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Eric Boerwinkle - One of the best experts on this subject based on the ideXlab platform.
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hypertensive apol1 risk allele carriers demonstrate greater blood pressure reduction with angiotensin receptor blockade compared to low risk carriers
PLOS ONE, 2019Co-Authors: Patrick N Cunningham, Zhiying Wang, John G Gums, Stephen T Turner, Julie A Johnson, Rhonda M Cooperdehoff, Megan L Grove, Amber L Beitelshees, Yan Gong, Eric BoerwinkleAbstract: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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lack of association between polymorphisms in stk39 a putative thiazide response gene and blood pressure response to hydrochlorothiazide
Pharmacogenetics and Genomics, 2010Co-Authors: Julio D. Duarte, Maximilian T Lobmeyer, Zhiying Wang, Arlene B Chapman, John G Gums, Taimour Y Langaee, Eric Boerwinkle, Stephen T Turner, Julie A JohnsonAbstract:STK39 was previously implicated as a hypertension susceptibility gene and is thought to be involved in control of Na+-Cl− cotransporter (NCC) activity. STK39 has been implicated as a putative thiazide diuretic response gene, as NCC activity is inhibited by Thiazides. Thus, we aimed to determine whether STK39 is a thiazide response gene. 195 “good” and 194 “poor” responders to hydrochlorothiazide (HCTZ) were genotyped for approximately 100 single nucleotide polymorphisms (SNPs) within 5000 bases of STK39. SNPs meeting criteria for advancement to replication analysis (P<0.01), along with those previously associated with hypertension, were then analyzed in a second population of 201 HCTZ-treated hypertensives. Two SNPs met these criteria and were analyzed for replication. However, neither these, nor previously implicated SNPs significantly associated with blood pressure response to HCTZ. These data suggest common variants in STK39 likely do not have a clinically relevant role in blood pressure response to HCTZ in hypertensives.
Julie A Johnson - One of the best experts on this subject based on the ideXlab platform.
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race specific comparisons of antihypertensive and metabolic effects of hydrochlorothiazide and chlorthalidone
The American Journal of Medicine, 2021Co-Authors: Lakshmi Manasa Chekka, Arlene B Chapman, John G Gums, Rhonda M Cooperdehoff, Julie A JohnsonAbstract:Abstract Background Chlorthalidone is recommended over hydrochlorothiazide (HCTZ) as the preferred thiazide, but the supporting evidence is not robust at routinely used doses, or in whites vs blacks, in whom differences in response to Thiazides are well known. We compare the efficacy and safety of HCTZ and chlorthalidone as first-line therapies for white and black hypertensive patients. Methods We compared treatment-related outcomes between the HCTZ arm (12.5 mg for 2-3 weeks; 25 mg for additional 6 weeks) of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR, n = 376) and chlorthalidone arm (15 mg for 2 weeks; 25 mg for additional 6 weeks) of PEAR-2 (n = 326) clinical trials, in 17–65-year-old mild-moderate uncomplicated hypertensive whites and blacks. Results Mean systolic/diastolic blood pressure (SBP/DBP) reduction with HCTZ vs chlorthalidone: 8 ± 8/4 ± 5 vs 12 ± 9/7 ± 5 mm Hg in whites (P Conclusion Compared with HCTZ, chlorthalidone showed greater blood pressure lowering and adverse metabolic effects in whites, but similar blood pressure lowering and greater adverse effects in blacks; suggesting that the recent guideline recommendations to choose chlorthalidone over HCTZ may not be warranted in blacks.
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hypertensive apol1 risk allele carriers demonstrate greater blood pressure reduction with angiotensin receptor blockade compared to low risk carriers
PLOS ONE, 2019Co-Authors: Patrick N Cunningham, Zhiying Wang, John G Gums, Stephen T Turner, Julie A Johnson, Rhonda M Cooperdehoff, Megan L Grove, Amber L Beitelshees, Yan Gong, Eric BoerwinkleAbstract: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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lack of association between polymorphisms in stk39 a putative thiazide response gene and blood pressure response to hydrochlorothiazide
Pharmacogenetics and Genomics, 2010Co-Authors: Julio D. Duarte, Maximilian T Lobmeyer, Zhiying Wang, Arlene B Chapman, John G Gums, Taimour Y Langaee, Eric Boerwinkle, Stephen T Turner, Julie A JohnsonAbstract:STK39 was previously implicated as a hypertension susceptibility gene and is thought to be involved in control of Na+-Cl− cotransporter (NCC) activity. STK39 has been implicated as a putative thiazide diuretic response gene, as NCC activity is inhibited by Thiazides. Thus, we aimed to determine whether STK39 is a thiazide response gene. 195 “good” and 194 “poor” responders to hydrochlorothiazide (HCTZ) were genotyped for approximately 100 single nucleotide polymorphisms (SNPs) within 5000 bases of STK39. SNPs meeting criteria for advancement to replication analysis (P<0.01), along with those previously associated with hypertension, were then analyzed in a second population of 201 HCTZ-treated hypertensives. Two SNPs met these criteria and were analyzed for replication. However, neither these, nor previously implicated SNPs significantly associated with blood pressure response to HCTZ. These data suggest common variants in STK39 likely do not have a clinically relevant role in blood pressure response to HCTZ in hypertensives.
