Hypertensive APOL1 risk allele carriers demonstrate greater blood pressure reduction with angiotensin receptor blockade compared to low risk carriers

• Published in: PloS one Vol. 14; no. 9; p. e0221957
• Main Authors: Cunningham, Patrick N., Wang, Zhiying, Grove, Megan L., Cooper-DeHoff, Rhonda M., Beitelshees, Amber L., Gong, Yan, Gums, John G., Johnson, Julie A., Turner, Stephen T., Boerwinkle, Eric, Chapman, Arlene B.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.09.2019; Public Library of Science (PLoS)
• Subjects: Adrenergic beta-antagonists; Adult; African Americans; African Americans - genetics; Age; Alleles; Angiotensin; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Angiotensins; Antihypertensive agents; Antihypertensives; Apolipoprotein L1 - genetics; Benzimidazoles - therapeutic use; Biology and Life Sciences; Blood pressure; Candesartan; Cardiovascular diseases; Carriers; Clinical trials; Complications and side effects; Development and progression; Diuretics; Drug therapy; Environmental science; Epidemiology; Female; Future predictions; Genes; Genetic engineering; Genome-Wide Association Study; Genomes; Genomics; Genotype; Genotype & phenotype; Genotypes; Health aspects; Humans; Hydrochlorothiazide; Hypertension; Hypertension - drug therapy; Hypertension - ethnology; Hypertension - genetics; Kidney diseases; Kidneys; Male; Medical schools; Medicine; Medicine and Health Sciences; Middle Aged; Minority & ethnic groups; Mortality; Nephrology; Patient outcomes; Pharmacogenomic Variants; Pharmacy; Polymorphism, Single Nucleotide; Pressure reduction; Public health; Risk; Risk factors; Sequence Analysis, DNA; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Tetrazoles - therapeutic use; Thiazides; Treatment Outcome; Chicago Illinois; Florida; United States > US; Illinois; Texas
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0221957

Hypertension (HTN) disproportionately affects African Americans (AAs), who respond better to thiazide diuretics than other antihypertensives. Variants of the APOL1 gene found in AAs are associated with a higher rate of kidney disease and play a complex role in cardiovascular disease. AA subjects from four HTN trials (n = 961) (GERA1, GERA2, PEAR1, and PEAR2) were evaluated for blood pressure (BP) response based on APOL1 genotype after 4-9 weeks of monotherapy with thiazides, beta blockers, or candesartan. APOL1 G1 and G2 variants were determined by direct sequencing or imputation. Baseline systolic BP (SBP) and diastolic BP (DBP) levels did not differ based on APOL1 genotype. Subjects with 1-2 APOL1 risk alleles had a greater SBP response to candesartan (-12.2 +/- 1.2 vs -7.5 +/- 1.8 mmHg, p = 0.03; GERA2), and a greater decline in albuminuria with candesartan (-8.3 +/- 3.1 vs +3.7 +/- 4.3 mg/day, p = 0.02). APOL1 genotype did not associate with BP response to thiazides or beta blockers. GWAS was performed to determine associations with BP response to candesartan depending on APOL1 genotype. While no SNPs reached genome wide significance, SNP rs10113352, intronic in CSMD1, predicted greater office SBP response to candesartan (p = 3.7 x 10-7) in those with 1-2 risk alleles, while SNP rs286856, intronic in DPP6, predicted greater office SBP response (p = 3.2 x 10-7) in those with 0 risk alleles. Hypertensive AAs without overt kidney disease who carry 1 or more APOL1 risk variants have a greater BP and albuminuria reduction in response to candesartan therapy. BP response to thiazides or beta blockers did not differ by APOL1 genotype. Future studies confirming this initial finding in an independent cohort are required.