Moran, Andrew E.
AU - Peloso, Gina M.
AU - Natarajan, Pradeep
AU - Khera, Amit V.
N1 - Publisher Copyright:
© 2023 American Medical Association. All rights reserved.
PY - 2023/3/8
Y1 - 2023/3/8
N2 - 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.
AB - 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.
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U2 - 10.1001/jamacardio.2022.5271
DO - 10.1001/jamacardio.2022.5271
M3 - Article
C2 - 36723951
AN - SCOPUS:85149948080
SN - 2380-6583
VL - 8
SP - 258
EP - 267
JO - JAMA Cardiology
JF - JAMA Cardiology
IS - 3
ER -