John G Gums - One of the best experts on this subject based on the ideXlab platform.
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race specific comparisons of antihypertensive and metabolic effects of hydrochlorothiazide and chlorthalidone
The American Journal of Medicine, 2021Co-Authors: Lakshmi Manasa Chekka, Arlene B Chapman, John G Gums, Rhonda M Cooperdehoff, Julie A JohnsonAbstract:Abstract Background Chlorthalidone is recommended over hydrochlorothiazide (HCTZ) as the preferred thiazide, but the supporting evidence is not robust at routinely used doses, or in whites vs blacks, in whom differences in response to Thiazides are well known. We compare the efficacy and safety of HCTZ and chlorthalidone as first-line therapies for white and black hypertensive patients. Methods We compared treatment-related outcomes between the HCTZ arm (12.5 mg for 2-3 weeks; 25 mg for additional 6 weeks) of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR, n = 376) and chlorthalidone arm (15 mg for 2 weeks; 25 mg for additional 6 weeks) of PEAR-2 (n = 326) clinical trials, in 17–65-year-old mild-moderate uncomplicated hypertensive whites and blacks. Results Mean systolic/diastolic blood pressure (SBP/DBP) reduction with HCTZ vs chlorthalidone: 8 ± 8/4 ± 5 vs 12 ± 9/7 ± 5 mm Hg in whites (P Conclusion Compared with HCTZ, chlorthalidone showed greater blood pressure lowering and adverse metabolic effects in whites, but similar blood pressure lowering and greater adverse effects in blacks; suggesting that the recent guideline recommendations to choose chlorthalidone over HCTZ may not be warranted in blacks.
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hypertensive apol1 risk allele carriers demonstrate greater blood pressure reduction with angiotensin receptor blockade compared to low risk carriers
PLOS ONE, 2019Co-Authors: Patrick N Cunningham, Zhiying Wang, John G Gums, Stephen T Turner, Julie A Johnson, Rhonda M Cooperdehoff, Megan L Grove, Amber L Beitelshees, Yan Gong, Eric BoerwinkleAbstract: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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targeted sequencing identifies a missense variant in the best3 gene associated with antihypertensive response to hydrochlorothiazide
Pharmacogenetics and Genomics, 2018Co-Authors: Sonal Singh, Zhiying Wang, Arlene B Chapman, John G Gums, Taimour Y Langaee, Stephen T Turner, Yan Gong, Mohamed H Shahin, Caitrin W Mcdonough, Kent R BaileyAbstract:Chromosome 12q15 was identified in Genetic Epidemiology of Response Assessment (GERA) and replicated in Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) for its association with blood pressure (BP) response to hydrochlorothiazide (HCTZ). However, the functional variant is unknown and we aimed to identify the likely functional variants through targeted sequencing. The chromosome 12q15 region was sequenced in 397 best and worst responders to HCTZ in PEAR (N=199) and GERA (N=198) hypertensive study participants. Logistic regression was used for the association analysis adjusting for age, sex, race, and principal components 1 and 2. For validation, the significant single nucleotide polymorphism was tested for association with the change in systolic (ΔSBP) and diastolic BP (ΔDBP) post-treatment in the entire PEAR (N=370) and GERA (N=570) cohorts. A novel missense polymorphism (G>A, Pro383Leu) in BEST3, rs61747221, was significantly associated with better HCTZ response (P=0.0021, odds ratio=2.05). It was validated in the entire cohort of PEAR (ΔSBP: P=0.021, β=-1.60, ΔDBP: P=0.023, β=-1.08) and GERA (ΔSBP: P=0.028, β=-1.95, ΔDBP: P=0.032, β=-1.28). BEST3 encodes the calcium sensitive chloride channel in the vascular smooth muscle implicated in the regulation of BP, especially in response to vasoconstrictors like angiotensin II. These results suggest that BEST3 is involved in the chronic BP lowering mechanism of Thiazides and highlight its importance as a genetic predictor of the BP response to thiazide diuretics.
