Angiotensin-related genetic determinants of cardiovascular disease in patients undergoing hemodialysis

Sharon M. Moe, Jin Long, Tae Hwi Linus Schwantes-An, Brian S. Decker, Leah Wetherill, Howard J. Edenberg, Xiaoling Xuei, Matteo Vatta, Tatiana M. Foroud, Glenn M. Chertow

Research output: Contribution to journalArticle

Abstract

Background: Cardiovascular mortality in patients receiving dialysis remains unacceptably high, with unexplained ancestry differences suggesting a genetic component. Methods: We analyzed DNA samples from 37% of subjects enrolled in the EValuation Of Cinacalcet Hydrochloride (HCl) Therapy to Lower CardioVascular Events (EVOLVE) trial, a randomized trial conducted in patients receiving hemodialysis with secondary hyperparathyroidism, comparing cinacalcet to placebo on a background of usual care. DNA was analyzed for single-nucleotide polymorphisms (SNPs) in the genes encoding the angiotensin-converting enzyme receptor type I (AGTR1) and angiotensin-converting enzyme (ACE). Survival analyses were conducted separately in European Ancestry (EA) and African Ancestry (AfAn) due to known differences in cardiovascular events, minor alleles for the same variant and the frequency of minor alleles. Our primary determination was a meta-analysis across both races. Results: Meta-analysis showed significant associations between rs5186 in AGTR1 and increased rates by 25-34% for the primary endpoint (composite of death or nonfatal myocardial infarction, hospitalization for unstable angina, heart failure or peripheral vascular event), all-cause mortality, cardiovascular mortality and heart failure; all P < 0.001. Three correlated SNPs in ACE were associated with lower rates of sudden cardiac death (SCD) in EA samples. One ACE SNP, rs4318, only found in the AfAn samples, was associated with a lower rate of SCD in the AfAn samples. Conclusions: The C allele in rs5186 in AGTR1 was associated with higher rates of death and major cardiovascular events in a meta-analysis of EA and AfAn patients with end-stage kidney disease. SNPs in ACE were associated with SCD.

Original languageEnglish (US)
Pages (from-to)1924-1931
Number of pages8
JournalNephrology Dialysis Transplantation
Volume34
Issue number11
DOIs
StatePublished - Nov 1 2019

Fingerprint

Angiotensins
Peptidyl-Dipeptidase A
Renal Dialysis
Cardiovascular Diseases
Single Nucleotide Polymorphism
Sudden Cardiac Death
Meta-Analysis
Mortality
Heart Failure
Alleles
Secondary Hyperparathyroidism
DNA
Unstable Angina
Survival Analysis
Gene Frequency
Chronic Kidney Failure
Blood Vessels
Dialysis
Hospitalization
Myocardial Infarction

Keywords

  • angiotensin
  • cardiovascular mortality
  • genetics
  • hemodialysis
  • renin-angiotensin-aldosterone system

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

Angiotensin-related genetic determinants of cardiovascular disease in patients undergoing hemodialysis. / Moe, Sharon M.; Long, Jin; Schwantes-An, Tae Hwi Linus; Decker, Brian S.; Wetherill, Leah; Edenberg, Howard J.; Xuei, Xiaoling; Vatta, Matteo; Foroud, Tatiana M.; Chertow, Glenn M.

In: Nephrology Dialysis Transplantation, Vol. 34, No. 11, 01.11.2019, p. 1924-1931.

Research output: Contribution to journalArticle

@article{8b1cf423d3c240f999fe30c430f7bdc0,
title = "Angiotensin-related genetic determinants of cardiovascular disease in patients undergoing hemodialysis",
abstract = "Background: Cardiovascular mortality in patients receiving dialysis remains unacceptably high, with unexplained ancestry differences suggesting a genetic component. Methods: We analyzed DNA samples from 37{\%} of subjects enrolled in the EValuation Of Cinacalcet Hydrochloride (HCl) Therapy to Lower CardioVascular Events (EVOLVE) trial, a randomized trial conducted in patients receiving hemodialysis with secondary hyperparathyroidism, comparing cinacalcet to placebo on a background of usual care. DNA was analyzed for single-nucleotide polymorphisms (SNPs) in the genes encoding the angiotensin-converting enzyme receptor type I (AGTR1) and angiotensin-converting enzyme (ACE). Survival analyses were conducted separately in European Ancestry (EA) and African Ancestry (AfAn) due to known differences in cardiovascular events, minor alleles for the same variant and the frequency of minor alleles. Our primary determination was a meta-analysis across both races. Results: Meta-analysis showed significant associations between rs5186 in AGTR1 and increased rates by 25-34{\%} for the primary endpoint (composite of death or nonfatal myocardial infarction, hospitalization for unstable angina, heart failure or peripheral vascular event), all-cause mortality, cardiovascular mortality and heart failure; all P < 0.001. Three correlated SNPs in ACE were associated with lower rates of sudden cardiac death (SCD) in EA samples. One ACE SNP, rs4318, only found in the AfAn samples, was associated with a lower rate of SCD in the AfAn samples. Conclusions: The C allele in rs5186 in AGTR1 was associated with higher rates of death and major cardiovascular events in a meta-analysis of EA and AfAn patients with end-stage kidney disease. SNPs in ACE were associated with SCD.",
keywords = "angiotensin, cardiovascular mortality, genetics, hemodialysis, renin-angiotensin-aldosterone system",
author = "Moe, {Sharon M.} and Jin Long and Schwantes-An, {Tae Hwi Linus} and Decker, {Brian S.} and Leah Wetherill and Edenberg, {Howard J.} and Xiaoling Xuei and Matteo Vatta and Foroud, {Tatiana M.} and Chertow, {Glenn M.}",
year = "2019",
month = "11",
day = "1",
doi = "10.1093/ndt/gfy191",
language = "English (US)",
volume = "34",
pages = "1924--1931",
journal = "Nephrology Dialysis Transplantation",
issn = "0931-0509",
publisher = "Oxford University Press",
number = "11",

