TY - JOUR
T1 - Exome-wide association study of plasma lipids in >300,000 individuals
AU - Liu, Dajiang J
AU - Peloso, Gina M
AU - Yu, Haojie
AU - Butterworth, Adam S
AU - Wang, Xiao
AU - Mahajan, Anubha
AU - Saleheen, Danish
AU - Emdin, Connor
AU - Alam, Dewan
AU - Alves, Alexessander Couto
AU - Amouyel, Philippe
AU - Di Angelantonio, Emanuele
AU - Arveiler, Dominique
AU - Assimes, Themistocles L
AU - Auer, Paul L
AU - Baber, Usman
AU - Ballantyne, Christie M
AU - Bang, Lia E
AU - Benn, Marianne
AU - Bis, Joshua C
AU - Boehnke, Michael
AU - Boerwinkle, Eric
AU - Bork-Jensen, Jette
AU - Bottinger, Erwin P
AU - Brandslund, Ivan
AU - Brown, Morris
AU - Busonero, Fabio
AU - Caulfield, Mark J
AU - Chambers, John C
AU - Chasman, Daniel I
AU - Chen, Y Eugene
AU - Chen, Yii-Der Ida
AU - Chowdhury, Rajiv
AU - Christensen, Cramer
AU - Chu, Audrey Y
AU - Connell, John M
AU - Frikke-Schmidt, Ruth
AU - Jensen, Gorm B
AU - Jørgensen, Marit E
AU - Kamstrup, Pia R
AU - Langsted, Anne
AU - Linneberg, Allan
AU - Nielsen, Jonas B
AU - Nielsen, Sune F
AU - Nordestgaard, Børge G
AU - Pisinger, Charlotta
AU - Tybjaerg-Hansen, Anne
AU - Varbo, Anette
AU - Wareham, Nick J
AU - Weeke, Peter E
AU - Charge Diabetes Working Group
AU - The EPIC-InterAct Consortium
AU - EPIC-CVD Consortium
AU - GOLD Consortium
AU - VA Million Veteran Program
PY - 2017
Y1 - 2017
N2 - 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-density-lipoprotein 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.
AB - 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-density-lipoprotein 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.
KW - Journal Article
UR - https://www.scopus.com/pages/publications/85035766416
U2 - 10.1038/ng.3977
DO - 10.1038/ng.3977
M3 - Journal article
C2 - 29083408
SN - 1061-4036
VL - 49
SP - 1758
EP - 1766
JO - Nature Genetics
JF - Nature Genetics
IS - 12
ER -