NADH dehydrogenase subunit-2 237 Leu/Met polymorphism modifies the effects of alcohol consumption on risk for hypertension in middle-aged Japanese men.

NADH dehydrogenase subunit-2 237 leucine/methionine (ND2-237 Leu/Met) polymorphism is associated with longevity in the Japanese population, and the ND2-237Met genotype may exert antiatherogenic effects. To investigate whether ND2-237 Leu/Met polymorphism is associated with risk of hypertension, we conducted a cross-sectional study of 398 Japanese male subjects. The frequency of hypertension was significantly higher in ND2-237Leu genotypic men than in ND2-237Met genotypic men. On analysis of covariance, the interaction between ND2-237 Leu/Met polymorphism and habitual drinking was significantly associated with both systolic blood pressure and diastolic blood pressure. Multiple logistic regression analysis revealed that the ND2-237Met genotype, particularly in younger subjects (age <60 years), had a lower odds ratio for hypertension than the ND2-237Leu genotype. Moreover, the association of ND2-237 Leu/Met polymorphism with hypertension may depend on the frequency of alcohol consumption. The odds ratio for hypertension was significantly higher in daily drinkers with ND2-237Leu when compared with non- or ex-drinkers with ND2-237Leu. However, the association between the ND2-237Met genotype and hypertension may not depend on the frequency of alcohol consumption. The present results suggest that ND2-237 Leu/Met polymorphism is associated with hypertension and that modification of hypertension risk is dependent on alcohol consumption in middle-aged Japanese men.     

Interaction between longevity-associated mitochondrial DNA 5178 C/A polymorphism and cigarette smoking on hematological parameters in Japanese men

Mitochondrial DNA 5178 C/A (mt5178 C/A), namely NADH dehydrogenase subunit 2 237 Leu/Met, polymorphism is as reported in literature associated with longevity and susceptibility to ischemic heart disease or cerebrovascular disorders in the Japanese population. Previous reports suggested that mt5178A genotype exerts antiatherogenic effects. The aim of this study was to investigate whether mt5178 C/A polymorphism is associated with hematological parameters, such as thrombogenic risk factors for myocardial infarction and stroke, in 321 healthy Japanese men. No significant differences were observed between mt5178 C/A genotypes, but in subjects with body mass index (BMI) of < or = 23, this polymorphism influenced the effects of habitual smoking on hematological parameters. Red blood cell (RBC) counts were significantly lower and mean corpuscular hemoglobin (MCH) levels were significantly higher in smokers with mt5178A than nonsmokers with mt5178A. Platelet counts were significantly higher in smokers with mt5178C than nonsmokers with mt5178C. Cigarette consumption was strongly associated with RBC counts, mean corpuscular volume levels, and MCH levels for men with mt5178A, and was associated with platelet counts for those with mt5178C. Moreover, BMI was significantly positively associated with RBC counts and platelet counts only in men with mt5178A, age was significantly negatively associated with RBC counts only in men with mt5178C. These data suggest that mt5178 C/A polymorphism may influence the effects of cigarette smoking on hematological parameters in healthy BMI < or = 23 Japanese men.     

Longevity-associated mitochondrial DNA 5178 A/C polymorphism modulates effects of daily drinking and cigarette consumption on serum triglyceride levels in middle-aged Japanese men

Mitochondrial DNA 5178 adenine/cytosine (mt5178 A/C) polymorphism is one of the longevity-associated mitochondrial DNA polymorphisms. The frequency of the mt5178A genotype is significantly higher in Japanese centenarians than in the general population. We previously reported that serum high-density lipoprotein cholesterol levels were significantly higher in men with mt5178A than in those with mt5178C. However, this significant difference disappeared after adjusting for drinking frequency. To investigate the interaction between mt5178 A/C polymorphism and habitual drinking on serum lipid levels, we performed an association study in 321 healthy middle-aged Japanese men. Interaction between mt5178 A/C polymorphism and daily drinking on serum triglyceride (TG) levels was observed (P=0.019). Moreover, interaction between mt5178 A/C polymorphism and cigarette consumption on serum TG levels was also observed (P=0.022). Multiple regression analysis showed that, in men with mt5178A, daily drinking decreased TG levels (P=0.025), and cigarette consumption increased TG levels (P<0.001), while in men with mt5178C, the effects of daily drinking and cigarette consumption on TG levels were unclear. No interaction was observed on other lipid levels. Longevity-associated mitochondrial DNA 5178 A/C polymorphism thus influences the effects of daily drinking and cigarette consumption on TG levels in middle-aged Japanese men.     

