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Genome wide association study of apparent treatment resistant hypertension in the CHARGE consortium: The CHARGE Pharmacogenetics Working Group

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  • VA Million Veteran Program and the CHARGE Pharmacogenetics Working group
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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 (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. 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.

Original languageEnglish
JournalAmerican Journal of Hypertension
Volume32
Issue number12
Pages (from-to)1146-1153
Number of pages8
ISSN0895-7061
DOIs
Publication statusPublished - 15 Nov 2019

    Research areas

  • blood pressure, genome-wide association study, hypertension, severe hypertension, treatment-resistant hypertension

ID: 58000628