Abstract: FR-PO562

APOL1 Hypertensive African Americans Show Greater BP Response and Urinary Albumin Reduction to Angiotensin Receptor Blockade with Different Genetic Predictors of Response versus Non-APOL1 Individuals

Session Information

Category: Hypertension

  • 1105 Hypertension: Clinical and Translational - Genetics and Epigenetics

Authors

  • Cunningham, Patrick, University of Chicago, Chicago, Illinois, United States
  • Wang, Zhiying, University of Houston, Houston, Texas, United States
  • Cooper-DeHoff, Rhonda M., University of Florida , Gainesville, Florida, United States
  • Chapman, Arlene B., University of Chicago, Chicago, Illinois, United States
Background

Hypertension (HBP) is common and disproportionately affects African Americans (AAs). HBP AAs typically are salt sensitive and respond more to thiazide diuretics, with a relatively suppressed renin-angiotensin-aldosterone axis. Variants of the APOL1 gene specific to AAs are associated with a higher rate of kidney disease and a complex role in cardiovascular disease. We sought to characterize HBP APOL1 AA individuals and their response to antihypertensive therapy.

Methods

HBP AA subjects from 4 trials (n=961) (PEAR1: NCT002465519 n=298, PEAR2: NCT01203852 n=190, GERA1 n=280, and GERA2 n=193: NCT 00005520) were evaluated at baseline after washout of BP meds. Genetic data was analyzed using Affymetrix or Illumina Human Omni1-Quad Beadchips. APOL1 G1 and G2 variants were imputed using g1000 (PEAR1, PEAR2), or direct sequencing (GERA1, GERA2). Genome wide association analyses included age, gender, baseline BP, and racial admixture as covariates.

Results

14.0% (n=135) were positive for two APOL1 risk alleles. APOL1 AAs had similar baseline office, home, ambulatory day and night SBP and DBP measures vs. others (n=827). APOL1 AAs had significantly higher serum creatinine concentrations (0.93+0.24 vs 0.87+0.21 mg/dl, p=0.006) and lower eGFR (98.7+19.6 v. 104.4+18.7 ml/min, p=0.0008). AAs with an APOL1 risk allele had a longer duration of HBP vs others (8.0+7.4 vs 6.7+7.5 yr, p=0.02). Subjects with an APOL1 risk allele had a greater SBP response to candesartan (12.2+1.2 vs 7.5+1.8 mmHg, p=0.03; GERA2), a trend toward greater DBP response (8.9+0.9 vs 6.3+1.2 mmHg, p=0.08), and a greater decline in albuminuria (-8.3+3.1 vs -3.7+4.3 mg/day, p=0.03). An intronic SNP rs17825860, within SDK1, predicted greater office SBP response (p=6.9 x 10-7) in APOL1 AAs, and rs286856, an intronic SNP within DPP6, predicted greater office SBP response (p=3.2 x 10-7) in APOL1 negative individuals.

Conclusion

HBP APOL1 AAs demonstrate early differences in eGFR and serum creatinine with a greater SBP response to angiotensin receptor blockade (ARB) before clinical evidence of cardiac or renal disease. Genetic variants of the podocyte protein SDK1, and DPP6, which binds voltage gated potassium channels, may influence BP response to ARBs depending on APOL1 status.

Funding

  • Other NIH Support