期刊
NATURE GENETICS
卷 49, 期 12, 页码 1758-+出版社
NATURE PORTFOLIO
DOI: 10.1038/ng.3977
关键词
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资金
- National Human Genome Research Institute of the National Institute of Health [R01HG008983]
- National Institute of Drug Abuse of the National Institute of Health [R21DA040177, R01DA037904]
- National Heart, Lung, and Blood Institute of the National Institutes of Health [K01HL125751]
- Stanley J. Sarnoff Cardiovascular Research Foundation
- Japanese Circulation Society
- National Institute for Health Research (NIHR) Exeter Clinical Research Facility
- ERC [323195, SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC]
- NIH [R01 DK106621, R01 DK107904, HL117491, HL129778, HL122684, HL094535, HL109946, R01 HL127564, R33 HL120781]
- University of Michigan Biological Sciences Scholars Program
- University of Michigan Department of Internal Medicine
- ERC Advanced Principal Investigator award
- Wellcome Trust Senior Fellow in Basic Biomedical Science [WT098017]
- NHLBI R21 from the NIH [HL121422-02]
- Medical Research Council, UK [MC_UU_12015/1]
- British Heart Foundation
- European Research Council Senior Investigator
- National Institute for Health Research (NIHR) Senior Investigator
- Massachusetts General Hospital
- Donovan Family Foundation
- MRC [MC_PC_14089, G9521010, MR/L003120/1, MR/P02811X/1, MC_PC_U127561128, MR/N005813/1, MC_UU_12015/1, G0600237, G0601261, MR/P013880/1, MR/M009203/1, MC_EX_MR/M009203/1] Funding Source: UKRI
- British Heart Foundation [RG/14/5/30893, RG/08/014/24067, RG/16/4/32218] Funding Source: researchfish
- Medical Research Council [MC_PC_13046, MR/P02811X/1, G9521010, MR/K026992/1, MR/N005813/1, MR/P013880/1, MC_UU_12015/1, G0601261, MC_PC_14089, MR/K006584/1, MR/M009203/1, G0600237, MR/L003120/1, MC_PC_13048, MC_EX_MR/M009203/1, MC_PC_U127561128] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10059, NF-SI-0611-10099, NF-SI-0512-10165, NF-SI-0512-10135, NF-SI-0512-10113] Funding Source: researchfish
- NNF Center for Basic Metabolic Research [Grarup Group] Funding Source: researchfish
- Novo Nordisk Fonden [NNF14OC0009819] Funding Source: researchfish
- Steno Diabetes Center Copenhagen (SDCC) [SDCC 3.A Complications] Funding Source: researchfish
- European Research Council (ERC) [323195] Funding Source: European Research Council (ERC)
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
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