1. In this genetic association study, among 209 537 participants, a protein-truncating variant (PTV) was identified in 0.4% of individuals, with an estimated untreated LDL cholesterol concentration of 32% to 37% lower in PTV carriers vs noncarriers.
2. The estimated coronary heart disease risk by age 75 was 3.7% in PTV carriers vs 7.0% in noncarriers.
Evidence Rating Level: 2 (Good)
Study Rundown: Coronary heart disease (CHD) is a leading cause of mortality often associated with high levels of low-density protein lipoprotein (LDL) cholesterol. Rare protein-truncating variants (PTVs) in the apolipoprotein B gene (APOB) or proprotein convertase subtilisin/kexin type 9 gene (PCSK9) are associated with lower levels of LDL cholesterol. The objective of this study was to evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk. A total of 19 073 US participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies, and 190 464 UK participants from the UK Biobank were included. The exposures of this study were PTVs in APOB and PCSK9, and the main outcomes were estimated untreated LDL cholesterol levels and CHD. Among the NHLBI participants,139 carried an APOB or PCSK9 PTV, which was associated with a 49 mg/dL lower estimated untreated LDL cholesterol level. The mean follow-up period was 21.5 years, at which incident CHD was observed in 8.6% of carriers vs 16.0% in noncarriers. Among the UK Biobank participants, 662 carried a PTV, which was associated with a 45 mg/dL lower estimated untreated LDL cholesterol level. The estimated CHD risk by age 75 was found to be 3.7% in carriers vs 7.0% in noncarriers. A major strength of this study was its large sample size. A limitation, however, was that due to the independent study design of each cohort, there were differences in recruitment criteria and defined CHD between groups.
Click to read the study in JAMA Cardiology
In-Depth [retrospective cohort]: This study evaluated the association of PTVs in the APOB and PCSK9 gene with LDL cholesterol levels and CHD risk. A total of 209 537 participants were included in this study, from 5 NHLBI studies (n = 19 073), and the UK Biobank (n = 209 537). Among the 19 073 NHLBI participants recruited between 1971 and 2002 (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. Among the 190 464 UK Biobank participants recruited between 2006 and 2010 (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 levels. The estimated risk of CHD by age 75 years was found to be 3.7% (95% CI, 2.0-5.3) in carriers vs 7.0% (95% CI, 6.9-7.2) in noncarriers, with an adjusted hazard ratio of 0.51 (95% CI, 0.32-0.81; P = .004). Interestingly, the associated reduction in estimated untreated LDL cholesterol was more pronounced in carriers of an APOB PTV, compared to those with a PCSK9 PTV with adjusted differences vs noncarriers of 74 mg/dL (95% CI, 60-87) and 43 mg/dL (95% CI, 36-50), respectively.
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