Menu Close

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


Irvin, Marguerite Ryan; Sitlani, Colleen M.; Floyd, James S.; Psaty, Bruce M.; Bis, Joshua C.; Wiggins, Kerri L.; Whitsel, Eric A.; Sturmer, Til; Stewart, James B.; & Raffield, Laura M., et al. (2019). Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group. American Journal of Hypertension, 32(12), 1146-1153. PMCID: PMC6856621


BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.
METHODS: We 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 (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 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.
RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 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.
CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.


Reference Type

Journal Article

Year Published


Journal Title

American Journal of Hypertension


Irvin, Marguerite Ryan
Sitlani, Colleen M.
Floyd, James S.
Psaty, Bruce M.
Bis, Joshua C.
Wiggins, Kerri L.
Whitsel, Eric A.
Sturmer, Til
Stewart, James B.
Raffield, Laura M.
Sun, Fangui J.
Liu, Ching-Ti
Xu, Hanfei
Cupples, L. Adrienne
Tanner, Rikki M.
Rossing, Peter
Smith, Albert V.
Zilhão, Nuno R.
Launer, Lenore J.
Noordam, Raymond
Rotter, Jerome I.
Yao, Jie
Li, Xiaohui
Guo, Xiuqing
Limdi, Nita A.
Sundaresan, Aishwarya
Lange, Leslie A.
Correa, Adolfo
Stott, David J.
Ford, Ian
Jukema, J. Wouter
Gudnason, Vilmundur
Mook-Kanamori, Dennis O.
Trompet, Stella
Palmas, Walter
Warren, Helen R.
Hellwege, Jacklyn N.
Giri, Ayush
O'Donnell, Christopher J.
Hung, Adriana M.
Edwards, Todd L.
Ahluwalia, Tarunveer S.
Arnett, Donna K.
Avery, Christy L.