Hypertension In Japanese Research Articles

Association of novel promoter single nucleotide polymorphisms in vasopressin V1a receptor gene with essential hypertension in nonobese Japanese

We studied the association between four novel single nucleotide polymorphisms (SNPs) in the promoter region of V1aR gene and essential hypertension in 620 Japanese subjects (365 hypertensives and 255 healthy). A significant association was found between one of the genotypes and alleles at SNP -6951 and hypertension in a subsample of nonobese individuals. This association demonstrated an independent risk for nonobese hypertension.

Association of Genetic Polymorphisms of Endothelin-Converting Enzyme-1 Gene with Hypertension in a Japanese Population and Rare Missense Mutation in Preproendothelin-1 in Japanese Hypertensives

Endothelin-1 (EDN1), a 21-amino acid peptide, is a potent vasoconstrictor with various pharmacological responses. EDN1 is synthesized from a 212-amino acid precursor protein, preproEDN1, through multiple proteolytic steps. Endothelin-converting enzyme (ECE) cleaves a Trp73-Val74 peptide bond in big-EDN1 to give rise to mature EDN1. In this study, we examined the possible association of genetic variations in ECE1 with hypertension in a general Japanese population and searched for missense mutations in and around the EDN1 polypeptide. We genotyped 5 single nucleotide polymorphisms (SNPs) in the ECE1 gene in 1,873 individuals from a general Japanese population and identified one SNP associated with hypertension in women (rs212528: TT vs. TC+CC: odds ratio=1.40; 95% confidence intervals: 1.04-1.89; p=0.026), after adjusting for confounding factors. The systolic blood pressure in women with the CC genotype was 6.44 mmHg higher than that in those with the TT genotype (p=0.007), after adjusting for the same factors. Next, to identify the missense mutations that may influence the biological activity of EDN1, we sequenced the genomic region that encodes EDN1 in 942 Japanese hypertensive patients. We identified a novel missense mutation, G36R, in one hypertensive patient, but no mutations were observed in EDN1. A gene polymorphism in EDN1, Lys198Asn, has been reported to be associated with hypertension in obese subjects. Taken together, these findings reveal that the EDN-ECE pathway is an important system involved in essential hypertension in Japanese.

Extensive Genetic Analysis of 10 Candidate Genes for Hypertension in Japanese

The identification of genes that contribute to essential hypertension has been hampered because of a lack of statistical power and problems with multiple testing. In the present study, we performed association analyses between the 161 single nucleotide polymorphisms of 10 candidate genes and hypertension in a Japanese population recruited from the Suita Study (n=3654). We found that 5 polymorphisms in the 3 genes (SLC9A2, UMOD, and ELN) were associated with hypertension status, and 4 of these 5 polymorphisms were also associated with blood pressure values with a classical criterion of P<0.05. However, when a Bonferroni correction for multiple testing was applied, none of the polymorphisms were associated with blood pressure levels. We also performed association analyses between these 5 polymorphisms and intermediate phenotypes corresponding with the functions of candidate genes, including the renin/aldosterone profile, plasma uric acid levels, and pulse wave velocity. The ELN 3'-untranslated region (-/A) polymorphism was found to significantly affect pulse wave velocity, an indicator of arterial stiffness. Associations of the ELN 3'-untranslated region (-/A) polymorphism with hypertension and pulse wave velocity were reconfirmed in another set of the study population. Thus, ELN seems to contribute to blood pressure regulation by affecting arterial stiffness in Japanese.

