title: The thiazide-sensitive Na(+)-Cl(-) cotransporter gene, C1784T, and adrenergic receptor-beta3 gene, T727C, may be gene polymorphisms susceptible to the antihypertensive effect of thiazide diuretics.
abstract: The response of blood pressure to thiazide diuretics (TZDs) differs among individuals. The prediction of the antihypertensive effect of TZDs is important for realizing individualized therapy in the management of hypertension. The aim of this study was to identify the single nucleotide polymorphisms (SNPs) susceptible to the antihypertensive effect of TZDs, particularly focusing on genes related to water-electrolyte absorption in the kidney. Seventy-six outpatients (mean age, 65.4+/-9.0 years) with essential hypertension (EHT) taking TZDs were retrospectively assessed. We defined as responders (R) those whose mean blood pressure was lowered by more than 5 mmHg after the use of TZDs. Forty-eight SNPs in 17 genes (ADD1, GNB3, TSC [SLC12A3], MLR [NR3C2], NCX1 [SLC8A1], WNK1, WNK4, AGT, ACE, AT1 [AGTR1], CYP11B2, ADRB1, ADRB2, ADRB3, ADRA1A, ADRA1B, ADRA2A) were genotyped in the 76 patients. The SNPs in TSC, MLR, NCX1, WNK1, and WNK4 were identified by direct sequencing and those with minor frequencies of greater than 5% were genotyped in this study. The comparison of polymorphism prevalence between R and non-responders (NR) showed significant differences in TSC C1784T (C allele vs. T allele, odds ratio (OR)=3.81, p =0.016, confidence interval (CI): 1.25-11.63) and ADRB3 T727C (Trp64Arg) (T allele vs. C allele, OR=4.59, p =0.005, CI: 1.54-13.68). The blood pressure (BP) in patients homozygous for the major alleles of both TSC C1784T and ADRB3 T727C were significantly reduced by TZD treatment; however, the BP in those homozygous for the minor allele and heterozygous (TSC C1784T: TT+CT; ADRB3 T727C: CC+CT) for both SNPs were not significantly changed after TZD treatment. Both newly detected TSC C1784T and ADRB3 T727C are gene polymorphisms susceptible to the antihypertensive effect of TZDs in patients with EHT. Thus, the prediction of BP reduction by TZDs may be possible by evaluating these two SNPs.
authors.affiliation: Division of Hypertension and Nephrology, National Cardiovascular Center, Suita, Japan.
authors.forename: Tetsutaro
authors.initials: T
authors.lastname: Matayoshi
authors.forename: Kei
authors.initials: K
authors.lastname: Kamide
authors.forename: Shin
authors.initials: S
authors.lastname: Takiuchi
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yoshii
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Miwa
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Takami
authors.forename: Chihiro
authors.initials: C
authors.lastname: Tanaka
authors.forename: Mariko
authors.initials: M
authors.lastname: Banno
authors.forename: Takeshi
authors.initials: T
authors.lastname: Horio
authors.forename: Satoko
authors.initials: S
authors.lastname: Nakamura
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakahama
authors.forename: Fumiki
authors.initials: F
authors.lastname: Yoshihara
authors.forename: Takashi
authors.initials: T
authors.lastname: Inenaga
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyata
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Kawano
mesh_terms: D001581:Benzothiadiazines; D002148:Calmodulin-Binding Proteins / Q000235:genetics; D004232:Diuretics; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D015778:Minor Histocompatibility Antigens; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D012084:Renin-Angiotensin System / Q000235:genetics; D012189:Retrospective Studies; D049993:Sodium Chloride Symporter Inhibitors / Q000627:therapeutic use*; D049992:Sodium Chloride Symporters; D019831:Sodium-Calcium Exchanger / Q000235:genetics; D064486:Solute Carrier Family 12, Member 3; D013564:Sympathetic Nervous System / Q000502:physiology; D027981:Symporters / Q000235:genetics*; D000076204:WNK Lysine-Deficient Protein Kinase 1; D000099291:Adducins
chemical_list: D001581:Benzothiadiazines; D002148:Calmodulin-Binding Proteins; D004232:Diuretics; D020962:Heterotrimeric GTP-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D017346:Protein Serine-Threonine Kinases; D022702:Receptors, Adrenergic, beta-3; D011955:Receptors, Drug; D018161:Receptors, Mineralocorticoid; D049993:Sodium Chloride Symporter Inhibitors; D049992:Sodium Chloride Symporters; D019831:Sodium-Calcium Exchanger; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D000076204:WNK Lysine-Deficient Protein Kinase 1; D000099291:Adducins; C454420:G-protein beta3 subunit; C578874:SLC12A3 protein, human; C110374:sodium-calcium exchanger 1; C064415:thiazide receptor; C498743:WNK1 protein, human; C433806:WNK4 protein, human