Loci influencing blood pressure identified using a cardiovascular gene-centric array

Santhi K. Ganesh, Vinicius Tragante, Wei Guo, Yiran Guo, Matthew B. Lanktree, Erin N. Smith, Toby Johnson, Berta Almoguera Castillo, John Barnard, Jens Baumert, Yen-Pei Christy Chang, Clara C. Elbers, Martin Farrall, Mary E. Fischer, Nora Franceschini, Tom R. Gaunt, Johannes M.I.H. Gho, Christian Gieger, Yan Gong, Aaron Isaacs, Marcus E. Kleber, Irene Mateo Leach, Caitrin W. McDonough, Matthijs F.L. Meijs, Olle Mellander, Cliona M. Molony, Ilja M. Nolte, Sandosh Padmanabhan, Tom S. Price, Ramakrishnan Rajagopalan, Jonathan Shaffer, Sonia Shah, Haiqing Shen, Nicole Soranzo, Peter J. van der Most, Erik P.A. Van Iperen, Jessic A. Van Setten, Judith M. Vonk, Li Zhang, Amber L. Beitelshees, Gerald S. Berenson, Deepak L. Bhatt, Jolanda M.A. Boer, Eric Boerwinkle, Ben Burkley, Amber Burt, Aravinda Chakravarti, Wei Chen, Rhonda M. Cooper-DeHoff, Sean P. Curtis, Albert Dreisbach, David Duggan, Georg B. Ehret, Richard R. Fabsitz, Myriam Fornage, Ervin Fox, Clement E. Furlong, Ron T. Gansevoort, Marten H. Hofker, G. Kees Hovingh, Susan A. Kirkland, Kandice Kottke-Marchant, Abdullah Kutlar, Andrea Z. LaCroix, Taimour Y. Langaee, Yun R. Li, Honghuang Lin, Kiang Liu, Steffi Maiwald, Rainer Malik, Gurunathan Murugesan, Christopher Newton-Cheh, Jeffery R. O'Connell, N. Charlotte Onland-Moret, Willem H. Ouwehand, Walter Palmas, Brenda W. Penninx, Carl J. Pepine, Mary Pettinger, Joseph F. Polak, Vasan S. Ramachandran, Jane Ranchalis, Susan Redline, Paul M. Ridker, Lynda M. Rose, Hubert Scharnag, Nicholas J. Schork, Daichi Shimbo, Alan R. Shuldiner, Sathanur R. Srinivasan, Ronald P. Stolk, Herman A. Taylor, Barbara Thorand, Mieke D. Trip, Cornelia M. van Duijn, W. Monique Verschuren, Cisca Wijmenga, Bernhard R. Winkelmann, Sharon Wyatt, J. Hunter Young, Bernhard O. Boehm, Mark J. Caulfield, Daniel I. Chasman, Karina W. Davidson, Pieter A. Doevendans, Garret A. FitzGerald, John G. Gums, Hakon Hakonarson, Hans L. Hillege, Thomas Illig, Gail P. Jarvik, Julie A. Johnson, John J.P. Kastelein, Wolfgang Koenig, Winfried März, Braxton D. Mitchell, Sarah S. Murray, Albertine J. Oldehinkel, Daniel J. Rader, Muredach P. Reilly, Alex P. Reiner, Eric E. Schadt, Roy L. Silverstein, Harold Snieder, Alice V. Stanton, André G. Uitterlinden, Pim van der Harst, Yvonne T. van der Schouw, Nilesh J. Samani, Andrew D. Johnson, Patricia B. Munroe, Paul I.W. de Bakker, Xiaofeng Zhu, Daniel Levy, Brendan J. Keating, Folkert W. Asselbergs

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.