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

Patrick N. Cunningham, Zhiying Wang, Megan L. Grove, Rhonda M. Cooper-DeHoff, Amber L. Beitelshees, Yan Gong, John G. Gums, Julie A. Johnson, Stephen T Turner, Eric Boerwinkle, Arlene B. Chapman

Research output: Contribution to journalArticle

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Original languageEnglish (US)
Article numbere0221957
JournalPloS one
Volume14
Issue number9
DOIs
StatePublished - Jan 1 2019

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angiotensins
Angiotensin Receptors
Blood pressure
blood pressure
African Americans
beta-adrenergic antagonists
Alleles
Blood Pressure
alleles
receptors
genotype
Thiazides
Genotype
kidney diseases
hypertension
Single Nucleotide Polymorphism
Albuminuria
antihypertensive agents
Kidney Diseases
diuretics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Cunningham, P. N., Wang, Z., Grove, M. L., Cooper-DeHoff, R. M., Beitelshees, A. L., Gong, Y., ... Chapman, A. B. (2019). Hypertensive APOL1 risk allele carriers demonstrate greater blood pressure reduction with angiotensin receptor blockade compared to low risk carriers. PloS one, 14(9), [e0221957]. https://doi.org/10.1371/journal.pone.0221957

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

In: PloS one, Vol. 14, No. 9, e0221957, 01.01.2019.

Research output: Contribution to journalArticle

Cunningham, PN, Wang, Z, Grove, ML, Cooper-DeHoff, RM, Beitelshees, AL, Gong, Y, Gums, JG, Johnson, JA, Turner, ST, Boerwinkle, E & Chapman, AB 2019, 'Hypertensive APOL1 risk allele carriers demonstrate greater blood pressure reduction with angiotensin receptor blockade compared to low risk carriers', PloS one, vol. 14, no. 9, e0221957. https://doi.org/10.1371/journal.pone.0221957
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. / Hypertensive APOL1 risk allele carriers demonstrate greater blood pressure reduction with angiotensin receptor blockade compared to low risk carriers. In: PloS one. 2019 ; Vol. 14, No. 9.
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abstract = "Background 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. Methods 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. Results 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. Conclusions 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.",
author = "Cunningham, {Patrick N.} and Zhiying Wang and Grove, {Megan L.} and Cooper-DeHoff, {Rhonda M.} and Beitelshees, {Amber L.} and Yan Gong and Gums, {John G.} and Johnson, {Julie A.} and Turner, {Stephen T} and Eric Boerwinkle and Chapman, {Arlene B.}",
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AU - Cunningham, Patrick N.

AU - Wang, Zhiying

AU - Grove, Megan L.

AU - Cooper-DeHoff, Rhonda M.

AU - Beitelshees, Amber L.

AU - Gong, Yan

AU - Gums, John G.

AU - Johnson, Julie A.

AU - Turner, Stephen T

AU - Boerwinkle, Eric

AU - Chapman, Arlene B.

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N2 - Background 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. Methods 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. Results 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. Conclusions 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.

AB - Background 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. Methods 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. Results 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. Conclusions 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.

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