Association between senescence‐related uncoupling protein 2 gene polymorphisms and abdominal obesity in Japanese subjects: The Tanno and Sobetsu study

Background: Uncoupling protein 2 (UCP2) plays an important role in regulating body weight, energy expenditure and insulin secretion. UCP2 is upregulated in white fat in response to fat feeding, and negatively controls insulin secretion. UCP2 also has a function that protects cells from apoptosis and oxidative stress, which shows UCP2 might be a senescence‐related gene. Previously, UCP2‐866G/A polymorphism in the promoter region has been reported to alter adipose tissue mRNA expression and is associated with obesity in Caucasians.Methods: In this study, we investigated the association between this polymorphism and obesity, insulin secretion and hypertension in the general Japanese population.Results: The allele frequency of UCP2‐866G/A polymorphism was significantly higher in Japanese subjects compared to Caucasians. It revealed that subjects only in the obese group with the AA type of UCP2‐866G/A polymorphism had significantly higher levels of body mass index (BMI) and waist circumference. Multiple logistic regression analysis showed that this polymorphism was independently associated with waist circumference. This positive association remained in the analysis of the subgroup younger than 65 years, but not in the older group. This polymorphism did not affect levels of insulin and homeostasis model assessment ratio (HOMA‐R).Conclusions: These results suggest that the AA type of UCP2‐866G/A polymorphism is related to abdominal obesity, which indicates the possible role of this polymorphism in causing metabolic syndromes.

Genetic Variations of HSD11B2 in Hypertensive Patients and in the General Population, Six Rare Missense/Frameshift Mutations

Mutations in the gene encoding 11beta-hydroxysteroid dehydrogenase type 2, HSD11B2, cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME). In AME, defective HSD11B2 enzyme activity results in overstimulation of the mineralocorticoid receptor (MR) by cortisol, causing sodium retention, hypokalemia, and salt-dependent hypertension. Here, we have studied whether genetic variations in HDS11B2 are implicated in essential hypertension in Japanese hypertensives and the general population. By sequencing the entire coding region and the promoter region of HDS11B2 in 953 Japanese hypertensives, we identified five missense mutations in 11 patients (L14F, n = 5; R74H, n = 1; R147H, n = 3; T156I, n = 1; R335H, n = 1) and one novel frameshift mutation (4884Gdel, n = 1) in a heterozygous state, in addition to 19 genetic variations. All genetic variations identified were rare, with minor allele frequencies less than 0.005. Four of 12 patients with the missense/frameshift mutations showed renal failure. Four missense mutations, L14F, R74H, R147H, and R335H, were successfully genotyped in the general population, with a sample size of 3,655 individuals (2,175 normotensives and 1,480 hypertensives). Mutations L14F, R74H, R147H, and R335H were identified in hypertensives (n = 6, 8, 3, and 0, respectively) and normotensives (n = 8, 12, 5, and 0, respectively) with a similar frequency, suggesting that these missense mutations may not strongly affect the etiology of essential hypertension. Since the allele frequency of all of the genetic variations identified in this study was rare, an association study was not conducted. Taken together, our results indicate that missense mutations in HSD11B2 do not substantially contribute to essential hypertension in Japanese.

A Nonsense Polymorphism (Y319X) of the Solute Carrier Family 6 Member 18 (SLC6A18) Gene is Not Associated with Hypertension and Blood Pressure in Japanese

We investigated the possible association of solute carrier family 6 member 18 (SLC6A18) with hypertension and blood pressure in Japanese, since the homologous murine XT2 gene was recently reported to be associated with hypertension. The entire coding region of SLC6A18 was sequenced in 30 unrelated Japanese subjects. The deleterious effects of the observed nonsynonymous single nucleotide polymorphisms (SNPs) on the phenotype were predicted using bioinformatics software. We tested the associations of one deleterious SNP (Y319X) with blood pressure and hypertension in a general population of 1,004 subjects in one area of Japan. Both quantitative and qualitative analyses adjusting for age and body mass index (BMI) as covariates were undertaken. Four synonymous (P7P, T32T, G37G and V387V), three missense (S12C, I32T and L478P) and one nonsense (Y319X: g1230757 C > G) polymorphisms were found. One of the synonymous polymorphisms was novel (V387V) by reference to the dbSNP database. The Y319X genotype distribution of CC:CG:GG in this population showed frequencies of 0.382, 0.461 and 0.156, respectively, which followed Hardy-Weinberg equilibrium. The nonsense polymorphism had odds ratios of 0.83 (confidence interval [CI] = 0.59-1.15, p = 0.26) in males and 0.96 (CI = 0.72-1.29, p = 0.80) in females with hypertension or current medication for hypertension. For the quantitative analysis, we excluded the current medication subgroup. The nonsense allele was not a significant predictor for systolic or diastolic blood pressure. This is the first report showing that a single polymorphism in SLC6A18 is not associated with hypertension or blood pressure in Japanese.

