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Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

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.

SUBMITTER: International Consortium for Blood Pressure Genome-Wide Association Studies

PROVIDER: S-EPMC3340926 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Ehret Georg B GB Munroe Patricia B PB Rice Kenneth M KM Bochud Murielle M Johnson Andrew D AD Chasman Daniel I DI Smith Albert V AV Tobin Martin D MD Verwoert Germaine C GC Hwang Shih-Jen SJ Pihur Vasyl V Vollenweider Peter P O'Reilly Paul F PF Amin Najaf N Bragg-Gresham Jennifer L JL Teumer Alexander A Glazer Nicole L NL Launer Lenore L Zhao Jing Hua JH Aulchenko Yurii Y Heath Simon S Sõber Siim S Parsa Afshin A Luan Jian'an J Arora Pankaj P Dehghan Abbas A Zhang Feng F Lucas Gavin G Hicks Andrew A AA Jackson Anne U AU Peden John F JF Tanaka Toshiko T Wild Sarah H SH Rudan Igor I Igl Wilmar W Milaneschi Yuri Y Parker Alex N AN Fava Cristiano C Chambers John C JC Fox Ervin R ER Kumari Meena M Go Min Jin MJ van der Harst Pim P Kao Wen Hong Linda WH Sjögren Marketa M Vinay D G DG Alexander Myriam M Tabara Yasuharu Y Shaw-Hawkins Sue S Whincup Peter H PH Liu Yongmei Y Shi Gang G Kuusisto Johanna J Tayo Bamidele B Seielstad Mark M Sim Xueling X Nguyen Khanh-Dung Hoang KD Lehtimäki Terho T Matullo Giuseppe G Wu Ying Y Gaunt Tom R TR Onland-Moret N Charlotte NC Cooper Matthew N MN Platou Carl G P CG Org Elin E Org Elin E Hardy Rebecca R Dahgam Santosh S Palmen Jutta J Vitart Veronique V Braund Peter S PS Kuznetsova Tatiana T Kuznetsova Tatiana T Uiterwaal Cuno S P M CS Adeyemo Adebowale A Palmas Walter W Campbell Harry H Ludwig Barbara B Tomaszewski Maciej M Tzoulaki Ioanna I Palmer Nicholette D ND Aspelund Thor T Garcia Melissa M Chang Yen-Pei C YP O'Connell Jeffrey R JR Steinle Nanette I NI Grobbee Diederick E DE Arking Dan E DE Kardia Sharon L SL Morrison Alanna C AC Hernandez Dena D Najjar Samer S McArdle Wendy L WL Hadley David D Brown Morris J MJ Connell John M JM Hingorani Aroon D AD Day Ian N M IN Lawlor Debbie A DA Beilby John P JP Lawrence Robert W RW Clarke Robert R Hopewell Jemma C JC Ongen Halit H Dreisbach Albert W AW Li Yali Y Young J Hunter JH Bis Joshua C JC Kähönen Mika M Viikari Jorma J Adair Linda S LS Lee Nanette R NR Chen Ming-Huei MH Olden Matthias M Pattaro Cristian C Bolton Judith A Hoffman JA Köttgen Anna A Bergmann Sven S Mooser Vincent V Chaturvedi Nish N Frayling Timothy M TM Islam Muhammad M Jafar Tazeen H TH Erdmann Jeanette J Kulkarni Smita R SR Bornstein Stefan R SR Grässler Jürgen J Groop Leif L Voight Benjamin F BF Kettunen Johannes J Howard Philip P Taylor Andrew A Guarrera Simonetta S Ricceri Fulvio F Emilsson Valur V Plump Andrew A Barroso Inês I Khaw Kay-Tee KT Weder Alan B AB Hunt Steven C SC Sun Yan V YV Bergman Richard N RN Collins Francis S FS Bonnycastle Lori L LL Scott Laura J LJ Stringham Heather M HM Peltonen Leena L Perola Markus M Vartiainen Erkki E Brand Stefan-Martin SM Staessen Jan A JA Wang Thomas J TJ Burton Paul R PR Soler Artigas Maria M Dong Yanbin Y Snieder Harold H Wang Xiaoling X Zhu Haidong H Lohman Kurt K KK Rudock Megan E ME Heckbert Susan R SR Smith Nicholas L NL Wiggins Kerri L KL Doumatey Ayo A Shriner Daniel D Veldre Gudrun G Viigimaa Margus M Kinra