Association of the longevity-associated mitochondrial DNA 5178 A/C polymorphism with serum protein fraction levels in healthy Japanese women

Mitochondrial DNA 5178 adenine/cytosine (mt5178 A/C) polymorphism was reported to be associated with longevity and susceptibility to adult-onset diseases in Japanese. To examine whether mt5178 A/C genotypes are associated with serum protein fraction profiles, we genotyped 461 healthy Japanese individuals, and studied the relationship of mt5178 A/C genotypes to both proportion and levels of serum protein fraction. The mt5178 A/C was genotyped using polymerase chain reaction-restriction fragment length polymorphism method. The alpha-1, alpha-2, and beta globulin proportions in females carrying mt5178A were significantly higher than those in females carrying mt5178C (P=0.002, 0.006, and 0.008, respectively). Moreover, the alpha-1, alpha-2, and beta globulin levels in females carrying mt5178A were significantly higher than those in females carrying mt5178C (P=0.001, 0.002, 0.018, respectively). This difference in globulin fraction level between the two genotypes was more evident in premenopausal females than in postmenopausal females. However, no such difference was found in males. These results provide the first evidence that the mt5178 A/C polymorphism may influence the serum protein fraction levels of the healthy Japanese women.     

Association of the mitochondrial DNA 5178A/C polymorphism with maternal inheritance and onset of type 2 diabetes in Japanese patients.

The mitochondrial DNA 5178A/C (mt5178A/C) polymorphism is associated with longevity and adult onset diseases. We investigated an association of the mt5178A/C polymorphism with the occurrence and clinical features of type 2 diabetes. Two hundred and seventy Japanese patients with type 2 diabetes (181 men and 89 women) and 254 control subjects without diabetes were studied. Patients with mutations at position 3243 in the mitochondrial DNA were excluded. Genotype was determined by the polymerase chain reaction-restriction fragment length polymorphism method. Various clinical features including age at disease onset were compared between the patients with the mt5178A and mt5178C alleles. Mt5178C was observed more frequently in patients with type 2 diabetes than in control subjects (65.9% vs 57.9%, P = 0.058). Clear information about the maternal history of diabetes was obtained from 233 diabetic patients. Patients with a maternal history of diabetes carried the mt5178C allele (58/75, 77.3%) more frequently than did patients without a maternal history of diabetes (100/158, 63.3%; P = 0.032) and control subjects (57.9%; P = 0.002). The mean age at onset of diabetes was significantly lower in patients with mt5178C (47.6 +/- 11.4 years) than in patients with mt5178A (51.5 +/- 10.0 years; P = 0.0073). The mt5178A/C polymorphism may be associated with maternal inheritance of type 2 diabetes and may influence the age at onset through deterioration of mitochondrial function.     

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.     

Lack of association between genetic polymorphism of CYP11B2 and hypertension in Japanese: the Suita Study.

Aldosterone synthase (CYP11B2) is a key enzyme in the biosynthesis of aldosterone. Recently, a polymorphism in the 5'-flanking region of the CYP11B2 gene [T(-344)C] has been reported to be associated with blood pressure and plasma aldosterone levels. We investigated the association between this polymorphism and hypertension in a large population-based sample of 4,000 Japanese. The genotype distribution in hypertensive subjects (n=1,535) was compared to that in normotensive subjects (n=2,514). In subjects not receiving antihypertensive medication, the influence of the genotype on blood pressure values adjusted for clinical covariates was analyzed. All analyses were performed separately for men and women. The genotype distribution did not differ between hypertensive and normotensive subjects in either men (frequency of C allele: 30.3% vs. 31.4%, p=0.48) or women (31.5% vs. 31.7%, p=0.93). 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 T(-344)C polymorphism of CYP11B2 is unlikely to influence blood pressure status in the Japanese population.     