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lack of association between polymorphisms in stk39 a putative thiazide response gene and blood pressure response to hydrochlorothiazide
Pharmacogenetics and Genomics, 2010Co-Authors: Julio D. Duarte, Maximilian T Lobmeyer, Zhiying Wang, Arlene B Chapman, John G Gums, Taimour Y Langaee, Eric Boerwinkle, Stephen T Turner, Julie A JohnsonAbstract:STK39 was previously implicated as a hypertension susceptibility gene and is thought to be involved in control of Na+-Cl− cotransporter (NCC) activity. STK39 has been implicated as a putative thiazide diuretic response gene, as NCC activity is inhibited by Thiazides. Thus, we aimed to determine whether STK39 is a thiazide response gene. 195 “good” and 194 “poor” responders to hydrochlorothiazide (HCTZ) were genotyped for approximately 100 single nucleotide polymorphisms (SNPs) within 5000 bases of STK39. SNPs meeting criteria for advancement to replication analysis (P<0.01), along with those previously associated with hypertension, were then analyzed in a second population of 201 HCTZ-treated hypertensives. Two SNPs met these criteria and were analyzed for replication. However, neither these, nor previously implicated SNPs significantly associated with blood pressure response to HCTZ. These data suggest common variants in STK39 likely do not have a clinically relevant role in blood pressure response to HCTZ in hypertensives.
Elena Brioni - One of the best experts on this subject based on the ideXlab platform.
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physiological interaction between α adducin and wnk1 nedd4l pathways on sodium related blood pressure regulation
Hypertension, 2008Co-Authors: Paolo Manunta, Gail Lavery, Peter S Braund, Claire Bodycote, Cristina Tantardini, Simona Delli Carpini, Marco Simonini, Chiara Lanzani, Laura Zagato, Elena BrioniAbstract:The kidney plays an important role in salt and blood pressure (BP) homeostasis. In previous studies, variants in the genes for α-adducin (ADD1), WNK1, and NEDD4L, which all regulate renal sodium absorption, have been associated with increased BP. However, findings have been inconsistent. We tested whether this is because of physiological interactions between the effects of variants in these genes. We assessed the single and combined effects of the ADD1 (Gly460Trp), WNK1 (rs880054 A/G), and NEDD4L (rs4149601 G/A) polymorphisms on renal and BP response to an acute Na load (n=344 subjects), BP decrease after 1 month of treatment with 12.5 mg of hydrochlorothiazide (n=193), and ambulatory 24-hour BP (n=690). Individually, the variants showed modest effects on some of the studied phenotypes. We found the ADD1 Trp allele to be permissive for the effects of variants of the other genes. In combination, the same variants (ADD1 Trp/WNK1 GG/Nedd4L GA+AA) showed a consistent effect on renal Na handling ( P =0.009) and acute BP response to a saline infusion ( P =0.021), BP lowering after thiazide treatment ( P =0.008), and nocturnal systolic BP ( P =0.044). Physiological interaction between the ADD1 and WNK1-NEDD4L pathways influences the effects of variants in these genes on sodium-related BP regulation. Relatively common alleles in the ADD1, WNK1, and NEDD4L genes when present in combination may have significant effects on renal sodium handling, BP, and antihypertensive response to Thiazides.
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physiological interaction between α adducin and wnk1 nedd4l pathways on sodium related blood pressure regulation
Hypertension, 2008Co-Authors: Paolo Manunta, Gail Lavery, Peter S Braund, Claire Bodycote, Cristina Tantardini, Simona Delli Carpini, Marco Simonini, Chiara Lanzani, Laura Zagato, Elena BrioniAbstract:The kidney plays an important role in salt and blood pressure (BP) homeostasis. In previous studies, variants in the genes for α-adducin (ADD1), WNK1, and NEDD4L, which all regulate renal sodium absorption, have been associated with increased BP. However, findings have been inconsistent. We tested whether this is because of physiological interactions between the effects of variants in these genes. We assessed the single and combined effects of the ADD1 (Gly460Trp), WNK1 (rs880054 A/G), and NEDD4L (rs4149601 G/A) polymorphisms on renal and BP response to an acute Na load (n=344 subjects), BP decrease after 1 month of treatment with 12.5 mg of hydrochlorothiazide (n=193), and ambulatory 24-hour BP (n=690). Individually, the variants showed modest effects on some of the studied phenotypes. We found the ADD1 Trp allele to be permissive for the effects of variants of the other genes. In combination, the same variants (ADD1 Trp/WNK1 GG/Nedd4L GA+AA) showed a consistent effect on renal Na handling ( P =0.009) and acute BP response to a saline infusion ( P =0.021), BP lowering after thiazide treatment ( P =0.008), and nocturnal systolic BP ( P =0.044). Physiological interaction between the ADD1 and WNK1-NEDD4L pathways influences the effects of variants in these genes on sodium-related BP regulation. Relatively common alleles in the ADD1, WNK1, and NEDD4L genes when present in combination may have significant effects on renal sodium handling, BP, and antihypertensive response to Thiazides.
