Genetic Architecture and Clinical Outcomes of Combined Lipid Disturbances.

Autor:	Gilliland T; Cardiovascular Research Center (T.G., M.S.S., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.), Massachusetts General Hospital, Boston, MA.; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (T.G., J.S.D., M.S.S., M.T., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.).; Department of Medicine, Harvard Medical School, Boston, MA (T.G., M.S.S., K.P., S.M.U., M.C.H., P.N.)., Dron JS; Center for Genomic Medicine (J.S.D., P.N.), Massachusetts General Hospital, Boston, MA.; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (T.G., J.S.D., M.S.S., M.T., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.)., Selvaraj MS; Cardiovascular Research Center (T.G., M.S.S., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.), Massachusetts General Hospital, Boston, MA.; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (T.G., J.S.D., M.S.S., M.T., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.).; Department of Medicine, Harvard Medical School, Boston, MA (T.G., M.S.S., K.P., S.M.U., M.C.H., P.N.)., Trinder M; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (T.G., J.S.D., M.S.S., M.T., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.).; Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada (M.T.)., Paruchuri K; Cardiovascular Research Center (T.G., M.S.S., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.), Massachusetts General Hospital, Boston, MA.; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (T.G., J.S.D., M.S.S., M.T., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.).; Department of Medicine, Harvard Medical School, Boston, MA (T.G., M.S.S., K.P., S.M.U., M.C.H., P.N.)., Urbut SM; Cardiovascular Research Center (T.G., M.S.S., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.), Massachusetts General Hospital, Boston, MA.; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (T.G., J.S.D., M.S.S., M.T., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.).; Department of Medicine, Harvard Medical School, Boston, MA (T.G., M.S.S., K.P., S.M.U., M.C.H., P.N.)., Haidermota S; Cardiovascular Research Center (T.G., M.S.S., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.), Massachusetts General Hospital, Boston, MA.; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (T.G., J.S.D., M.S.S., M.T., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.)., Bernardo R; Cardiovascular Research Center (T.G., M.S.S., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.), Massachusetts General Hospital, Boston, MA.; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (T.G., J.S.D., M.S.S., M.T., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.)., Uddin MM; Cardiovascular Research Center (T.G., M.S.S., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.), Massachusetts General Hospital, Boston, MA.; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (T.G., J.S.D., M.S.S., M.T., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.)., Honigberg MC; Cardiovascular Research Center (T.G., M.S.S., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.), Massachusetts General Hospital, Boston, MA.; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (T.G., J.S.D., M.S.S., M.T., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.).; Department of Medicine, Harvard Medical School, Boston, MA (T.G., M.S.S., K.P., S.M.U., M.C.H., P.N.)., Peloso GM; Department of Biostatistics, Boston University School of Public Health, Boston, MA (G.M.P.)., Natarajan P; Cardiovascular Research Center (T.G., M.S.S., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.), Massachusetts General Hospital, Boston, MA.; Center for Genomic Medicine (J.S.D., P.N.), Massachusetts General Hospital, Boston, MA.; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA (T.G., J.S.D., M.S.S., M.T., K.P., S.M.U., S.H., R.B., M.M.U., M.C.H., P.N.).; Department of Medicine, Harvard Medical School, Boston, MA (T.G., M.S.S., K.P., S.M.U., M.C.H., P.N.).
Jazyk:	angličtina
Zdroj:	Circulation research [Circ Res] 2024 Jul 05; Vol. 135 (2), pp. 265-276. Date of Electronic Publication: 2024 Jun 03.
DOI:	10.1161/CIRCRESAHA.123.323973
Abstrakt:	Background: Dyslipoproteinemia often involves simultaneous derangements of multiple lipid traits. We aimed to evaluate the phenotypic and genetic characteristics of combined lipid disturbances in a general population-based cohort. Methods: Among UK Biobank participants without prevalent coronary artery disease, we used blood lipid and apolipoprotein B concentrations to ascribe individuals into 1 of 6 reproducible and mutually exclusive dyslipoproteinemia subtypes. Incident coronary artery disease risk was estimated for each subtype using Cox proportional hazards models. Phenome-wide analyses and genome-wide association studies were performed for each subtype, followed by in silico causal gene prioritization and heritability analyses. Additionally, the prevalence of disruptive variants in causal genes for Mendelian lipid disorders was assessed using whole-exome sequence data. Results: Among 450 636 UK Biobank participants: 63 (0.01%) had chylomicronemia; 40 005 (8.9%) had hypercholesterolemia; 94 785 (21.0%) had combined hyperlipidemia; 13 998 (3.1%) had remnant hypercholesterolemia; 110 389 (24.5%) had hypertriglyceridemia; and 49 (0.01%) had mixed hypertriglyceridemia and hypercholesterolemia. Over a median (interquartile range) follow-up of 11.1 (10.4-11.8) years, incident coronary artery disease risk varied across subtypes, with combined hyperlipidemia exhibiting the largest hazard (hazard ratio, 1.92 [95% CI, 1.84-2.01]; P =2×10 -16 ), even when accounting for non-HDL-C (hazard ratio, 1.45 [95% CI, 1.30-1.60]; P =2.6×10 -12 ). Genome-wide association studies revealed 250 loci significantly associated with dyslipoproteinemia subtypes, of which 72 (28.8%) were not detected in prior single lipid trait genome-wide association studies. Mendelian lipid variant carriers were rare (2.0%) among individuals with dyslipoproteinemia, but polygenic heritability was high, ranging from 23% for remnant hypercholesterolemia to 54% for combined hyperlipidemia. Conclusions: Simultaneous assessment of multiple lipid derangements revealed nuanced differences in coronary artery disease risk and genetic architectures across dyslipoproteinemia subtypes. These findings highlight the importance of looking beyond single lipid traits to better understand combined lipid and lipoprotein phenotypes and implications for disease risk. Competing Interests: P. Natarajan reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech/ Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Foresite Labs, Genentech/ Roche, GV, HeartFlow, Magnet Biomedicine, Merck, and Novartis, scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio, scientific co-founder of TenSixteen Bio, equity in MyOme, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the resent work. The other authors report no conflicts.
Databáze:	MEDLINE
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