Relation between the angiotensin-converting enzyme insertion/deletion polymorphism and blood pressure in Japanese male subjects

Inconsistent results have been reported regarding the association of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and hypertension. Recent studies of population-based samples of three different areas in Japan presented conflicting results regarding this association. We, thus, investigated the relation between the ACE I/D polymorphism and blood pressure (BP), or the frequency of hypertension, respectively, in 706 Japanese male subjects who participated in the health check-up programme of our hospital. The ACE I/D polymorphism was determined by the polymerase chain reaction technique. Of 706 subjects, 203 were found to have hypertension and the other 503 were found to be normotensive. In all subjects, the frequencies of the DD, ID, and II genotypes were 0.123, 0.432, and 0.445, respectively, and the allelic frequency of the D allele was 0.339. In the younger subjects aged <50 years (n=264), neither systolic nor diastolic BP differed significantly among the genotypes. Conversely, in the older subjects aged > or =50 years (n=442), the systolic BP was significantly higher by 5.9 mmHg in the subjects with the ID genotype than those with the II genotype (P<0.01), and the diastolic BP was significantly higher in the subjects with the DD and ID genotypes by 5.1 and 3.3 mmHg, respectively than those with the II genotype (P<0.05 for each), although age, BMI, percentage of smoking habits, drinking habits, or the use of antihypertensive drugs did not differ significantly among the genotypes. In addition, in the older subjects, the hypertensive subjects showed significantly higher frequencies of the DD and ID genotypes and the D allele than the normotensive subjects. These results demonstrated that there was no significant association of the ACE I/D polymorphism with BP or a prevalence of hypertension in younger Japanese men aged <50 years but there was in older Japanese men aged > or =50 years.     

Angiotensin converting enzyme genetic polymorphism is not associated with hypertension in a cross-sectional sample of a Japanese population: the Shibata Study

BACKGROUND: The studies on the association of deletion/ insertion (D/I) polymorphism of angiotensin converting enzyme (ACE) gene with blood pressure and hypertension reported contradictory results. Because there was no population-based study in Japan, we examine the hypothesized association in a cross-sectional sample of a Japanese cohort. METHODS AND RESULTS: The blood pressure of 464 men and 876 women aged 40-80 years was measured, and their DNA was analyzed for ACE D/I genotypes. The prevalence of the D allele was 38.7 and 39.2% in men and women, respectively (overall 39%). There was a tendency for higher covariate (age, body mass index, albuminuria, hematocrit, alcohol consumption, smoking, diabetes mellitus, ischemic heart disease and antihypertensive medication) adjusted mean levels of diastolic blood pressure for the DD genotype in men but not in women. However, this tendency disappeared after dichotomization of blood pressure into diagnostic categories (normotension and hypertension). Results did not differ when the subjects were divided into two age groups (< or = 59 and > or = 60 years). Covariate-adjusted odds ratios for hypertension for presence of the D allele were close to the null value of one. ACE genetic variation accounted for only 0.1 and 0.7% of the inter-individual variation in systolic and diastolic blood pressure in men. These estimates were 0.2 and 0.1%, respectively, in women. CONCLUSION: Although there is a tendency of higher diastolic blood pressure in men with DD genotypes, there is no convincing evidence that ACE genotypes are associated with hypertension in this Japanese population.     

Preproghrelin Leu72Met variant contributes to overweight in middle-aged men of a Japanese large cohort

OBJECTIVE: To investigate whether Leu72Met polymorphism of the preproghrelin gene is associated with overweight/obesity in middle-aged and older Japanese. DESIGN: Cross-sectional analysis. SUBJECTS: A total of 2238 community-dwelling middle-aged and older Japanese people (age: 40-79 years) who participated in the first wave of examinations in the National Institute for Longevity Sciences - Longitudinal Study of Aging from April 1998 to March 2000. MEASUREMENTS: The Leu72Met polymorphism of prepoghrelin gene, anthropometric variables including body weight, body mass index (BMI), waist circumference, waist-to-hip ratio and whole-fat mass and biochemical variables including serum lipid levels, fasting plasma glucose, insulin and homeostasis model assessment for insulin resistance. RESULTS: The frequencies of the Leu72Leu, Leu72Met and Met72Met alleles were 63.4, 32.7 and 4.0%, respectively. No differences in the genotype distributions of the Leu72Met polymorphism were found between genders or age groups, and no significant associations were observed between polymorphism and anthropometric variables in women and older men. However, middle-aged men who were 72Met allele carriers showed a higher body weight change from body weight at 18 years of age, as well as a higher waist circumference and a tendency to a higher waist-hip-ratio than noncarriers. Although there were no significant differences in the genotype distribution according to BMI in women and older men, a significantly higher frequency of the 72Met allele was found in the higher BMI group (BMI> or =25 kg/m(2)) of middle-aged men than in the normal-weight group. No significant associations were observed between polymorphism and serum lipid, glucose or insulin levels. CONCLUSIONS: These results suggest that the 72Met allele of the preproghrelin gene is a contributing factor for midlife weight change in men.     

