The Thiazide-Sensitive Na+-Cl- Cotransporter Gene, C1784T, and Adrenergic Receptor-β3 Gene, T727C, May Be Gene Polymorphisms Susceptible to the Antihypertensive Effect of Thiazide Diuretics

Abstract

IntroductionThiazide diuretics (TZDs) have been most widely used as a first line antihypertensive drug (1,2). Recently, the ALLHAT study confirmed the usefulness of TZDs for the reduction of blood pressure (BP) and cardiovascular diseases in comparison with newer antihypertensive drugs, including Ca channel blockers (CCBs) such as amlodipine and angiotensin converting enzyme inhibitors (ACEIs) such as lisinopril in about 40,000 hypertensive patients with high risk factors (3). TZDs are not only effective as a monotherapy for hypertension, but are also very useful for combination therapy with other antihypertensive drugs (4). Moreover, the use of a TZD as a drug therapy for hypertension, which is a chronic and lifelong disease, would be very good from the viewpoint of the cost of drugs, because TZDs are the cheapest of all antihypertensive drugs. However, the response of BP to TZDs differs among individuals, and TZDs often induce side effects, such as hypokalemia and lipid, glucose and uric acid metabolism abnormalities (4). Therefore, it would be useful to determine the individual sensitivity to a TZD before prescribing it.Regarding previous findings about gene polymorphisms that influence TZD-sensitivity, Turner et al. (5) reported that the β3-subunit of the G protein (GNB3) C825T polymorphism was related to the antihypertensive effect of a TZD in Caucasian and African-American subjects with essential hypertension (EHT). Glorioso et al. (6) also demonstrated that the α-adducin (ADD1) Gly460Trp polymorphism is the gene conferring susceptibility to the antihypertensive effect of TZDs in Italian hypertensives. This ADD1 Gly460Trp polymorphism was also suggested to confer susceptibility to saltsensitivity in Caucasians and Asians with EHT (7).Mutations of causative genes have recently been detected in several monogenic electrolyte disorders, such as mutations in the thiazide-sensitive Na-Cl cotransporter (TSC) gene for Gitelman syndrome (8, 9), the WNK1 and 4 genes for Gordon syndrome (pseudohypoaldosteronism type II) (10) and the mineral corticoid receptor (MLR) for pseudohypoaldosteronism type I (PHA I) (11). TZDs are commonly effective for treating Gitelman syndrome and Gordon syndrome. We also focused on the Na /Ca 2 exchanger gene (NCX1), because its impairment was recently reported in mesangial cells from salt-sensitive hypertensive rats (12). TZDs are known to be effective for salt-sensitive hypertension. It is also known that the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) are activated in response to changes in circulating blood volume after TZD administration. Therefore, it is expected that gene polymorphisms related to the RAAS and SNS might be involved in the antihypertensive effect of TZDs. The present study investigated the gene polymorphism influencing the TZD-sensitivity by analyzing mainly single nucleotide polymorphisms (SNPs) of several water-electrolyte-related genes, including GN3B, ADD1, TSC, MLR, NCX1, WNK1, WNK4 and RAAS-and SNS-related genes, to antici...

A Physiologic Approach to the Pharmacogenomics of Hypertension

“…Rs4994, a polymorphism in ADRB3, has been evaluated in hypertensive studies. This variant is associated with essential hypertension in Han Chinese 64 , mean thiazide BP response in Japanese individuals 65 , and pulse pressure variation between atenolol and losartan in whites 17 . These associations were not corrected for a multiple testing penalty and have not been replicated.…”

Association of variants in renal salt reabsorption-related gene SLC12A3 with essential hypertension in a Mongolian population

“…Therefore, with an increase of TSC activity, greater amounts of sodium and chloride might be transported from the kidneys to the plasma, resulting in an increased efficiency of kidney sodium reabsorption. Matayoshi et al (2004) indicated that the BP in patients with essential hypertension who were homozygous for the major alleles of the SLC12A3 C1784T mutation was reduced by thiazide diuretics; however, the BP levels in those patients homozygous for the minor allele or in heterozygotes were not changed by thiazide diuretics. Thus, they suggested that Japanese patients with essential hypertension carrying the C1784T mutation of SLC12A3 were susceptible to the antihypertensive effect of thiazide diuretics.…”

Pharmacogenomic approaches to study the effects of antihypertensive drugs

“…These studies investigated the association of RAS gene polymorphisms and responses to antihypertensive drugs, including angiotensin I-converting enzyme inhibitors (ACEIs), 13 angiotensin II receptor blockers (ARBs), 14 beta blockers 15 and diuretics. 16 Our group also endeavored to clarify the susceptible gene polymorphisms to thiazide diuretics 17 and calcium channel blockers (CCBs) 18 by candidate genes approaches, although there are very limited reports about gene polymorphisms associated with the effects of CCBs. We clarified the associations between CACNA1D rs312481G4A and rs3774426C4T, and CACNA1C 527974G4A and treatment with a more significant reduction in BP for the combined presence of the L type of CCB's antihypertensive effect in this paper.…”