Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group

Irvin, M.R.; Sitlani, C.M.; Floyd, J.S.; Psaty, B.M.; Bis, J.C.; Wiggins, K.L.; Whitsel, E.A.; Sturmer, T.; Stewart, J.; Raffield, L.; Sun, F.G.; Liu, C.T.; Xu, H.F.; Cupples, A.L.; Tanner, R.M.; Rossing, P.; Smith, A.; Zilhao, N.R.; Launer, L.J.; Noordam, R.; Rotter, J.I.; Yao, J.; Li, X.H.; Guo, X.Q.; Limdi, N.; Sundaresan, A.; Lange, L.; Correa, A.; Stott, D.J.; Ford, I.; Jukema, J.W.; Gudnason, V.; Mook-Kanamori, D.O.; Trompet, S.; Palmas, W.; Warren, H.R.; Hellwege, J.N.; Giri, A.; O'Donnell, C.; Hung, A.M.; Edwards, T.L.; Ahluwalia, T.S.; Arnett, D.K.; Avery, C.L.; VA Million Vet Program; CHARGE Pharmacogenetics Working Gr

doi:doi:10.1093/ajh/hpz150

BACKGROUNDOnly a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.METHODSWe conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP >= 140 mm Hg and/or diastolic BP >= 90 mm Hg) or 4 or more medication classes regardless of BP control (n(EA) = 931, n(AA) = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (n(EA) = 14,210, n(AA) = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (n(EA) = 5,266, n(AA) = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used...Show moreBACKGROUNDOnly a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.METHODSWe conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP >= 140 mm Hg and/or diastolic BP >= 90 mm Hg) or 4 or more medication classes regardless of BP control (n(EA) = 931, n(AA) = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (n(EA) = 14,210, n(AA) = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (n(EA) = 5,266, n(AA) = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.RESULTSThe known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 x 10(-8)) and in the race-combined analysis (P = 1.5 x 10(-9)) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.CONCLUSIONThis genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.Show less

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Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group