Interaction between Serotonin 2A Receptor and Endothelin-1 Variants in Association with Hypertension in Japanese

Serotonin has been implicated in the pathogenesis of hypertension because of its ability to induce vasoconstriction via stimulation of serotonin 2 (5-HT2) receptors. Recently, an association between the T102C functional polymorphism of the serotonin 2A (5-HT2A) receptor gene and hypertension in the UK has been reported. Another association study, however, failed to replicate this association in a Chinese population. We therefore investigated the possible association between the 5-HT2A T102C polymorphism and hypertension in two large Japanese populations (n = 2,968 total). We also investigated the possible interaction between the 5-HT2A T102C polymorphism and the G/T (Lys198Asn) polymorphism of the endothelin-1 (ET-1) gene, based on robust biological evidence for the existence of an interaction between the serotonin and endothelin systems. The results showed that there was no significant difference in the frequencies of the alleles and genotypes between the hypertensive and normotensive subjects. However, a significant interaction between the 5-HT2A T102C and ET-1 G/T polymorphisms in their association with hypertension (p = 0.0040) and with diastolic blood pressure (p = 0.0013) was revealed. A marginally significant interaction in the association with systolic blood pressure was also shown (p = 0.045). The associations of the 5-HT2A T102C polymorphism with hypertension and diastolic blood pressure in ET-1 T allele carriers were significant (p = 0.0056 and 0.021, respectively). The association of the 5-HT2A T102C polymorphism with systolic blood pressure in ET-1 T allele carriers was marginally significant (p = 0.054). Thus, the present study suggests that the 5-HT2A T102C and ET-1 G/T polymorphisms are interactively associated with hypertension.

Dissecting Hypertension by Obesity Identifies a Locus at 1p36

The elevated arterial pressure that defines essential hypertension is regarded as the manifestation of a diverse array of interacting genetic and environmental causes. As such, hypertension is a heterogeneous disorder in which multiple contributing factors are responsible for the overarching phenotype of high blood pressure that is the primary clinical manifestation observed. Such heterogeneity has undoubtedly hampered efforts to elucidate the genetic basis of essential hypertension. Overweight and obesity are well known to increase the risk of essential hypertension. Yet, there are many hypertensive individuals whose weight is normal. So does obesity hypertension have a different underlying genetic cause than lean hypertension? In the current issue, Pausova et al report finding a locus with suggestive linkage to hypertension and then reanalyzed their data after dividing their families into lean and obese.1 Of considerable interest, the significance of the linkage peak increased for the obese families but disappeared in the case of the families with hypertension who were not obese. The striking contrast in results for each category of hypertension lends strong support to the idea that hypertension of obesity has a different genetic basis than other categories of hypertension. Not only is this finding important in discovery of the genetic basis of obesity hypertension, but it has obvious implications for approaches that might be used to identify the basis for other “intermediate phenotypes” of hypertension. The study by Pausova et al involved 55 extended families from the geographically remote French-Canadian Saguenay/Lac-St-Jean region of Quebec. This relatively small, isolated population has been spared the level of genetic “noise” present in populations elsewhere. As a result, the degree of genetic homogeneity should be elevated and likely contributed to the …

Risk factors for occlusive lesions of intracranial arteries in stroke‐free Japanese