Sanjay S Prabhakaran Dorairaj D Tripathy Vikal V Langefeld Carl D CD Rosengren Annika A Thelle Dag S DS Corsi Anna Maria AM Singleton Andrew A Forrester Terrence T Hilton Gina G McKenzie Colin A CA Salako Tunde T Iwai Naoharu N Kita Yoshikuni Y Ogihara Toshio T Ohkubo Takayoshi T Okamura Tomonori T Ueshima Hirotsugu H Umemura Satoshi S Eyheramendy Susana S Meitinger Thomas T Wichmann H-Erich HE Cho Yoon Shin YS Kim Hyung-Lae HL Lee Jong-Young JY Scott James J Sehmi Joban S JS Zhang Weihua W Hedblad Bo B Nilsson Peter P Smith George Davey GD Wong Andrew A Narisu Narisu N Stančáková Alena A Raffel Leslie J LJ Yao Jie J Kathiresan Sekar S O'Donnell Christopher J CJ Schwartz Stephen M SM Ikram M Arfan MA Longstreth W T WT Mosley Thomas H TH Seshadri Sudha S Shrine Nick R G NR Wain Louise V LV Morken Mario A MA Swift Amy J AJ Laitinen Jaana J Prokopenko Inga I Zitting Paavo P Cooper Jackie A JA Humphries Steve E SE Danesh John J Rasheed Asif A Goel Anuj A Hamsten Anders A Watkins Hugh H Bakker Stephan J L SJ van Gilst Wiek H WH Janipalli Charles S CS Mani K Radha KR Yajnik Chittaranjan S CS Hofman Albert A Mattace-Raso Francesco U S FU Oostra Ben A BA Demirkan Ayse A Isaacs Aaron A Rivadeneira Fernando F Lakatta Edward G EG Orru Marco M Scuteri Angelo A Ala-Korpela Mika M Kangas Antti J AJ Lyytikäinen Leo-Pekka LP Soininen Pasi P Tukiainen Taru T Würtz Peter P Ong Rick Twee-Hee RT Dörr Marcus M Kroemer Heyo K HK Völker Uwe U Völzke Henry H Galan Pilar P Hercberg Serge S Lathrop Mark M Zelenika Diana D Deloukas Panos P Mangino Massimo M Spector Tim D TD Zhai Guangju G Meschia James F JF Nalls Michael A MA Sharma Pankaj P Terzic Janos J Kumar M V Kranthi MV Denniff Matthew M Zukowska-Szczechowska Ewa E Wagenknecht Lynne E LE Fowkes F Gerald R FG Charchar Fadi J FJ Schwarz Peter E H PE Hayward Caroline C Guo Xiuqing X Rotimi Charles C Bots Michiel L ML Brand Eva E Samani Nilesh J NJ Polasek Ozren O Talmud Philippa J PJ Nyberg Fredrik F Kuh Diana D Laan Maris M Hveem Kristian K Palmer Lyle J LJ van der Schouw Yvonne T YT Casas Juan P JP Mohlke Karen L KL Vineis Paolo P Raitakari Olli O Ganesh Santhi K SK Wong Tien Y TY Tai E Shyong ES Cooper Richard S RS Laakso Markku M Rao Dabeeru C DC Harris Tamara B TB Morris Richard W RW Dominiczak Anna F AF Kivimaki Mika M Marmot Michael G MG Miki Tetsuro T Saleheen Danish D Chandak Giriraj R GR Coresh Josef J Navis Gerjan G Salomaa Veikko V Han Bok-Ghee BG Zhu Xiaofeng X Kooner Jaspal S JS Melander Olle O Ridker Paul M PM Bandinelli Stefania S Gyllensten Ulf B UB Wright Alan F AF Wilson James F JF Ferrucci Luigi L Farrall Martin M Tuomilehto Jaakko J Pramstaller Peter P PP Elosua Roberto R Soranzo Nicole N Sijbrands Eric J G EJ Altshuler David D Loos Ruth J F RJ Shuldiner Alan R AR Gieger Christian C Meneton Pierre P Uitterlinden Andre G AG Wareham Nicholas J NJ Gudnason Vilmundur V Rotter Jerome I JI Rettig Rainer R Uda Manuela M Strachan David P DP Witteman Jacqueline C M JC Hartikainen Anna-Liisa AL Beckmann Jacques S JS Boerwinkle Eric E Vasan Ramachandran S RS Boehnke Michael M Larson Martin G MG Järvelin Marjo-Riitta MR Psaty Bruce M BM Abecasis Gonçalo R GR Chakravarti Aravinda A Elliott Paul P van Duijn Cornelia M CM Newton-Cheh Christopher C Levy Daniel D Caulfield Mark J MJ Johnson Toby T

