A multilocus approach to the antihypertensive pharmacogenetics of hydrochlorothiazide

Objectives To assess the influence of variations in multiple candidate genes on inter-individual variation in diastolic blood pressure (DBP) response to hydrochlorothiazide. Methods A community-based sample of 585 adults with essential hypertension underwent monotherapy with hydrochlorothiazide for 4 weeks. In a nested case–control design, 195 individuals in the highest tertile of DBP response (responders) and 195 individuals in the lowest tertile of DBP response (non-responders) were genotyped for 45 polymorphisms in 19 candidate genes. For those polymorphisms where the set association approach found to be significantly associated with DBP response, logistic regression was performed to estimate the odds ratio (OR) for response associated variation in the identified genotype/haplotype. Results Two polymorphisms in the sodium channel &ggr;-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were significantly associated with blood pressure response to hydrochlorothiazide. In the final experiment for the set association model P=0.038. In the logistic regression analyses, compared to subjects with the CT/CT haplotype of the SCNN1G gene, those with the GA/GA haplotype had OR 5.21 of being a DBP responder [95% CI 1.65–16.47]. Compared to subjects with the GT genotype of the ENOSA_rs1799983 polymorphism, those with the GG genotype had an OR 2.19 of being a DBP responder [95% CI 1.27–3.77]. Conclusions Two polymorphisms in the sodium channel &ggr;-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were associated with significant differences in odds of DBP response to hydrochlorothiazide. Follow-up studies are needed to define the functional genetic variations and their mechanisms of pharmacogenetic effects.

[1]  Peter Donnelly,et al.  A comparison of bayesian methods for haplotype reconstruction from population genotype data. , 2003, American journal of human genetics.

[2]  J. Lalouel,et al.  Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase , 1992, Nature genetics.

[3]  L Zagato,et al.  Polymorphisms of alpha-adducin and salt sensitivity in patients with essential hypertension. , 1997, Lancet.

[4]  H. Melhus,et al.  Polymorphisms in the angiotensinogen and angiotensin II type 1 receptor gene are related to change in left ventricular mass during antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial , 2002, Journal of hypertension.

[5]  A. Di Giorgio,et al.  Combined 17α-Hydroxylase/17,20-Lyase Deficiency Caused by Phe93Cys Mutation in the CYP17 Gene , 2002 .

[6]  T. Ogihara,et al.  Association of a Sodium Channel α Subunit Promoter Variant with Blood Pressure , 2001 .

[7]  E. Boerwinkle,et al.  Interacting effects of gender and genotype on blood pressure response to hydrochlorothiazide. , 2002, Kidney international.

[8]  R. Lifton,et al.  Molecular pathogenesis of inherited hypertension with hyperkalemia: The Na–Cl cotransporter is inhibited by wild-type but not mutant WNK4 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[9]  H. Melhus,et al.  Angiotensinogen gene polymorphisms: relationship to blood pressure response to antihypertensive treatment. Results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial. , 2004, American journal of hypertension.

[10]  Thomas Lumley,et al.  Diuretic therapy, the alpha-adducin gene variant, and the risk of myocardial infarction or stroke in persons with treated hypertension. , 2002, JAMA.

[11]  P. Donnelly,et al.  A new statistical method for haplotype reconstruction from population data. , 2001, American journal of human genetics.

[12]  T. Ogihara,et al.  Association of Sodium Channel &ggr;-Subunit Promoter Variant With Blood Pressure , 2001, Hypertension.

[13]  E. Boerwinkle,et al.  Effects of endothelial nitric oxide synthase, alpha-adducin, and other candidate gene polymorphisms on blood pressure response to hydrochlorothiazide. , 2003, American journal of hypertension.

[14]  D J Reda,et al.  Single-Drug Therapy for Hypertension in Men -- A Comparison of Six Antihypertensive Agents with Placebo , 1993 .

[15]  E. Boerwinkle,et al.  C825T Polymorphism of the G Protein &bgr;3-Subunit and Antihypertensive Response to a Thiazide Diuretic , 2001, Hypertension.

[16]  D. Nebert,et al.  Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist? , 1999, Clinical genetics.

[17]  J. Ott,et al.  Trimming, weighting, and grouping SNPs in human case-control association studies. , 2001, Genome research.

[18]  Cristina Barlassina,et al.  Polymorphisms of α-adducin and salt sensitivity in patients with essential hypertension , 1997, The Lancet.

[19]  J. Lalouel,et al.  A chimaeric llβ-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension , 1992, Nature.

[20]  T. Ishimitsu,et al.  Positive association of CYP11B2 gene polymorphism with genetic predisposition to essential hypertension , 2002, Journal of Human Hypertension.

[21]  Cristina Barlassina,et al.  ACE and &agr;-Adducin Polymorphism as Markers of Individual Response to Diuretic Therapy , 2003, Hypertension.

[22]  J. Pepper,et al.  Coexistence of functioning beta 1- and beta 2-adrenoceptors in single myocytes from human ventricle. , 1993, Circulation.

[23]  R. Collins,et al.  Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. , 1994, British medical bulletin.

[24]  Alex P. Reiner,et al.  Diuretic Therapy, the α-Adducin Gene Variant, and the Risk of Myocardial Infarction or Stroke in Persons With Treated Hypertension , 2002 .

[25]  Eric Boerwinkle,et al.  Predictors of antihypertensive response to a standard dose of hydrochlorothiazide for essential hypertension. , 2002, Kidney international.

[26]  E. Vesell.  Therapeutic Lessons from Pharmacogenetics , 1997, Annals of Internal Medicine.

[27]  C. Sander,et al.  Genomic medicine and the future of health care. , 2000, Science.

[28]  L. Schild,et al.  Hypertension caused by a truncated epithelial sodium channel γ subunit: genetic heterogeneity of Liddle syndrome , 1995, Nature Genetics.

[29]  E. Neer.  Heterotrimeric C proteins: Organizers of transmembrane signals , 1995, Cell.

[30]  N. Glorioso,et al.  The role of alpha-adducin polymorphism in blood pressure and sodium handling regulation may not be excluded by a negative association study. , 1999, Hypertension.

[31]  Pettinger Wa,et al.  Single-drug therapy for hypertension in men. , 1993 .

[32]  J. Horisberger,et al.  Epithelial Sodium Channel: A Ligand-Gated Channel? , 2004, Nephron Physiology.

[33]  R. Eckel,et al.  Lipoprotein lipase. A multifunctional enzyme relevant to common metabolic diseases. , 1989, The New England journal of medicine.

[34]  M. Arisawa,et al.  Overt nephrogenic diabetes insipidus in mice lacking the CLC-K1 chloride channel , 1999, Nature Genetics.