Mitochondrial 5178A/C genotype is associated with acute myocardial infarction.

A single nucleotide polymorphism of mitochondrial 5178A/C, causing a Met to Leu replacement within the NADH dehydrogenase subunit, is reported to be associated with longevity. The purpose of the present study was to assess the contribution of mitochondrial polymorphisms, particularly the 5178A/C genotype, to the susceptibility to acute myocardial infarction (AMI) in a Japanese study population. There were 4 groups: 150 patients with AMI, 150 with essential hypertension, 100 with diabetes mellitus, and 150 subjects matched for age and sex who served as the control group. Mitochondrial 5178A/C was detected by the polymerase chain reaction restriction fragment length polymorphism method. The allelic frequency of 5178C was significantly higher in the AMI group than in the control group, and this difference was more marked in younger patients. There were differences in allelic frequencies among the essential hypertension group, diabetes mellitus group and control group, but a higher frequency of the C allele was seen in the AMI group compared with the essential hypertension and diabetes mellitus groups. This particular polymorphism was found to be associated with development of AMI, especially in younger patients and constitutes a new risk factor for AMI.     

Ghrelin基因Leu72Met多态性与胰岛素分泌、胰岛素抵抗和糖调节受损的相关性

目的探讨ghrelin基因Leu72Met（C408A）多态性与胰岛素分泌、胰岛素抵抗和糖调节受损（IGR）之间的关系。方法用PCR-RFLP法对126例IGR和423例NGT者进行ghrelin基因Leu72Met多态性分析。同时检测生化指标和临床参数。结果NGT组分为BMI〈24．0kg／m^2和BMI≥24．0kg／m^2两组,比较OGTT各点血糖、胰岛素和HOMA-IR、HOMA-β,结果提示组内CC基因型者和CA＋AA基因型者间,上述指标均无统计学差异。NGT和IGR组ghrelin基因C408A分布和等位基因频率无统计学差异。IGR组CC基因型者DBP明显低于CA＋AA基因型者;血尿酸水平均明显高于CA＋AA基因型者。结论ghrelin基因Leu72Met与血压和血尿酸水平相关。     

Angiotensinogen polymorphisms and elevated blood pressure in the general population: the Copenhagen City Heart Study

In the present study, we tested the hypothesis that the Met235Thr and Thr174Met mutations were associated or not with elevated blood pressure. We genotyped 9100 women and men from the Danish general population, of whom 54% had elevated blood pressure. Of the 9100, 41% and 12% carried the Thr235 and Met174 mutations, respectively; the Met174 mutation always occurred on the same allele as the Thr235 mutation. On multifactorial logistic regression analysis, women homozygous for Thr235 versus noncarriers had an odds ratio for elevated blood pressure of 1.29 (95% CI 1.05 to 1.58), which increased to 1.50 (1.15 to 1.96) if they also were homozygous for Thr174 (noncarrier of Met174). Women homozygous for Thr235 also had an increased risk of isolated elevated systolic blood pressure (1.37; 1.02 to 1.84) and of mild blood pressure elevation (1.40; 1.10 to 1.77). We found no statistically significant association between elevated blood pressure and genotype in men or among genotype and systolic blood pressure, diastolic blood pressure, or pulse pressure in either gender. Homozygosity for both Thr235 and Thr174 was associated with a 10% increase in plasma angiotensinogen levels in both genders compared with homozygosity for Met235 and Thr174; however, systolic and diastolic blood pressures were positively correlated to plasma angiotensinogen levels in women only. In conclusion, in this large-scale study of the general population, double homozygosity for Thr235 and Thr174 in the angiotensinogen gene is associated with a 10% increase in angiotensinogen levels and is a risk factor for elevated blood pressure in women but not in men.     