}

TY - JOUR

T1 - Angiotensin-related genetic determinants of cardiovascular disease in patients undergoing hemodialysis

AU - Moe, Sharon M.

AU - Long, Jin

AU - Schwantes-An, Tae Hwi Linus

AU - Decker, Brian S.

AU - Wetherill, Leah

AU - Edenberg, Howard J.

AU - Xuei, Xiaoling

AU - Vatta, Matteo

AU - Foroud, Tatiana M.

AU - Chertow, Glenn M.

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Background: Cardiovascular mortality in patients receiving dialysis remains unacceptably high, with unexplained ancestry differences suggesting a genetic component. Methods: We analyzed DNA samples from 37% of subjects enrolled in the EValuation Of Cinacalcet Hydrochloride (HCl) Therapy to Lower CardioVascular Events (EVOLVE) trial, a randomized trial conducted in patients receiving hemodialysis with secondary hyperparathyroidism, comparing cinacalcet to placebo on a background of usual care. DNA was analyzed for single-nucleotide polymorphisms (SNPs) in the genes encoding the angiotensin-converting enzyme receptor type I (AGTR1) and angiotensin-converting enzyme (ACE). Survival analyses were conducted separately in European Ancestry (EA) and African Ancestry (AfAn) due to known differences in cardiovascular events, minor alleles for the same variant and the frequency of minor alleles. Our primary determination was a meta-analysis across both races. Results: Meta-analysis showed significant associations between rs5186 in AGTR1 and increased rates by 25-34% for the primary endpoint (composite of death or nonfatal myocardial infarction, hospitalization for unstable angina, heart failure or peripheral vascular event), all-cause mortality, cardiovascular mortality and heart failure; all P < 0.001. Three correlated SNPs in ACE were associated with lower rates of sudden cardiac death (SCD) in EA samples. One ACE SNP, rs4318, only found in the AfAn samples, was associated with a lower rate of SCD in the AfAn samples. Conclusions: The C allele in rs5186 in AGTR1 was associated with higher rates of death and major cardiovascular events in a meta-analysis of EA and AfAn patients with end-stage kidney disease. SNPs in ACE were associated with SCD.

AB - Background: Cardiovascular mortality in patients receiving dialysis remains unacceptably high, with unexplained ancestry differences suggesting a genetic component. Methods: We analyzed DNA samples from 37% of subjects enrolled in the EValuation Of Cinacalcet Hydrochloride (HCl) Therapy to Lower CardioVascular Events (EVOLVE) trial, a randomized trial conducted in patients receiving hemodialysis with secondary hyperparathyroidism, comparing cinacalcet to placebo on a background of usual care. DNA was analyzed for single-nucleotide polymorphisms (SNPs) in the genes encoding the angiotensin-converting enzyme receptor type I (AGTR1) and angiotensin-converting enzyme (ACE). Survival analyses were conducted separately in European Ancestry (EA) and African Ancestry (AfAn) due to known differences in cardiovascular events, minor alleles for the same variant and the frequency of minor alleles. Our primary determination was a meta-analysis across both races. Results: Meta-analysis showed significant associations between rs5186 in AGTR1 and increased rates by 25-34% for the primary endpoint (composite of death or nonfatal myocardial infarction, hospitalization for unstable angina, heart failure or peripheral vascular event), all-cause mortality, cardiovascular mortality and heart failure; all P < 0.001. Three correlated SNPs in ACE were associated with lower rates of sudden cardiac death (SCD) in EA samples. One ACE SNP, rs4318, only found in the AfAn samples, was associated with a lower rate of SCD in the AfAn samples. Conclusions: The C allele in rs5186 in AGTR1 was associated with higher rates of death and major cardiovascular events in a meta-analysis of EA and AfAn patients with end-stage kidney disease. SNPs in ACE were associated with SCD.

KW - angiotensin

KW - cardiovascular mortality

KW - genetics

KW - hemodialysis

KW - renin-angiotensin-aldosterone system

UR - http://www.scopus.com/inward/record.url?scp=85074446739&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074446739&partnerID=8YFLogxK

U2 - 10.1093/ndt/gfy191

DO - 10.1093/ndt/gfy191

M3 - Article

C2 - 29982608

AN - SCOPUS:85074446739

VL - 34

SP - 1924

EP - 1931

JO - Nephrology Dialysis Transplantation

JF - Nephrology Dialysis Transplantation

SN - 0931-0509

IS - 11

ER -