Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk / Ehret, Georg B.; Munroe, Patricia B.; Rice, Kenneth M.; Bochud, Murielle; Johnson, Andrew D.; Chasman, Daniel I.; Smith, Albert V.; Tobin, Martin D.; Verwoert, Germaine C.; Hwang, Shih-Jen; Pihur, Vasyl; Vollenweider, Peter; O'Reilly, Paul F.; Amin, Najaf; Bragg-Gresham, Jennifer L.; Teumer, Alexander; Glazer, Nicole L.; Launer, Lenore; Zhao, Jing Hua; Aulchenko, Yurii; Heath, Simon; Sober, Siim; Parsa, Afshin; Luan, Jian'An; Arora, Pankaj; Dehghan, Abbas; Zhang, Feng; Lucas, Gavin; Hicks, Andrew A.; Jackson, Anne U.; Peden, John F.; Tanaka, Toshiko; Wild, Sarah H.; Rudan, Igor; Igl, Wilmar; Milaneschi, Yuri; Parker, Alex N.; Fava, Cristiano; Chambers, John C.; Fox, Ervin R.; Kumari, Meena; Go, Min Jin; van der Harst, Pim; Kao, Wen Hong Linda; Sjögren, Marketa; Vinay, D. G.; Alexander, Myriam; Tabara, Yasuharu; Shaw-Hawkins, Sue; Whincup, Peter H.; Liu, Yongmei; Shi, Gang; Kuusisto, Johanna; Tayo, Bamidele; Seielstad, Mark; Sim, Xueling; Hoang Nguyen, Khanh-Dung; Lehtimäki, Terho; Matullo, Giuseppe; Wu, Ying; Gaunt, Tom R.; Charlotte Onland-Moret, N.; Cooper, Matthew N.; Platou, Carl G. P.; Org, Elin; Hardy, Rebecca; Dahgam, Santosh; Palmen, Jutta; Vitart, Veronique; Braund, Peter S.; Kuznetsova, Tatiana; Uiterwaal, Cuno S. P. M.; Adeyemo, Adebowale; Palmas, Walter; Campbell, Harry; Ludwig, Barbara; Tomaszewski, Maciej; Tzoulaki, Ioanna; Palmer, Nicholette D.; Aspelund, Thor; Garcia, Melissa; Chang, Yen-Pei C.; O'Connell, Jeffrey R.; Steinle, Nanette I.; Grobbee, Diederick E.; Arking, Dan E.; Kardia, Sharon L.; Morrison, Alanna C.; Hernandez, Dena; Najjar, Samer; Mcardle, Wendy L.; Hadley, David; Brown, Morris J.; Connell, John M.; Hingorani, Aroon D.; Day, Ian N. M.; Lawlor, Debbie A.; Beilby, John P.; Lawrence, Robert W.; Clarke, Robert; Hopewell, Jemma C.; Ongen, Halit; Dreisbach, Albert W.; Li, Yali; Hunter Young, J.; Bis, Joshua C.; Kähönen, Mika; Viikari, Jorma; Adair, Linda S.; Lee, Nanette R.; Chen, Ming-Huei; Olden, Matthias; Pattaro, Cristian; Bolton, Judith A Hoffman; Köttgen, Anna; Bergmann, Sven; Mooser, Vincent; Chaturvedi, Nish; Frayling, Timothy M.; Islam, Muhammad; Jafar, Tazeen H.; Erdmann, Jeanette; Kulkarni, Smita R.; Bornstein, Stefan R.; Grässler, Jürgen; Groop, Leif; Voight, Benjamin F.; Kettunen, Johannes; Howard, Philip; Taylor, Andrew; Guarrera, Simonetta; Ricceri, Fulvio; Emilsson, Valur; Plump, Andrew; Barroso, Inês; Khaw, Kay-Tee; Weder, Alan B.; Hunt, Steven C.; Sun, Yan V.; Bergman, Richard N.; Collins, Francis