High systolic blood pressure is associated with Val/Val genotype in the catechol-o-methyltransferase gene. The Nord-Trøndelag Health Study (HUNT)

BACKGROUND: The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism, Val158Met. A few studies on animals have shown a relationship between the COMT gene and BP, but whether this exists in human beings is unclear. The aim of this study was to evaluate the relationship between codon 158 COMT gene polymorphism and BP in a population-based cohort. METHODS: In the 1995-97 Nord-Tr?ndelag Health Study (HUNT), the association between Val/Met polymorphism at the COMT gene and BP was evaluated in a group of 2966 nondiabetic individuals. RESULTS: Among the 2591 individuals without current use of antihypertensive drugs, systolic BP > or =140 mm Hg was more likely among persons with Val/Val genotype compared with the other genotypes (44.8% v 39.1%, P = .02). In the multivariate analysis the prevalence odds ratio for having the Val/Val genotype was 1.63 (95% CI = 1.18 to 2.24) among individuals with systolic BP > or =160 mm Hg compared with those with systolic BP <140 mm Hg. Val/Val genotype was also more likely (OR = 1.30, 95% CI = 1.04 to 1.63) among individuals with hypertension (as defined by use of antihypertensive medication, systolic BP > or =140 mm Hg, or diastolic BP > or =90 mm Hg) than among those with normal BP. CONCLUSIONS: Based on the study findings, the Val/Val genotype appears to be associated with a higher prevalence of increased systolic BP compared with the Met/Met or Met/Val genotypes at the COMTgene.     

Leucine7 to proline7 polymorphism in the preproneuropeptide Y is associated with the progression of carotid atherosclerosis, blood pressure and serum lipids in Finnish men.

A rather common leucine7-to-proline7 (Leu7Pro) polymorphism in the preproneuropeptide Y (prepro-NPY) gene signal peptide may be important in blood pressure regulation, cholesterol metabolism and the pathogenesis of atherosclerosis in humans. We examined the associations of the Leu7Pro polymorphism with carotid atherosclerotic progression, blood pressure and serum lipids in a population-based sample of 966 men aged 42-60 years in Finland. The Pro7 substitution (carrier frequency 12.2%) was associated with accelerated four-year increase in the mean (P=0.01) and maximal (P=0.007) common carotid intima-media thickness (IMT) and with slightly increased systolic (P=0.03) and diastolic (P=0.02) blood pressures, adjusted for other major risk factors. Men with Pro7 substitution had 30.6% (95% CI 6.9-54.0%) greater increase in the mean IMT and 20.0% (95% CI 5.3-34.4%) greater increase in the maximal IMT than men with Leu7/Leu7 genotype. The Pro7 substitution was also related to increased serum total cholesterol (P=0.01) and LDL cholesterol (P=0.02) in obese (body mass index (BMI)>30 kg/m(2)) men. This study provides important evidence suggesting that the Pro7 substitution in the prepro-NPY is an important risk factor for accelerated atherosclerotic progression, increased blood pressure and increased serum cholesterol in humans.     

Peroxisome proliferator-activated receptor-gammaPro12Ala polymorphism and the association with blood pressure in type 2 diabetes: skaraborg hypertension and diabetes project

OBJECTIVE: This study explored whether the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma (PPARgamma) is associated with blood pressure in subjects with type 2 diabetes. DESIGN: A community-based, cross-sectional observation study. SETTING: Primary care. PATIENTS: One hundred and ninety-two men and 192 women with type 2 diabetes who consecutively underwent annual follow-up. MAIN OUTCOME MEASURE: The PPARgammaPro12Ala genotype was determined by polymerase chain reaction-based techniques. Associations between genotype and blood pressure were analysed by linear regression and expressed as differences in blood pressure (delta) with 95% confidence interval (CI). RESULTS: The mean systolic blood pressure and the diastolic blood pressure were 160 mmHg (standard deviation = 22.8) and 84 mmHg (standard deviation = 9.6), respectively. Subjects with Pro/Ala (24%) or Ala/Ala (2%) had lower diastolic blood pressure (delta = 2.8; 95% CI, 0.6-5.0) when adjusted for age and gender compared with Pro/Pro subjects (74%). This association was restricted to men (delta = 4.4; 95% CI, 1.3-7.4), who also had a borderline significant difference in systolic blood pressure (delta = 6.9; 95% CI, -0.8 to 13.8). In men the difference in diastolic blood pressure remained after adjustment for age, body mass index, serum triglycerides, serum insulin and haemoglobin A(1c) (delta = 4.6; 95% CI, 1.1-8.1). A subanalysis of normotensive men (n = 100) confirmed the difference associated with the Pro12Ala polymorphism in diastolic blood pressure (delta = 5.2; 95% CI, 0.6-10.0). CONCLUSIONS: The common Pro12Ala polymorphism in PPARgamma is associated with lower diastolic blood pressure in male subjects with type 2 diabetes.     

