A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure.

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Citation: Human Molecular Genetics. 28(15):2615-2633, 2019 08 01.PMID: 31127295Institution: MedStar Health Research InstituteForm of publication: Journal ArticleMedline article type(s): Journal ArticleSubject headings: *Arterial Pressure/ge [Genetics] | *Continental Population Groups/ge [Genetics] | *Gene-Environment Interaction | *Hypertension/ge [Genetics] | *Polymorphism, Genetic | *Smoking/ae [Adverse Effects] | Adolescent | Adult | Aged | Aged, 80 and over | Antiporters/ge [Genetics] | Blood Pressure/ge [Genetics] | Caspase 9/ge [Genetics] | Ethnic Groups/ge [Genetics] | Female | Genome-Wide Association Study | Humans | Hypertension/et [Etiology] | Male | Membrane Proteins/ge [Genetics] | Middle Aged | Receptors, Vasopressin/ge [Genetics] | Sulfate Transporters/ge [Genetics] | Tumor Suppressor Proteins/ge [Genetics] | Young AdultYear: 2019ISSN:
  • 0964-6906
Name of journal: Human molecular geneticsAbstract: Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 x 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings. Copyright (c) The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].All authors: Afaq S, Alfred T, Alver M, Amin N, Amini M, Arking DE, Arnett DK, Aschard H, Aslibekyan S, Aung T, Barr RG, Bartz TM, Becker DM, Bentley AR, Bielak LF, Bierut LJ, Boehnke M, Boerwinkle E, Boissel M, Bottinger EP, Bouchard C, Bowden DW, Braund PS, Brody JA, Broeckel U, Brown MR, Cade B, Campbell A, Canouil M, Caulfield MJ, Chai JF, Chakravarti A, Chambers JC, Chasman DI, Chen X, Chen YI, Cheng CY, Cocca M, Collins FS, Connell JM, Cooper RS, Cupples LA, de Faire U, de Las Fuentes L, de Mutsert R, de Silva HJ, Deary IJ, Divers J, Dorajoo R, Dorr M, Duan Q, Eaton CB, Ehret G, Elliott P, Esko T, Evangelou E, Evans MK, Farrall M, Faul JD, Feitosa MF, Fornage M, Forouhi NG, Forrester T, Fox ER, Franceschini N, Franco OH, Franks PW, Freedman BI, Friedlander Y, Froguel P, Gandin I, Gao C, Gao H, Gasparini P, Gauderman WJ, Gieger C, Gigante B, Giulianini F, Goel A, Gu CC, Gudnason V, Guo X, Gupta P, Hagenaars SP, Harris SE, Harris TB, Hartwig FP, Hayward C, He J, He M, Heikkinen S, Heng CK, Hixson J, Hofman A, Horimoto ARVR, Horta BL, Howard BV, Hsu FC, Hung YJ, Hunt SC, Irvin MR, Jackson AU, Jia Y, Jonas JB, Kamatani Y, Kammerer CM, Kardia SLR, Kasturiratne A, Kato N, Katsuya T, Kaufman J, Kerrison ND, Khor CC, Kilpelainen TO, Koh WP, Koistinen HA, Komulainen P, Kooner JS, Kooperberg CB, Kraja AT, Krieger JE, Kritchevsky SB, Kubo M, Kuhnel B, Kutalik Z, Kuusisto J, Laakso M, Lakka TA, Langefeld CD, Langenberg C, Launer LJ, Laurie CC, Leander K, Lee JH, Lee WJ, Lehne B, Lehtimaki T, Levy D, Lewis CE, Li C, Li Y, Liang KW, Lifelines Cohort Study, Lim SH, Lin KH, Liu CT, Liu J, Liu Y, Loh M, Lohman KK, Loos RJF, Louie T, Lu Y, Luan J, Lyytikainen LP, Magi R, Magnusson PKE, Manning AK, Marten J, Matoba N, Matsuda K, McKenzie CA, Meitinger T, Metspalu A, Milani L, Momozawa Y, Mook-Kanamori DO, Morrison AC, Mosley TH Jr, Munroe PB, Musani SK, Nalls MA, Nasri U, Nelson CP, Noordam R, Ntalla I, O'Connell JR, Ogunniyi A, Oldehinkel AJ, Palmas WR, Palmer ND, Pankow JS, Pedersen NL, Pereira AC, Perls T, Peters A, Peyser PA, Polasek O, Porteous D, Province MA, Psaty BM, Raitakari OT, Rankinen T, Rao DC, Rauramaa R, Redline S, Reiner AP, Renstrom F, Rettig R, Rice K, Rice TK, Richard MA, Ridker PM, Robino A, Robinson JG, Rose LM, Rotimi CN, Rotter JI, Rudan I, Sabanayagam C, Salako BL, Samani NJ, Sandow K, Schmidt CO, Schreiner PJ, Schwander K, Scott J, Scott RA, Scott WR, Sever P, Sheu WHH, Shu XO, Sim X, Sims M, Sitlani CM, Smith AV, Smith BH, Smith JA, Snieder H, Sofer T, Stancakova A, Starr JM, Strauch K, Sung YJ, Tai ES, Tajuddin SM, Takeuchi F, Tang H, Taylor KD, Tayo BO, Teo YY, Tham YC, Uitterlinden AG, van Dam RM, van der Harst P, van der Most PJ, van Duijn CM, Varga TV, Vojinovic D, Wagenknecht LE, Waken RJ, Waldenberger M, Wang H, Wang L, Wang Y, Wang YX, Ware EB, Wareham NJ, Warren HR, Watkins H, Wei WB, Weir DR, Weiss S, Wen W, Wickremasinghe AR, Wilson G, Winkler TW, Wojczynski MK, Wong TY, Wu T, Xiang YB, Yanek LR, Yao J, Yuan JM, Zhang W, Zhao JH, Zhao W, Zhou Y, Zhu X, Zonderman ABOriginally published: Human Molecular Genetics. 28(15):2615-2633, 2019 Aug 01.Fiscal year: FY2020Digital Object Identifier: Date added to catalog: 2019-06-21
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Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 x 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings. Copyright (c) The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

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