Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.
Black or African American
/ genetics
Aged
Antihypertensive Agents
/ adverse effects
Blood Pressure
/ drug effects
Case-Control Studies
DNA (Cytosine-5-)-Methyltransferases
/ genetics
DNA Methyltransferase 3A
DNA-Binding Proteins
/ genetics
Drug Resistance
/ genetics
Dystrophin-Associated Proteins
/ genetics
Europe
/ epidemiology
Female
Genetic Loci
Genome-Wide Association Study
Humans
Hypertension
/ drug therapy
Male
Middle Aged
Myosin Heavy Chains
/ genetics
Myosin Type V
/ genetics
Neuropeptides
/ genetics
Pharmacogenetics
Pharmacogenomic Variants
Polymorphism, Single Nucleotide
Risk Assessment
Risk Factors
Transcription Factors
/ genetics
United States
/ epidemiology
White People
/ genetics
blood pressure
genome-wide association study
hypertension
severe hypertension
treatment-resistant hypertension
Journal
American journal of hypertension
ISSN: 1941-7225
Titre abrégé: Am J Hypertens
Pays: United States
ID NLM: 8803676
Informations de publication
Date de publication:
15 11 2019
15 11 2019
Historique:
received:
19
07
2019
revised:
10
09
2019
accepted:
13
09
2019
pubmed:
24
9
2019
medline:
2
9
2020
entrez:
24
9
2019
Statut:
ppublish
Résumé
Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. 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. 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. This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.
Sections du résumé
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.
Identifiants
pubmed: 31545351
pii: 5572670
doi: 10.1093/ajh/hpz150
pmc: PMC6856621
doi:
Substances chimiques
Antihypertensive Agents
0
CASZ1 protein, human
0
DNA-Binding Proteins
0
DNMT3A protein, human
0
DTNB protein, human
0
Dystrophin-Associated Proteins
0
MYO5B protein, human
0
Neuropeptides
0
Transcription Factors
0
DNA (Cytosine-5-)-Methyltransferases
EC 2.1.1.37
DNA Methyltransferase 3A
EC 2.1.1.37
Myosin Type V
EC 3.6.1.-
Myosin Heavy Chains
EC 3.6.4.1
Types de publication
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1146-1153Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL120393
Pays : United States
Organisme : NCRR NIH HHS
ID : UL1 RR025005
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201800014I
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL130114
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL086694
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK079626
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201800014C
Pays : United States
Organisme : NHLBI NIH HHS
ID : K24 HL133373
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK063491
Pays : United States
Organisme : NIMHD NIH HHS
ID : HHSN268201800013I
Pays : United States
Organisme : NIH HHS
ID : S10 OD023680
Pays : United States
Organisme : NICHD NIH HHS
ID : K12 HD043483
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201800015I
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG023629
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL073410
Pays : United States
Organisme : ORD VA
ID : RES 13-457
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL120393
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG004402
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000124
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL105756
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL116640
Pays : United States
Informations de copyright
© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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