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.

FIGURE 1

Linkage disequilibrium linkage disequilibrium plots for ACE: linkage disequilibrium plots for the ACE SNPs examined in the EA population (A = EA D’, B = EA r²), and the AfAn population (C = AfAn D’, D = AfAn r²). SNPs in higher linkage disequilibrium are represented by darker squares. Higher measures of linkage disequilibrium indicate higher correlation between SNP genotypes, and should therefore result in similar P-values.

FIGURE 2

Probability of endpoint events and SNP rs5186 of the AGT1R gene: unadjusted Kaplan–Meier Curve for survival, or being free from the endpoints in Supplementary Table 1: primary composite endpoints from the EVOLVE study (death or first non-fatal myocardial infarction, unstable angina, heart failure or peripheral vascular event), in the EA population (A) and AfAn population (B); all-cause mortality (EA, C; AfAn, D); cardiovascular mortality (EA, E; AfAn, F); and heart failure (EA, G; AfAn, H). Each genotype group is represented by a different colored line as shown in the legend in each panel, which denotes whether there is one or two adenine (A) or cytosine (C) alleles at position 1166 of the gene. The color-shaded area represents the 95% CI.