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

Abstract

BackgroundHypertension (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.MethodsAA 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.ResultsBaseline 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.ConclusionsHypertensive 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.

APOL1 Nephropathy: From Genetics to Clinical Applications

“…Until specific therapies become available, an important goal is to understand whether APOL1 nephropathy responds to any current therapies. One recent study suggests that hypertension in Black individuals may respond differently to angiotensinconverting enzyme inhibitors on the basis of APOL1 genotype, with APOL1 high-risk genotype carriers experiencing greater response in BP than noncarriers (76). To date, there is no definitive evidence that the course of APOL1 nephropathy is ameliorated by any particular regimen in either its FSGS or CKD presentations, although the larger datasets that have the power to identify optimal treatments have not yet been fully tapped.…”

Association of West African ancestry and blood pressure control among African Americans taking antihypertensive medication in the Jackson Heart Study

“…Although blood pressure has a high degree of heritability, genetic variants identified to date explain only a small percentage (~<3%) of the interindividual variation in blood pressure . Candidate gene and genome‐wide studies have identified pharmacogenetic variants associated with the BP‐lowering response to antihypertensive medications (particularly thiazide diuretics [ NEDD4L] and beta blockers [ ADRB1] ) although the effect sizes of individual variants are quite small . However, the effectiveness of antihypertensive medication does vary by ancestral group (eg, African, Asian, and European ancestry), which may be related, in part, to genetic factors that vary in frequency according to historical geographic separations (ie, Europeans, Asians, and Africans living partially isolated in unique environments for tens of thousands of years) .…”

APOL1 nephropathy – a population genetics success story

“…1 ). Surprisingly, is it not proven that nonspecific therapies that block angiotensin II synthesis or the angiotensin receptor, are more beneficial with regard to slowing kidney disease progression, other than a greater blood pressure response in HR APOL1 genotype [ 102 ]. Sodium glucose cotransporter 2 (SGLT2) inhibitors, that have markedly changed the landscape of kidney function and cardiovascular outcomes, regardless of diabetic status, should be specifically examined in individuals with APOL1 HR genotype.…”