Abstract: FR-PO561

Genetic Factors Predicting BP Response to Thiazides Differ in Hypertensive African Americans with and without APOL1 Genotypes

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

Essential hypertension (HBP) is common, and disproportionately affects African Americans (AAs) with higher rates of cardiovascular and renal disease. Recently, variants of the APOL1 gene have been associated with a higher rate of kidney disease, with studies suggesting a complex role in cardiovascular disease. We investigated whether genetic background in APOL1 affected individuals predicted sensitivity to thiazide diuretics in in AA with HBP.

Methods

We combined AA patients from three HBP trials (PEAR1: NCT002465519, n=298, PEAR2: NCT01203852, n=190, and GERA1, n=280) to assess whether APOL1 genotype predicted BP response to thiazide diuretics. Subjects with elevated serum creatinine or significant proteinuria were excluded from these studies. Patient genetic data (n=570) was analyzed by Affymetrix or Illumina Human Omni1-Quad Beadchip with correction for age, gender, baseline BP, and racial admixture. G1 and G2 variant alleles were detected by imputation using the g1000 data set (PEAR1, PEAR2), or by direct sequencing (GERA1). GWAS was performed on this data set to detect SNPs associated with differential response to thiazides.

Results

14.9% of this combined HBP cohort (n=85) was positive for two APOL1 risk alleles. SBP or DBP at baseline and SBP or DBP response to thiazides, as measured by office or home cuff were similar between APOL1 negative and positive individuals. GWAS performed after adjusting for APOL1 genotype found that an intronic SNP rs111955547, located in ROBO2, was associated with a significantly decreased response to thiazides for office DBP (p=4.8 x 10-8). Similarly, rs12943080, located in an intronic SNP in SNF8, was associated with a significantly decreased response to thiazides for night time SBP (p=5.0 x 10-7).

Conclusion

Although HBP APOL1 AA individuals demonstrated similar BP responses to thiazides, genetic variants of ROBO2, which has a known role in podocyte development, as well as SNF8, which interacts with TRPC6, responsible for autosomal dominant FSGS, may identify individuals with poor response to thiazide diuretics.

Funding

  • Other NIH Support