03674nas a2200457 4500008004100000022001400041245015600055210006900211260001600280520226600296100002402562700002302586700001602609700002102625700002402646700001802670700002102688700002402709700002202733700002002755700001602775700002702791700002002818700002202838700001902860700002702879700001702906700002302923700002102946700001702967700002002984700002203004700002203026700002303048700002603071700002103097700002003118700002303138700001903161856003603180 2023 eng d a2380-659100aAssociation of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease.0 aAssociation of Rare ProteinTruncating DNA Variants in APOB or PC c2023 Feb 013 a

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.

1 aDron, Jacqueline, S1 aPatel, Aniruddh, P1 aZhang, Yiyi1 aJurgens, Sean, J1 aMaamari, Dimitri, J1 aWang, Minxian1 aBoerwinkle, Eric1 aMorrison, Alanna, C1 ade Vries, Paul, S1 aFornage, Myriam1 aHou, Lifang1 aLloyd-Jones, Donald, M1 aPsaty, Bruce, M1 aTracy, Russell, P1 aBis, Joshua, C1 aVasan, Ramachandran, S1 aLevy, Daniel1 aHeard-Costa, Nancy1 aRich, Stephen, S1 aGuo, Xiuqing1 aTaylor, Kent, D1 aGibbs, Richard, A1 aRotter, Jerome, I1 aWiller, Cristen, J1 aOelsner, Elizabeth, C1 aMoran, Andrew, E1 aPeloso, Gina, M1 aNatarajan, Pradeep1 aKhera, Amit, V uhttps://chs-nhlbi.org/node/9285