The aim of this study was to identify relevant risk factors for occlusive lesions of the intracranial arteries in stroke-free population. The subjects of this study were 425 patients without a history of stroke or transient ischemic attack and without any abnormality on a neurological examination who consecutively visited a neurology clinic between January 1994 and June 2001 requesting medical evaluation for possible cerebrovascular diseases. Subjects included 245 men and 180 women ranging in age from 33 to 89 years (mean+/-SD=64.0+/-10.0 years). We performed cervical and intracranial magnetic resonance angiography (MRA) in all subjects. Using a validated rating scheme of MRA for occlusive lesions, we evaluated the degree of stenoses in the extracranial portion of the internal carotid artery (ICA) and the intracranial arteries including the intracranial portion of the ICA, middle cerebral artery (MCA) stem, intracranial portion of the vertebral artery (VA), and basilar artery (BA). More than 25% stenoses were regarded as significant lesions in this study. Multiple logistic regression analyses showed that significant and independent predictors for extracranial ICA lesions were age, hyperlipidemia, and ischemic heart disease (IHD), those for intracranial ICA lesions were age, hypertension, diabetes mellitus, and IHD, those for MCA lesions were age and hypertension, those for intracranial VA lesions were hyperlipidemia and IHD, and those for BA lesions were hypertension and diabetes mellitus. The present study suggested that atherosclerosis of the intracranial VA was related to hyperlipidemia and IHD as was the case for the extracranial carotid artery, whilst atherosclerosis of other sites of intracranial arteries was associated with hypertension and diabetes mellitus in stroke-free Japanese.

A Novel Missense Mutation, F826Y, in the Mineralocorticoid Receptor Gene in Japanese Hypertensives: Its Implications for Clinical Phenotypes

A gain-of-function mutation resulting in the S810L amino acid substitution in the hormone-binding domain of the mineralocorticoid receptor (MR, locus symbol NR3C2) is responsible for early-onset hypertension that is exacerbated in pregnancy. The objective of this study was to test whether other types of missense mutations in the hormone-binding domain could be implicated in hypertension in Japanese. Here, we screened 942 Japanese patients with hypertension for the S810L mutation in exon 6 in the MR. We did not identify the S810L mutation in our hypertensive population, indicating that S810L does not play a major role in the etiology of essential hypertension in Japanese. However, we identified a novel missense mutation, F826Y, in three patients in a heterozygous state, in addition to four single nucleotide polymorphisms, including one synonymous mutation (L809L). The F826Y mutation is present in the MR hormone-binding domain and might affect the ligand affinity. The F826Y mutation was also identified in 13 individuals (5 hypertensives and 8 normotensives) in a Japanese general population (n=3,655). The allele frequency was 0.00178. The frequencies of the F826Y mutation in the hypertensive population (3/942) and in the hypertensive group (5/ 1,480) and the normotensive group (8/2,175) in the general population were not significantly different, suggesting that this mutation does not greatly affect hypertension. Although it is unclear at present whether or not the F826Y mutation makes a substantial contribution to the mineralocorticoid receptor activity, this missense mutation may contribute, to some extent, to clinical phenotypes through its effects on MR.

Association between Angiotensin II Type 1 Receptor Gene Polymorphism and Essential Hypertension: the Ohasama Study

Gene targeting approaches have suggested that the angiotensin II type 1 receptor (AT1R) is involved in blood pressure (BP) regulation and modulation of the effect of angiotensin II. The A1166C polymorphism of the AT1 receptor gene (AT1R/A1166C) is associated with hypertension in Caucasians, but not in Japanese. The goal of this study, the Ohasama Study, was to examine the association between AT1R/A1166C and hypertension, especially home BP, in the Japanese general population. The Ohasama Study was a cohort study based on Japanese rural residents of Ohasama Town in the northern part of Japan. Subjects who gave informed consent to the study protocol and genetic analysis were recruited. Home BP was measured twice in the morning within 1 h of waking up and in the evening just before going to bed. The TaqMan polimerase chain reaction (PCR) method clearly determined AT1R/A1166C genotypes (n =1,207). The genotype distribution of AT1R/A1166C was as follows: AA 84%; AC 15%; CC 1%. There was almost no difference in baseline characteristics among the AT1R genotypes (AA, AC, CC). In the subjects not receiving antihypertensive medication (n =817), both casual BP and home BP were not different among the AT1R genotypes after adjusting for confounding factors (age, sex, body mass index, current smoking habit and current alcohol consumption). The frequency of hypertension showed no difference among AT1R genotypes after adjusting for confounding factors, though the AC and CC genotypes were more frequent in hypertensives than in normotensives. Our data suggested that the AT1R/A1166C polymorphism is not a major genetic predisposing factor for hypertension in Japanese.

