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 TGrich 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.

Exome-wide association study of plasma lipids in >300,000 individuals

Ferrario M.;
2017-01-01

Abstract

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 TGrich 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.
2017
APOBEC-1 COMPLEMENTATION FACTOR; CODING-SEQUENCE VARIANTS; TYROSINE KINASE JAK2; B MESSENGER-RNA; MACULAR DEGENERATION; GENETIC ARCHITECTURE; LOW-FREQUENCY; MYELOPROLIFERATIVE DISORDERS; CARDIOVASCULAR-DISEASE; CLONAL HEMATOPOIESIS
Liu, D. J.; Peloso, G. M.; Yu, H.; Butterworth, A. S.; Wang, X.; Mahajan, A.; Saleheen, D.; Emdin, C.; Alam, D.; Alves, A. C.; Amouyel, P.; Angelantonio, E. D.; Arveiler, D.; Assimes, T. L.; Auer, P. L.; Baber, U.; Ballantyne, C. M.; Bang, L. E.; Benn, M.; Bis, J. C.; Boehnke, M.; Boerwinkle, E.; Bork-Jensen, J.; Bottinger, E. P.; Brandslund, I.; Brown, M.; Busonero, F.; Caulfield, M. J.; Chambers, J. C.; Chasman, D. I.; Chen, Y. E.; Chen, Y. -D. I.; Chowdhury, R.; Christensen, C.; Chu, A. Y.; Connell, J. M.; Cucca, F.; Cupples, L. A.; Damrauer, S. M.; Davies, G.; Deary, I. J.; Dedoussis, G.; Denny, J. C.; Dominiczak, A.; Dube, M. -P.; Ebeling, T.; Eiriksdottir, G.; Esko, T.; Farmaki, A. -E.; Feitosa, M. F.; Ferrario, M.; Ferrieres, J.; Ford, I.; Fornage, M.; Franks, P. W.; Frayling, T. M.; Frikke-Schmidt, R.; Fritsche, L. G.; Frossard, P.; Fuster, V.; Ganesh, S. K.; Gao, W.; Garcia, M. E.; Gieger, C.; Giulianini, F.; Goodarzi, M. O.; Grallert, H.; Grarup, N.; Groop, L.; Grove, M. L.; Gudnason, V.; Hansen, T.; Harris, T. B.; Hayward, C.; Hirschhorn, J. N.; Holmen, O. L.; Huffman, J.; Huo, Y.; Hveem, K.; Jabeen, S.; Jackson, A. U.; Jakobsdottir, J.; Jarvelin, M. -R.; Jensen, G. B.; Jorgensen, M. E.; Jukema, J. W.; Justesen, J. M.; Kamstrup, P. R.; Kanoni, S.; Karpe, F.; Kee, F.; Khera, A. V.; Klarin, D.; Koistinen, H. A.; Kooner, J. S.; Kooperberg, C.; Kuulasmaa, K.; Kuusisto, J.; Laakso, M.; Lakka, T.; Langenberg, C.; Langsted, A.; Launer, L. J.; Lauritzen, T.; Mliewald, D. C.; Lin, L. A.; Linneberg, A.; Loos, R. J. F.; Lu, Y.; Lu, X.; Magi, R.; Malarstig, A.; Manichaikul, A.; Manning, A. K.; Mantyselka, P.; Marouli, E.; Masca, N. G. D.; Maschio, A.; Meigs, J. B.; Melander, O.; Metspalu, A.; Morris, A. P.; Morrison, A. C.; Mulas, A.; Muller-Nurasyid, M.; Munroe, P. B.; Neville, M. J.; Nielsen, S. F.; Nielsen, J. B.; Nordestgaard, B. G.; Ordovas, J. M.; Mehran, R.; O'Donnell, C. J.; Orho-Melander, M.; Molony, C. M.; Muntendam, P.; Padmanabhan, S.; Palmer, C. N. A.; Pasko, D.; Patel, A. P.; Pedersen, O.; Perola, M.; Peters, A.; Pisinger, C.; Pistis, G.; Polasek, O.; Poulter, N.; Psaty, B. M.; Rader, D. J.; Rasheed, A.; Rauramaa, R.; Reilly, D. F.; Reiner, A. P.; Renstrom, F.; Rich, S. S.; Ridker, P. M.; Rioux, J. D.; Robertson, N. R.; Roden, D. M.; Rotter, J. I.; Rudan, I.; Salomaa, V.; Samani, N. J.; Sanna, S.; Sattar, N.; Schmidt, E. M.; Scott, R. A.; Sever, P.; Sevilla, R. S.; Shaffer, C. M.; Sim, X.; Sivapalaratnam, S.; Small, K. S.; Smith, A. V.; Smith, B. H.; Somayajula, S.; Southam, L.; Spector, T. D.; Speliotes, E. K.; Starr, J. M.; Stirrups, K. E.; Stitziel, N.; Strauch, K.; Stringham, H. M.; Surendran, P.; Tada, H.; Tall, A. R.; Tang, H.; Tardif, J. -C.; Taylor, K. D.; Trompet, S.; Tsao, P. S.; Tuomilehto, J.; Tybjaerg-Hansen, A.; Zuydam, N. R. V.; Varbo, A.; Varga, T. V.; Virtamo, J.; Waldenberger, M.; Wang, N.; Wareham, N. J.; Warren, H. R.; Weeke, P. E.; Weinstock, J.; Wessel, J.; Wilson, J. G.; Wilson, P. W. F.; Xu, M.; Yaghootkar, H.; Young, R.; Zeggini, E.; Zhang, H.; Zheng, N. S.; Zhang, W.; Zhang, Y.; Zhou, W.; Zhou, Y.; Zoledziewska, M.; Howson, J. M. M.; Danesh, J.; Mccarthy, M. I.; Cowan, C. A.; Abecasis, G.; Deloukas, P.; Musunuru, K.; Willer, C. J.; Kathiresan, S.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11383/2098126
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