Association Analysis Between Hypertension and CYBA, CLCNKB, and KCNMB1 Functional Polymorphisms in the Japanese Population-The Suita Study-

Abstract

ssential hypertension (HT) is a multifactorial disorder influenced by both genetic and environmental factors. Over the past few years, a large number of genetic polymorphisms of candidate genes have been tested for their association with HT, but with controversial results, probably because of inadequate sample size, ethnic differences, and/or population stratification. The practical implications of an association study strongly depend on the reproducibility of the findings. 1 Recently, 3 specific functional polymorphisms have been reported to be associated with HT: the G(-930)A polymorphism of CYBA (p22 phox ), 2 the E65K polymorphism of KCNMB1, 3 and the T481S polymorphism of CLCNKB. 4,5 CYBA (p22 phox ) is a major component of NAD(P)H oxidase, and the NAD(P)H oxidase system is considered to be the most important source of superoxide anion in vascular tissues. 6,7 The superoxide anion has been suspected of involvement in the pathogenesis of HT through the inactivation of NO produced by NO synthetase (NOS3) in the vascular endothelium. Moreno et al reported that the G allele of CYBA had higher promoter activity and is associated with HT. 2 Blood pressure (BP) depends on the resistance of resistant vessels, and a key element of arterial tone is the largeconductance Ca 2+ and voltage-dependent K + (BK) channel. The BK channel is formed by an ion-conducting subunit and a regulatory 1 subunit (KCNMB1). An activating gainof-function mutation, the K65 allele, is reported to be associated with a low prevalence of diastolic HT. 3 The chloride channel ClC-Kb is expressed in the distal nephron and is known to be responsible for classic Bartter syndrome. The S481 allele has been reported to confer a strong gain-of-function effect that leads to enhanced NaCl re-absorption, and as expected, susceptibility to HT, in a Caucasian population. 5 All 3 polymorphisms have functional significance and are thus intriguing candidate genes. However, the sample sizes of the studies to date have been relatively small, or the descriptions of the epidemiological aspects rather weak. The purpose of the present study was to replicate findings of the previous association studies in a large epidemiological cohort representing the general population in Japan and to evaluate the possible importance of these polymorphisms. Methods Study PopulationThe selection criteria and design of the Suita Study have been previously described. [8][9][10] The present study was Background Reproducibility of results is important for the validity of genetic association studies. Recently, 3 functional polymorphisms, G(-930)A in CYBA, T481S in CLCNKB, and E65K in KCNMB1, were reported to be associated with blood pressure (BP) status and the aim of this study was to confirm those findings using a large cohort representing the general Japanese population. Methods and ResultsThe study population consisted of 3,652 subjects recruited from the Suita study as representive of the general population in Japan. The genotypes of the 3 polymorphisms were determined by the Taq...

Non-effect of p22-phox −930A/G polymorphism on end-organ damage in Brazilian hypertensive patients

“…3,6 In the present report, we did not confirm this presumed association in a sample of Brazilian subjects, suggesting that the À930A/G variant of p22-phox might not confer susceptibility to hypertension. Nevertheless, further studies in larger populations are required to elucidate this issue.…”

“…Although the frequencies of genotypes for the À930A/G polymorphism in hypertensive patients marginally differed from those in normotensives subjects (w 2 ¼ 6.38, P ¼ 0.04), there was no significant increase in GG genotype frequency in hypertensives (37%) in comparison to normotensives (28%), which contrasts with previous data obtained in other populations. 3,6 In order to enhance statistical power and given the described functional effect of GG in comparison to AA and AG genotypes, 3,4 AA subjects were added to AG ones. There were no differences regarding gender, age, diabetes mellitus, smoking, blood pressure, body mass index, abdominal circumference, metabolic profile, C-reactive protein as well as markers of renal damage and echocardiographic parameters between the genotype groups (AA/AG and GG) in hypertensive subjects.…”

E65 K polymorphism in KCNMB1 gene is not associated with ischaemic heart disease in Spanish patients

“…Allelic frequencies (0.1037 and 0.1224 for the K allele in parents and offspring, respectively) were similar to those previously described (Ferna´ndez-Ferna´ndez et al 2004;Kokubo et al 2005).…”

“…Functional findings together with epidemiological data lead the authors to the conclusion that the K allele has a protective effect against the severity of diastolic hypertension, suggesting that this mutation might offer a more efficient feedback mechanism for vascular smooth muscle contractility. Nevertheless, a very recent study has not been able to reproduce these results in a sample of 2130 Japanese hypertensive subjects (Kokubo et al 2005).…”

Genetics of arterial hypertension and hypotension

“…It occurs in 12% of white Europeans and 22% of black Africans (Jeck et al 2004). In one study, hypertension frequency increased from 25% in carriers of the wild-type gene to 45% in carriers of the mutation, findings that were not confirmed by other groups (Jeck et al 2004;Kokubo et al 2005;Speirs et al 2005).…”