S.; Bonnycastle, Lori L.; Scott, Laura J.; Stringham, Heather M.; Peltonen, Leena; Perola, Markus; Vartiainen, Erkki; Brand, Stefan-Martin; Staessen, Jan A.; Wang, Thomas J.; Burton, Paul R.; Artigas, Maria Soler; Dong, Yanbin; Snieder, Harold; Wang, Xiaoling; Zhu, Haidong; Lohman, Kurt K.; Rudock, Megan E.; Heckbert, Susan R.; Smith, Nicholas L.; Wiggins, Kerri L.; Doumatey, Ayo; Shriner, Daniel; Veldre, Gudrun; Viigimaa, Margus; Kinra, Sanjay; Prabhakaran, Dorairaj; Tripathy, Vikal; Langefeld, Carl D.; Rosengren, Annika; Thelle, Dag S.; Corsi, Anna Maria; Singleton, Andrew; Forrester, Terrence; Hilton, Gina; Mckenzie, Colin A.; Salako, Tunde; Iwai, Naoharu; Kita, Yoshikuni; Ogihara, Toshio; Ohkubo, Takayoshi; Okamura, Tomonori; Ueshima, Hirotsugu; Umemura, Satoshi; Eyheramendy, Susana; Meitinger, Thomas; Wichmann, H. -Erich; Cho, Yoon Shin; Kim, Hyung-Lae; Lee, Jong-Young; Scott, James; Sehmi, Joban S.; Zhang, Weihua; Hedblad, Bo; Nilsson, Peter; Smith, George Davey; Wong, Andrew; Narisu, Narisu; Stančáková, Alena; Raffel, Leslie J.; Yao, Jie; Kathiresan, Sekar; O'Donnell, Christopher J.; Schwartz, Stephen M.; Arfan Ikram, M.; Longstreth Jr., W. T.; Mosley, Thomas H.; Seshadri, Sudha; Shrine, Nick R. G.; Wain, Louise V.; Morken, Mario A.; Swift, Amy J.; Laitinen, Jaana; Prokopenko, Inga; Zitting, Paavo; Cooper, Jackie A.; Humphries, Steve E.; Danesh, John; Rasheed, Asif; Goel, Anuj; Hamsten, Anders; Watkins, Hugh; Bakker, Stephan J. L.; van Gilst, Wiek H.; Janipalli, Charles S.; Radha Mani, K.; Yajnik, Chittaranjan S.; Hofman, Albert; Mattace-Raso, Francesco U. S.; Oostra, Ben A.; Demirkan, Ayse; Isaacs, Aaron; Rivadeneira, Fernando; Lakatta, Edward G.; Orru, Marco; Scuteri, Angelo; Ala-Korpela, Mika; Kangas, Antti J.; Lyytikäinen, Leo-Pekka; Soininen, Pasi; Tukiainen, Taru; Würtz, Peter; Twee-HeeOng, Rick; Dörr, Marcus; Kroemer, Heyo K.; Völker, Uwe; Völzke, Henry; Galan, Pilar; Hercberg, Serge; Lathrop, Mark; Zelenika, Diana; Deloukas, Panos; Mangino, Massimo; Spector, Tim D.; Zhai, Guangju; Meschia, James F.; Nalls, Michael A.; Sharma, Pankaj; Terzic, Janos; Kranthi Kumar, M. V.; Denniff, Matthew; Zukowska-Szczechowska, Ewa; Wagenknecht, Lynne E.; Fowkes, F. Gerald R.; Charchar, Fadi J.; Schwarz, Peter E. H.; Hayward, Caroline; Guo, Xiuqing; Rotimi, Charles; Bots, Michiel L.; Brand, Eva; Samani, Nilesh J.; Polasek, Ozren; Talmud, Philippa J.; Nyberg, Fredrik; Kuh, Diana; Laan, Maris; Hveem, Kristian; Palmer, Lyle J.; van der Schouw, Yvonne T.; Casas, Juan P.; Mohlke, Karen