Serial study on the association between body mass index and hypertension in rural Japanese

The objective of this study was to examine the association between body mass index (BMI) and blood pressure. Two sets of cross-sectional data were obtained from annual health examinations for adults aged 40 years and over (n=1,327 in 1993; n=1,302 in 2000) in Tsunagi area of Kumamoto Prefecture, Japan. BMI was associated with mean blood pressure and with prevalence of hypertension both in 1993 and 2000. The association was independent of age, smoking status and alcohol consumption. A significant increase in risk of hypertension was found in most categories of BMI 25.0 and above, and a greater than three fold increase in those with BMI of 27 and above compared with those with BMI of 18.5-22.9. Although mean blood pressure and prevalence of hypertension sharply decreased in 2000 compared with that in 1993, BMI was positively and independently associated with increased blood pressure.

Lack of Association between Angiotensin II Type 1 Receptor Gene Polymorphism and Hypertension in Japanese.

Angiotensin II type 1 (AT1) receptor mediates the vasoconstriction and growth-promoting effect of angiotensin II in humans. It has been reported that a polymorphism of the AT1 receptor gene (an A/C transversion at position 1166; A1166C) may be associated with essential hypertension (HT). However, several conflicting results have also been reported. Therefore, we conducted an association study between A1166C variants of the AT1 receptor gene and hypertension in the Japanese population. We genotyped this variant in 3,918 subjects (1,492 hypertensive subjects and 2,426 normotensive subjects) recruited from the Suita study. In subjects not receiving antihypertensive medication, the influence of the genotype on blood pressure values adjusted for clinical covariates was analyzed. The genotype distribution did not differ between hypertensive and normotensive subjects in either men (frequency of the C allele: 8.1% vs. 7.8%, p=0.74) or women (8.1% vs. 7.7%, p=0.60). There were no significant differences in systolic blood pressure, diastolic blood pressure, or pulse pressure among the three genotypes in either men or women who had not received hypertensive medication. Our data suggest that the A1166C polymorphism of AT1 receptor is unlikely to influence blood pressure status in the Japanese population.

Epidemiological evidence of an association between SLC6A2 gene polymorphism and hypertension.

Selective blockade of the norepinephrine transporter with reboxetine has been reported to induce a slight but significant increase in blood pressure. This study was designed to examine the relation of genetic variants of the norepinephrine transporter gene (solute carrier family 6, member 2; SLC6A2) with hypertension in a Japanese population. We genotyped five genetic variants of SLC6A2, three in the promoter region and two in the intronic sequence, in 1,950 subjects recruited from the Suita study. One of the variants, an A > G polymorphism in the promoter region (Promoter 3 polymorphism), was found to be associated with hypertension. Multiple logistic analysis indicated that sex (p = 0.0223), age (p < 0.0001), body mass index (p < 0.0001), alcohol consumption (p = 0.0002), and the Promoter 3 genotype (AA = 1, AG + GG = 2) (p = 0.0090) were predictive of hypertensive status. The odds ratio of the AG + GG genotypes for hypertension was 1.35 (95% confidence interval: 1.08-1.69) over the AA genotype. SLC6A2 may be one of the genes that contribute to hypertension in Japanese. To our knowledge, this is the first report to detect associations between SLC6A2 genetic variants and blood pressure.

Serial Study on the Association between Body Mass Index and Hypertension in Rural Japanese

The objective of this study was to examine the association between body mass index (BMI) and blood pressure. Two sets of cross-sectional data were obtained from annual health examinations for adults aged 40 years and over (n=1,327 in 1993; n=1,302 in 2000) in Tsunagi area of Kumamoto Prefecture, Japan. BMI was associated with mean blood pressure and with prevalence of hypertension both in 1993 and 2000. The association was independent of age, smoking status and alcohol consumption. A significant increase in risk of hypertension was found in most categories of BMI 25.0 and above, and a greater than three fold increase in those with BMI of 27 and above compared with those with BMI of 18.5–22.9. Although mean blood pressure and prevalence of hypertension sharply decreased in 2000 compared with that in 1993, BMI was positively and independently associated with increased blood pressure.

