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

on behalf of eMERGE network

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 × 105) 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 × 105) 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.

Original languageEnglish
Pages (from-to)295-304
Number of pages10
JournalPharmacogenomics Journal
Volume19
Issue number3
DOIs
Publication statusPublished - 01-06-2019

Fingerprint

Genome-Wide Association Study
Hypertension
Odds Ratio
trandolapril
Hispanic Americans
Stroke
Alleles
Blood Pressure
Verapamil
Secondary Prevention
Pharmaceutical Preparations
Meta-Analysis
Coronary Artery Disease
Genome
Kidney

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

on behalf of eMERGE network. / Genome-wide association analysis of common genetic variants of resistant hypertension. In: Pharmacogenomics Journal. 2019 ; Vol. 19, No. 3. pp. 295-304.
@article{f55f2ad7a0bc4f1a95e01d4e6b2ba410,
title = "Genome-wide association analysis of common genetic variants of resistant hypertension",
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.",
author = "{on behalf of eMERGE network} and {El Rouby}, Nihal and McDonough, {Caitrin W.} and Yan Gong and McClure, {Leslie A.} and Mitchell, {Braxton D.} and Horenstein, {Richard B.} and Talbert, {Robert L.} and Crawford, {Dana C.} and Gitzendanner, {Matthew A.} and Atsushi Takahashi and Toshihiro Tanaka and Michiaki Kubo and Pepine, {Carl J.} and Cooper-DeHoff, {Rhonda M.} and Benavente, {Oscar R.} and Shuldiner, {Alan R.} and Michiaki Kubo",
year = "2019",
month = "6",
day = "1",
doi = "10.1038/s41397-018-0049-x",
language = "English",
volume = "19",
pages = "295--304",
journal = "Pharmacogenomics Journal",
issn = "1470-269X",
publisher = "Nature Publishing Group",
number = "3",

}

Genome-wide association analysis of common genetic variants of resistant hypertension. / on behalf of eMERGE network.

In: Pharmacogenomics Journal, Vol. 19, No. 3, 01.06.2019, p. 295-304.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association analysis of common genetic variants of resistant hypertension

AU - on behalf of eMERGE network

AU - El Rouby, Nihal

AU - McDonough, Caitrin W.

AU - Gong, Yan

AU - McClure, Leslie A.

AU - Mitchell, Braxton D.

AU - Horenstein, Richard B.

AU - Talbert, Robert L.

AU - Crawford, Dana C.

AU - Gitzendanner, Matthew A.

AU - Takahashi, Atsushi

AU - Tanaka, Toshihiro

AU - Kubo, Michiaki

AU - Pepine, Carl J.

AU - Cooper-DeHoff, Rhonda M.

AU - Benavente, Oscar R.

AU - Shuldiner, Alan R.

AU - Kubo, Michiaki

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85053779227&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053779227&partnerID=8YFLogxK

U2 - 10.1038/s41397-018-0049-x

DO - 10.1038/s41397-018-0049-x

M3 - Article

AN - SCOPUS:85053779227

VL - 19

SP - 295

EP - 304

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

SN - 1470-269X

IS - 3

ER -