Stephen T Turner - One of the best experts on this subject based on the ideXlab platform.
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hypertensive apol1 risk allele carriers demonstrate greater blood pressure reduction with angiotensin receptor blockade compared to low risk carriers
PLOS ONE, 2019Co-Authors: Patrick N Cunningham, Zhiying Wang, John G Gums, Stephen T Turner, Julie A Johnson, Rhonda M Cooperdehoff, Megan L Grove, Amber L Beitelshees, Yan Gong, Eric BoerwinkleAbstract: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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targeted sequencing identifies a missense variant in the best3 gene associated with antihypertensive response to hydrochlorothiazide
Pharmacogenetics and Genomics, 2018Co-Authors: Sonal Singh, Zhiying Wang, Arlene B Chapman, John G Gums, Taimour Y Langaee, Stephen T Turner, Yan Gong, Mohamed H Shahin, Caitrin W Mcdonough, Kent R BaileyAbstract:Chromosome 12q15 was identified in Genetic Epidemiology of Response Assessment (GERA) and replicated in Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) for its association with blood pressure (BP) response to hydrochlorothiazide (HCTZ). However, the functional variant is unknown and we aimed to identify the likely functional variants through targeted sequencing. The chromosome 12q15 region was sequenced in 397 best and worst responders to HCTZ in PEAR (N=199) and GERA (N=198) hypertensive study participants. Logistic regression was used for the association analysis adjusting for age, sex, race, and principal components 1 and 2. For validation, the significant single nucleotide polymorphism was tested for association with the change in systolic (ΔSBP) and diastolic BP (ΔDBP) post-treatment in the entire PEAR (N=370) and GERA (N=570) cohorts. A novel missense polymorphism (G>A, Pro383Leu) in BEST3, rs61747221, was significantly associated with better HCTZ response (P=0.0021, odds ratio=2.05). It was validated in the entire cohort of PEAR (ΔSBP: P=0.021, β=-1.60, ΔDBP: P=0.023, β=-1.08) and GERA (ΔSBP: P=0.028, β=-1.95, ΔDBP: P=0.032, β=-1.28). BEST3 encodes the calcium sensitive chloride channel in the vascular smooth muscle implicated in the regulation of BP, especially in response to vasoconstrictors like angiotensin II. These results suggest that BEST3 is involved in the chronic BP lowering mechanism of Thiazides and highlight its importance as a genetic predictor of the BP response to thiazide diuretics.
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lack of association between polymorphisms in stk39 a putative thiazide response gene and blood pressure response to hydrochlorothiazide
Pharmacogenetics and Genomics, 2010Co-Authors: Julio D. Duarte, Maximilian T Lobmeyer, Zhiying Wang, Arlene B Chapman, John G Gums, Taimour Y Langaee, Eric Boerwinkle, Stephen T Turner, Julie A JohnsonAbstract:STK39 was previously implicated as a hypertension susceptibility gene and is thought to be involved in control of Na+-Cl− cotransporter (NCC) activity. STK39 has been implicated as a putative thiazide diuretic response gene, as NCC activity is inhibited by Thiazides. Thus, we aimed to determine whether STK39 is a thiazide response gene. 195 “good” and 194 “poor” responders to hydrochlorothiazide (HCTZ) were genotyped for approximately 100 single nucleotide polymorphisms (SNPs) within 5000 bases of STK39. SNPs meeting criteria for advancement to replication analysis (P<0.01), along with those previously associated with hypertension, were then analyzed in a second population of 201 HCTZ-treated hypertensives. Two SNPs met these criteria and were analyzed for replication. However, neither these, nor previously implicated SNPs significantly associated with blood pressure response to HCTZ. These data suggest common variants in STK39 likely do not have a clinically relevant role in blood pressure response to HCTZ in hypertensives.