Nature 20110911 7367

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 desc ...[more]

PMID: 21909115

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Project description:ImportanceHypertension remains the major cardiovascular disease risk factor globally, but variability in measured blood pressure may result in suboptimal management. Whether genetic contributors to elevated blood pressure may complementarily inform cardiovascular disease risk assessment is unknown.ObjectiveTo examine incident cardiovascular disease by blood pressure polygenic risk score independent of measured blood pressures and antihypertensive medication prescriptions.Design, setting, and participantsThe cohort study (UK Biobank) recruited UK residents aged 40 to 69 years between March 2006 and August 2010. Participants without a prior physician diagnosis of cardiovascular disease, including myocardial infarction, stroke, or heart failure, were included. Excluded were individuals with mismatch between self-reported and genotypically inferred sex, sex aneuploidy, missing genotype rates of 1% or greater, and excess genotypic heterozygosity. Data analyses were performed from September 25, 2021, to July 21, 2022.ExposuresMeasured blood pressure and externally derived blood pressure polygenic risk score stratified by hypertension diagnosis and management, which included normal blood pressure (<130/80 mm Hg without antihypertensives), untreated hypertension (systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥80 mm Hg without antihypertensives), and treated hypertension (current antihypertensives prescriptions).Main outcomes and measuresComposite of first incident myocardial infarction, stroke, heart failure, or cardiovascular-related death.ResultsOf the 331 078 study participants included (mean [SD] age at enrollment, 56.9 [8.1] years; 178 824 female [54.0%]), 83 094 (25.1%) had normal blood pressure, 197 597 (59.7%) had untreated hypertension, and 50 387 (15.2%) had treated hypertension. Over a median (IQR) follow-up of 11.1 (10.4-11.8) years, the primary outcome occurred in 15 293 participants. Among those with normal blood pressure, untreated hypertension, and treated hypertension, each SD increase in measured systolic blood pressure was associated with hazard ratios of 1.08 (95% CI, 0.93-1.25), 1.20 (95% CI, 1.16-1.23), and 1.16 (95% CI, 1.11-1.20), respectively, for the primary outcome. Among these same categories, each SD increase in genetically predicted systolic blood pressure was associated with increased hazard ratios of 1.13 (95% CI, 1.05-1.20), 1.04 (95% CI, 1.01-1.07), and 1.06 (95% CI, 1.02-1.10), respectively, for the primary outcome independent of measured blood pressures and other covariates. Findings were similar for measured and genetically predicted diastolic blood pressure.Conclusions and relevanceBlood pressure polygenic risk score may augment identification of individuals at heightened cardiovascular risk, including those with both normal blood pressure and hypertension. Whether it may also guide antihypertensive initiation or intensification requires further study.

Project description:ImportanceThe relationship between exposure to lower low-density lipoprotein cholesterol (LDL-C) and lower systolic blood pressure (SBP) with the risk of cardiovascular disease has not been reliably quantified.ObjectiveTo assess the association of lifetime exposure to the combination of both lower LDL-C and lower SBP with the lifetime risk of cardiovascular disease.Design, setting, and participantsAmong 438 952 participants enrolled in the UK Biobank between 2006 and 2010 and followed up through 2018, genetic LDL-C and SBP scores were used as instruments to divide participants into groups with lifetime exposure to lower LDL-C, lower SBP, or both. Differences in plasma LDL-C, SBP, and cardiovascular event rates between the groups were compared to estimate associations with lifetime risk of cardiovascular disease.ExposuresDifferences in plasma LDL-C and SBP compared with participants with both genetic scores below the median. Genetic risk scores higher than the median were associated with lower LDL-C and lower SBP.Main outcomes and measuresOdds ratio (OR) for major coronary events, defined as coronary death, nonfatal myocardial infarction, or coronary revascularization.ResultsThe mean age of the 438 952 participants was 65.2 years (range, 40.4-80.0 years), 54.1% were women, and 24 980 experienced a first major coronary event. Compared with the reference group, participants with LDL-C genetic scores higher than the median had 14.7-mg/dL lower LDL-C levels and an OR of 0.73 for major coronary events (95% CI, 0.70-0.75; P < .001). Participants with SBP genetic scores higher than the median had 2.9-mm Hg lower SBP and an OR of 0.82 for major coronary events (95% CI, 0.79-0.85, P < .001). Participants in the group with both genetic scores higher than the median had 13.9-mg/dL lower LDL-C, 3.1-mm Hg lower SBP, and an OR of 0.61 for major coronary events (95% CI, 0.59-0.64; P < .001). In a 4 × 4 factorial analysis, exposure to increasing genetic risk scores and lower LDL-C levels and SBP was associated with dose-dependent lower risks of major coronary events. In a meta-regression analysis, combined exposure to 38.67-mg/dL lower LDL-C and 10-mm Hg lower SBP was associated with an OR of 0.22 for major coronary events (95% CI, 0.17-0.26; P < .001), and 0.32 for cardiovascular death (95% CI, 0.25-0.40; P < .001).Conclusions and relevanceLifelong genetic exposure to lower levels of low-density lipoprotein cholesterol and lower systolic blood pressure was associated with lower cardiovascular risk. However, these findings cannot be assumed to represent the magnitude of benefit achievable from treatment of these risk factors.

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Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

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Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

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