L.; Vineis, Paolo; Raitakari, Olli; Ganesh, Santhi K.; Wong, Tien Y.; Shyong Tai, E.; Cooper, Richard S.; Laakso, Markku; Rao, Dabeeru C.; Harris, Tamara B.; Morris, Richard W.; Dominiczak, Anna F.; Kivimaki, Mika; Marmot, Michael G.; Miki, Tetsuro; Saleheen, Danish; Chandak, Giriraj R.; Coresh, Josef; Navis, Gerjan; Salomaa, Veikko; Han, Bok-Ghee; Zhu, Xiaofeng; Kooner, Jaspal S.; Melander, Olle; Ridker, Paul M.; Bandinelli, Stefania; Gyllensten, Ulf B.; Wright, Alan F.; Wilson, James F.; Ferrucci, Luigi; Farrall, Martin; Tuomilehto, Jaakko; Pramstaller, Peter P.; Elosua, Roberto; Soranzo, Nicole; Sijbrands, Eric J. G.; Altshuler, David; Loos, Ruth J. F.; Shuldiner, Alan R.; Gieger, Christian; Meneton, Pierre; Uitterlinden, Andre G.; Wareham, Nicholas J.; Gudnason, Vilmundur; Rotter, Jerome I.; Rettig, Rainer; Uda, Manuela; Strachan, David P.; Witteman, Jacqueline C. M.; Hartikainen, Anna-Liisa; Beckmann, Jacques S.; Boerwinkle, Eric; Vasan, Ramachandran S.; Boehnke, Michael; Larson, Martin G.; Järvelin, Marjo-Riitta; Psaty, Bruce M.; Abecasis, Gonçalo R.; Chakravarti, Aravinda; Elliott, Paul; van Duijn, Cornelia M.; Newton-Cheh, Christopher; Levy, Daniel; Caulfield, Mark J.; Johnson, Toby; Tang, H; Knowles, J; Hlatky, M; Fortmann, S; Assimes, Tl; Quertermous, T; Go, A; Iribarren, C; Absher, D; Risch, N; Meyers, R; Sidney, S; Ziegler, A; Schillert, A; Bickel, C; Sinning, C; Rupprecht, Hj; Lackner, K; Wild, P; Schnabel, R; Blankenberg, S; Zeller, T; Münzel, T; Perret, C; Cambien, F; Tiret, L; Nicaud, V; Proust, C; Dehghan, A; Hofman, A; Uitterlinden, A; van Duijn, C; Levy, D; Whitteman, J; Cupples, La; Demissie-Banjaw, S; Ramachandran, V; Smith, A; Gudnason, V; Boerwinkle, E; Folsom, A; Morrison, A; Psaty, Bm; Chen, Iy; Rotter, Ji; Bis, J; Volcik, K; Rice, K; Taylor, Kd; Marciante, K; Smith, N; Glazer, N; Heckbert, S; Harris, T; Lumley, T; Kong, A; Thorleifsson, G; Thorgeirsson, G; Holm, H; Gulcher, Jr; Stefansson, K; Andersen, K; Gretarsdottir, S; Thorsteinsdottir, U; Preuss, M; Schreiber, S; Meitinger, T; König, Ir; Lieb, W; Hengstenberg, C; Schunkert, H; Erdmann, J; Fisher, M; Grosshennig, A; Medack, A; Stark, K; Linsel-Nitschke, P; Bruse, P; Aherrahrou, Z; Peters, A; Loley, C; Willenborg, C; Nahrstedt, J; Freyer, J; Gulde, S; Doering, A; Meisinger, C; Wichmann, He; Klopp, N; Illig, T; Meinitzer, A; Tomaschitz, A; Halperin, E; Dobnig, H; Scharnagl, H; Kleber, M; Laaksonen, R; Pilz, S; Grammer, Tb; Stojakovic, T; Renner, W; März, W; Böhm, Bo; Winkelmann, Br; Winkler, K; Hoffmann, M; O'Donnell, Cj; Voight, Bf; Altshuler