Genome-wide association analysis of common genetic variants of resistant hypertension

Published: April 25th, 2019

Category: News, Publications

Rouby, N. E., C. W. McDonough, Y. Gong, L. A. McClure, B. D. Mitchell, R. B. Horenstein, R. L. Talbert, D. C. Crawford, M. A. Gitzendanner, A. Takahashi, T. Tanaka, M. Kubo, C. J. Pepine, R. M. Cooper-DeHoff, O. R. Benavente, A. R. Shuldiner, and J. A. Johnson. 2018. Genome-wide association analysis of common genetic variants of resistant hypertension. The Pharmacogenomics Journal 1.

Abstract

Resistant hypertension (RHTN), defined as uncontrolled blood pressure (BP) ≥ 140/90 using three or more drugs or controlled BP (<140/90) using four or more drugs, is associated with adverse outcomes, including decline in kidney function. We conducted a genome-wide association analysis in 1194 White and Hispanic participants with hypertension and coronary artery disease from the INternational VErapamil-SR Trandolapril STudy—GENEtic Substudy (INVEST-GENES). Top variants associated with RHTN at p < 10−4 were tested for replication in 585 White and Hispanic participants with hypertension and subcortical strokes from the Secondary Prevention of Subcortical Strokes GENEtic Substudy (SPS3-GENES). A genetic risk score for RHTN was created by summing the risk alleles of replicated RHTN signals. rs11749255 in MSX2 was associated with RHTN in INVEST (odds ratio (OR) (95% CI) = 1.50 (1.2–1.8), p = 7.3 × 10−5) and replicated in SPS3 (OR = 2.0 (1.4–2.8), p = 4.3 × 10−5), with genome-wide significance in meta-analysis (OR = 1.60 (1.3–1.9), p = 3.8 × 10−8). Other replicated signals were in IFLTD1 and PTPRD. IFLTD1 rs6487504 was associated with RHTN in INVEST (OR = 1.90 (1.4–2.5), p = 1.1 × 10−5) and SPS3 (OR = 1.70 (1.2–2.5), p = 4 × 10−3). PTPRD rs324498, a previously reported RHTN signal, was among the top signals in INVEST (OR = 1.60 (1.3–2.0), p = 3.4 × 10−5) and replicated in SPS3 (OR = 1.60 (1.1–2.4), one-sided p = 0.005). Participants with the highest number of risk alleles were at increased risk of RHTN compared to participants with a lower number (p-trend = 1.8 × 10−15). Overall, we identified and replicated associations with RHTN in the MSX2, IFLTD1, and PTPRD regions, and combined these associations to create a genetic risk score.

 

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