Alcohol reduces insulin–hypertension relationship in a general population The Hisayama study

Insulin resistance may be a factor in the etiology of hypertension, and habitual alcohol intake may modify this relationship. We prospectively examined this hypothesis in 1,133 nonhypertensive, nondiabetic Japanese subjects, aged 40–79 years. Alcohol drinkers were more frequent among men than women at baseline (57.7 vs. 8.2%). The age-adjusted incidence of hypertension significantly increased with the elevating baseline insulin levels in women (P = .003 for trend), but not in men. The age- and sex-adjusted insulin levels and insulin resistance index decreased with elevating alcohol intake, while fasting glucose levels remained unchanged, suggesting that alcohol improves insulin sensitivity. Among nondrinkers, the age-adjusted incidence of hypertension significantly increased with elevating insulin tertiles in both sexes (P = .048 and .002 for trend in men and women, respectively), but not among drinkers. Our findings suggest a close association between insulin resistance and the incidence of hypertension in Japanese. However, alcohol modified and reduced this relationship.

Association of cardiovascular risk factors and endothelial dysfunction in japanese hypertensive patients: implications for early atherosclerosis.

Although hypertension, hyperlipidemia, diabetes and smoking are known risk factors of atherosclerosis in Caucasians, their relative contributions to early atherosclerosis among Japanese are unknown. Decrease in flow-mediated dilation (FMD) of the brachial artery is a useful marker of endothelial dysfunction and early atherosclerosis. To evaluate the relative contribution of hypertension to early atherogenesis, we determined FMD, as well as plasma levels of tissue-type plasminogen activator (t-PA; a sensitive index of endothelial damage) and tumor necrosis factor (TNF)-a and interleukin (IL)-6 (established markers of inflammation) in normotensive and hypertensive patients under treatment. FMD was significantly reduced as the number of risk factors increased, suggesting that accumulations of risk factors were related to endothelial dysfunction. FMD was reduced in hypertensives (9.9 +/- 5.8 (SD) %) compared to normotensives (14.6 +/- 7.6, p<0.01) despite good blood pressure control (139 +/- 20/80 +/- 14 mmHg in hypertensives). Nitroglycerine-induced endothelium-independent vasodilation was not altered in hypertensives (16.0 +/- 6.3%) as compared to normotensives (16.7 +/- 5.8). Plasma t-PA, TNF-alpha, and IL-6 levels were increased in hypertensives despite good blood pressure control. Thus, hypertension alone is a high risk for early atherosclerosis. Persistent endothelial damage and moderate inflammation may increase the risk of early atherosclerosis synergistically under the presence of hypertension in Japanese.

Epidemiologic study of the association of low-Km mitochondrial acetaldehyde dehydrogenase genotypes with blood pressure level and the prevalence of hypertension in a general population.

In Japanese and other Asians, the prevalence of genetically decreased mitochondrial aldehyde dehydrogenase (ALDH2) activity is higher than in Caucasians. The aim of this study was to elucidate the relation between ALDH2 genotypes and blood pressure levels or hypertension in Japanese. After obtaining informed consent for genetic analysis from 917 men and 1,478 women who lived in a mountainous farming region near Kyoto and who were free from cardiovascular disease and liver dysfunction, the authors identified the ALDH2 genotype in all subjects. Differences in blood pressure level among genotypes were then compared by analysis of covariance, and the relation between genotypes and hypertension was also analyzed by logistic regression analysis. The frequencies of genotypes *1/*1, *1/*2, and *2/*2 were 44.7%, 46.9% and 8.4% in men, and 50.1%, 43.2% and 6.8% in women, respectively. In men, systolic and diastolic blood pressures tended to decrease in the order of *1/*1>*1/*2>*2/*2. However, adjustment for confounding factors including alcohol consumption resulted in the disappearance of significance. Logistic regression analysis adjusted for the same confounding factors for men showed that the odds ratios (OR) of being hypertensive in the *2 allele to not having *2 allele were 0.67 (95% confidence interval (CI): 0.47-0.96). However, in the subgroup analyses, this relation was not observed in the group having a below-median level of alcohol consumption (OR = 0.92; 95% CI: 0.53-1.62) or in the group not taking antihypertensive agents (OR = 0.77; 95% CI: 0.52-1.15). Furthermore, we did not observe any relation between the ALDH2/*2 allele and hypertension in women (OR = 1.07; 95% CI: 0.80-1.42). The results suggest that there may be no causal relation between hypertension and the ALDH2 genotype per se, after excluding for some confounding factors, especially for alcohol drinking.