, D; Siscovick, Ds; Musunuru, K; Peltonen, L; Barbalic, M; Melander, O; Elosua, R; Kathiresan, S; Schwartz, Sm; Salomaa, V; Guiducci, C; Burtt, N; Gabriel, Sb; Stewart, Af; Wells, Ga; Chen, L; Jarinova, O; Roberts, R; Mcpherson, R; Dandona, S; Pichard, Ad; Rader, Dj; Devaney, J; Lindsay, Jm; Kent, Km; Qu, L; Satler, L; Burnett, Ms; Li, M; Reilly, Mp; Wilensky, R; Waksman, R; Epstein, S; Mattha, W; Knouf, Cw; Waterworth, Dm; Hakonarson, Hh; Walker, M; Mooser, V; Hall, As; Balmforth, Aj; Wright, Bj; Nelson, C; Thompson, Jr; Samani, Nj; Braund, Ps; Ball, Sg; Smith, Nl; Felix, Jf; Morrison, Ac; Demissie, S; Glazer, Nl; Loehr, Lr; Cupples, La; Dehghan, A; Lumley, T; Rosamond, Wd; Lieb, W; Rivadeneira, F; Bis, Jc; Folsom, Ar; Benjamin, E; Aulchenko, Ys; Haritunians, T; Couper, D; Murabito, J; Wang, Ya; Stricker, B; Gottdiener, Js; Chang, Pp; Wang, Tj; Rice, Km; Hofman, A; Heckbert, Sr; Fox, Er; O'Donnell, Cj; Uitterlinden, Ag; Rotter, Ji; Willerson, Jt; Levy, D; van Duijn, Cm; Psaty, Bm; Witteman, Jc; Boerwinkle, E; Vasan, Rs; Köttgen, A; Pattaro, C; Böger, Ca; Fuchsberger, C; Olden, M; Glazer, Nl; Parsa, A; Gao, X; Yang, Q; Smith, Av; O'Connell, Jr; Li, M; Schmidt, H; Tanaka, T; Isaacs, A; Ketkar, S; Hwang, Sj; Johnson, A; Dehghan, A; Teumer, A; Paré, G; Atkinson, Ej; Zeller, T; Lohman, K; Cornelis, Mc; Probst-Hensch, Nm; Kronenberg, F; Tönjes, A; Hayward, C; Aspelund, T; Eiriksdottir, G; Launer, Lj; Harris, Tb; Rampersaud, E; Mitchell, Bd; Arking, De; Boerwinkle, E; Struchalin, M; Cavalieri, M; Singleton, A; Giallauria, Francesco; Metter, J; de Boer, J; Haritunians, T; Lumley, T; Siscovick, D; Psaty, Bm; Zillikens, Mc; Oostra, Ba; Feitosa, M; Province, M; de Andrade, M; Turne, St; Schillert, A; Ziegler, A; Wild, Ps; Schnabel, Rb; Wilde, S; Munzel, Tf; Leak, Ts; Illig, T; Klopp, N; Meisinger, C; Wichmann, He; Koenig, W; Zgaga, L; Zemunik, T; Kolcic, I; Minelli, C; Hu, Fb; Johansson, A; Igl, W; Zaboli, G; Wild, Sh; Wright, Af; Campbell, H; Ellinghaus, D; Schreiber, S; Aulchenko, Ys; Felix, Jf; Rivadeneira, F; Uitterlinden, Ag; Hofman, A; Imboden, M; Nitsch, D; Brandstätter, A; Kollerits, B; Kedenko, L; Mägi, R; Stumvoll, M; Kovacs, P; Boban, M; Campbell, S; Endlich, K; Völzke, H; Kroemer, Hk; Nauck, M; Völker, U; Polasek, O; Vitart, V; Badola, S; Parker, An; Ridker, Pm; Kardia, Sl; Blankenberg, S; Liu, Y; Curhan, Gc; Franke, A; Rochat, T; Paulweber, B; Prokopenko, I; Wang, W; Gudnason, V; Shuldiner, Ar; Coresh, J; Schmidt, R; Ferrucci, L; Shlipak, Mg; van