The Leu554Phe polymorphism in the E-selectin gene is associated with blood pressure in overweight people

BACKGROUND: Associations between circulating concentrations of E-selectin, blood pressure and obesity, and between the Leu554Phe (L/F554) polymorphism and blood pressure have been documented. OBJECTIVES: To investigate how the E-selectin L/F554 polymorphism is involved in longitudinal blood pressure changes, and how this polymorphism interacts with body mass index (BMI) on blood pressure. DESIGN AND PARTICIPANTS: For this study, 478 men and 546 women were selected from the Stanislas cohort, a French longitudinal study of volunteers for a free health check-up. These individuals underwent two examinations (t(0) and t(+5)) and were not taking medication that can affect blood pressure. RESULTS: At t(0), no relationship was observed between L/F554 polymorphism and blood pressure. However at t(+5), systolic blood pressure (SBP) was greater in individuals carrying the F allele, and the L/F554 polymorphism was associated with SBP in interaction with BMI (P < 0.001 in men and P < 0.05 for women). There was a steeper increase in SBP with BMI greater than 25 kg/m2 in carriers of the F allele than in LL homozygotes. Similar results were observed for diastolic blood pressure in men (P = 0.0103). CONCLUSION: These results suggest a BMI-specific effect of L/F554 polymorphism of the E-selectin gene on blood pressure, and strengthen the hypothesis that E-selectin is implicated in hypertension.     

NAD(P)H oxidase p22phox gene C242T polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics

Mutations in the NAD(P)H oxidase gene may be associated with abnormal superoxide generation, nitric oxide (NO) availability and cardiovascular diseases. We investigated the prevalence of the NAD(P)H oxidase p22phox gene C242T polymorphism, and its possible association with blood pressure, NO production, salt sensitivity and cardiovascular risk factors in Hispanics. Genotype frequencies were as follows: CC, 52.9%; CT, 40.3%; and TT, 6.8%. There were no significant differences in systolic blood pressure, diastolic blood pressure, age, weight, fasting and post-load glucose levels, LDL and HDL cholesterol, triglyceride and urinary albumin levels in subjects with CC, CT or the TT genotypes. Presence of the T allele was associated with increased salt sensitivity in women, but not in men. NO metabolite excretion was markedly decreased both in women and men with the TT genotype (CC: 868+/-79 micromol/day; CT: 839+/-75 micromol/day; TT: 534+/-78 micromol/day; P<0.05). In conclusion, the prevalence of the NAD(P)H oxidase p22phox gene C242T polymorphism in Venezuelans was comparable to that of Caucasians, but different from that of Chinese and Japanese. Although the T allele was not associated with cardiovascular risk factors, hyperinsulinaemia or hypertension, in women, it appeared to be a genetic susceptibility factor for salt sensitivity. Both in women and men, the p22phox gene may play a role in the genetic control of NO levels.     

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.     

Gene polymorphisms of the renin-angiotensin system and age-related changes in systolic and diastolic blood pressure in subjects with hypertension

BACKGROUND: Few studies have examined to what extent genes might modulate the changes of systolic and diastolic blood pressure (BP) with age although, in older populations, systolic BP and diastolic BP vary with age in opposite directions. METHODS: This study involved 205 men and 99 women with either systolic-diastolic or isolated systolic hypertension. Age was > 50 years. Using polymerase chain reaction, four gene polymorphisms related to the renin-angiotensin system were independently investigated in men and women. Adjustments to cardiovascular and renal risk factors as well to the sodium/potassium extracellular space ratio were performed. RESULTS: Regarding the angiotensin-converting enzyme (ACE) gene polymorphism, in men > 50 years of age, the slope (mm Hg per unit of age) of the age-diastolic BP (and not age-systolic BP) relationships significantly (P = .0092) differed between genotypes: - 0.79 +/- 0.15 (P < .0001) for the DD genotype, -0.53 +/- 0.10 for the ID genotype (P < .0001), and -0.23 +/- 0.11 for II genotypes (P = NS). Such findings were not observed in the female population in which the age-diastolic BP curves were substantially flatter than in men. No comparable results were observed for gene polymorphisms related either to angiotensinogen or to angiotensin II type 1 receptor. CONCLUSIONS: In men > 50 years of age, the ACE gene polymorphism modulates the physiologic age-induced reduction of diastolic BP. The D allele might contribute to enhance this reduction, a finding that needs confirmation using prospective studies.