Association analyses between genetic polymorphisms of endothelial nitric oxide synthase gene and hypertension in Japanese: The Suita Study.

Endothelium-derived nitric oxide plays a key role in the regulation of vascular tone. Recently, endothelial nitric oxide synthase (eNOS) gene polymorphisms were reported to be associated with hypertension or coronary spasm. We investigated the association between the eNOS gene polymorphisms and hypertension in a large population-based sample of 4055 Japanese. We investigated two polymorphisms of the eNOS gene, Glu298Asp polymorphism of exon 7 and T(-786)C polymorphism of the promoter region. The genotype distribution in hypertensive subjects was compared to that in the other subjects. The influence of the genotype on blood pressure values was analyzed in the subjects not taking hypertensive medication. The promoter activities of the eNOS gene with the (-786)T or (-786)C allele were measured by a luciferase reporter gene assay. There was significant linkage disequilibrium between the two polymorphisms (P < 0.0001). The genotype distribution of the Glu298Asp or T(-786)C polymorphism did not differ between the hypertensive and the other subjects. No significant differences in the blood pressure of subjects not taking hypertensive medication were observed among the three genotypes of Glu298Asp or T(-786)C polymorphisms. No significant differences in the promoter activity were observed between bovine endothelial cells transfected with the (-786)T and (-786)C alleles. Our data suggested that these polymorphisms of the eNOS gene are unlikely to be major factors in the susceptibility to hypertension in the Japanese population studied.

Association analysis of beta(2)-adrenergic receptor polymorphisms with hypertension in Japanese.

Significant evidence has been provided for the pathophysiological involvement of the beta(2)-adrenergic receptor (ADRB2) in hypertension. Among ADRB2 polymorphisms identified to date, 2 amino acid substitutions, Arg16Gly and Gln27Glu, and a promoter variant, T-47C, are considered functionally important. In particular, Arg16Gly was shown to be associated with hypertension in black and white subjects. To investigate the relevance of ADRB2 polymorphisms to hypertension, we undertook an extensive association study in a Japanese population. An association was tested in 2 ways. First, a case-control study was conducted in 842 hypertensive and 633 normotensive subjects. In addition to the overall comparison between case and control groups, each was stratified by body mass index and compared with an independent panel of 525 diabetic subjects. Second, ANOVA and multivariate analyses were performed to test the significance of an association between ADRB2 genotype and the level of blood pressure within the entire population except for 395 subjects who had been under treatment for hypertension. Although no significant association was observed for Arg16Gly and T-47C, 2 analytical methods indicated a marginal association (P:=0.01 to 0.04) between the Glu27 variant and lower blood pressure levels. Given such a normotensive propensity, the odds ratio for Glu27 versus Gln27 allele frequencies was estimated to be 0.74, with a wide confidence interval (95% CI, 0.55 to 0.99) reflecting the low Glu27-allele frequency (6% to 8%) in Japanese. There were no apparent confounding influences of obesity and diabetes on the postulated association. Our data suggest that 3 ADRB2 polymorphisms tested are unlikely to confer principal genetic susceptibility for hypertension in the Japanese population. However, further investigation is warranted to clarify the relevance of ADRB2 polymorphisms to blood pressure regulation.