Duijn, Cm; Borecki, I; Krämer, Bk; Rudan, I; Gyllensten, U; Wilson, Jf; Witteman, Jc; Pramstaller, Pp; Rettig, R; Hastie, N; Chasman, Di; Kao, Wh; Heid, Im; Fox, Cs; Vasan, R; Glazer, Nl; Felix, Jf; Lieb, W; Wild, Ps; Felix, Sb; Watzinger, N; Larson, Mg; Smith, Nl; Dehghan, A; Grosshennig, A; Schillert, A; Teumer, A; Schmidt, R; Kathiresan, S; Lumley, T; Aulchenko, Ys; König, Ir; Zeller, T; Homuth, G; Struchalin, M; Aragam, J; Bis, Jc; Rivadeneira, F; Erdmann, J; Schnabel, Rb; Dörr, M; Zweiker, R; Lind, L; Rodeheffer, Rj; Greiser, Kh; Levy, D; Haritunians, T; Deckers, Jw; Stritzke, J; Lackner, Kj; Völker, U; Ingelsson, E; Kullo, I; Haerting, J; O'Donnell, Cj; Heckbert, Sr; Stricker, Bh; Ziegler, A; Reffelmann, T; Redfield, Mm; Werdan, K; Mitchell, Gf; Rice, K; Arnett, D; Hofman, A; Gottdiener, Js; Uitterlinden, Ag; Meitinger, T; Blettner, M; Friedrich, N; Wang, Tj; Psaty, Bm; van Duijn, Cm; Wichmann, He; Munzel, Tf; Kroemer, Hk; Benjamin, Ej; Rotter, Ji; Witteman, Jc; Schunkert, H; Schmidt, H; Völzke, H; Blankenberg, S; Chambers, Jc; Zhang, W; Lord, Gm; van der Harst, P; Lawlor, Da; Sehmi, Js; Gale, Dp; Wass, Mn; Ahmadi, Kr; Bakker, Sj; Beckmann, J; Bilo, Hj; Bochud, M; Brown, Mj; Caulfield, Mj; Connell, Jm; Cook, Ht; Cotlarciuc, I; Davey Smith, G; de Silva, R; Deng, G; Devuyst, O; Dikkeschei, Ld; Cook, Ht; Cotlarciuc, I; Davey Smith, G; de Silva, R; Deng, G; Devuyst, O; Dikkeschei, Ld; Dimkovic, T; Dockrell, M; Dominiczak, A; Ebrahim, S; Eggermann, T; Farrall, M; Ferrucci, L; Floege, J; Forouhi, Ng; Gansevoort, Rt; Han, X; Hedblad, B; Homan van der Heide, Jj; Hepkema, Bg; Hernandez-Fuentes, M; Hypponen, E; Johnson, T; de Jong, Pe; Kleefstra, N; Lagou, V; Lapsley, M; Li, Y; Loos, Rj; Luan, J; Luttropp, K; Maréchal, C; Melander, O; Munroe, Pb; Nordfors, L; Parsa, A; Peltonen, L; Penninx, Bw; Perucha, E; Pouta, A; Prokopenko, I; Roderick, Pj; Ruokonen, A; Samani, Nj; Sanna, S; Schalling, M; Schlessinger, D; Schlieper, G; Seelen, Ma; Shuldiner, Ar; Sjögren, M; Smit, Jh; Snieder, H; Soranzo, N; Spector, Td; Stenvinkel, P; Sternberg, Mj; Swaminathan, R; Tanaka, T; Ubink-Veltmaat, Lj; Uda, M; Vollenweider, P; Wallace, C; Waterworth, D; Zerres, K; Waeber, G; Wareham, Nj; Maxwell, Ph; Mccarthy, Mi; Jarvelin, Mr; Mooser, V; Abecasis, Gr; Lightstone, L; Scott, J; Navis, G; Elliot, P; Kooner, Js.. - In: NATURE. - ISSN 0028-0836. - 478:7367(2011), pp. 103-109. [10.1038/nature10405]
Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk
Giallauria, FrancescoMembro del Collaboration Group
;
2011
Abstract
Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
