Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project.

Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3×10(-5); allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1×10(-11)). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9×10(-4)). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4×10(-18)). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6×10(-7)) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension.

Accumulation of common polymorphisms is associated with development of hypertension: a 12-year follow-up from the Ohasama study.

Hypertension is a complex multi-factorial and polygenic disorder. Nevertheless, most studies have focused on single-gene effects. Furthermore, a majority of these studies have been cross-sectional and diagnosed hypertension using conventional blood pressure (BP) measurements, which are known to be subject to biases, including the so-called white-coat effect. Thus, we performed a longitudinal association study to clarify the effects of polymorphism accumulation on the development of hypertension that is defined on the basis of self-measured BP at home (home BP). In 403 Japanese aged 40-79 years with home normotension (home BP <135/85 mm Hg, and not treated with antihypertensive medication at baseline), we examined the associations of 51 single-nucleotide polymorphisms (SNPs) classically nominated or reported to be associated with hypertension in the Japanese Millennium Genome Project for Hypertension with a 12-year risk of progression to home hypertension (home BP >or=135/85 mm Hg, or start of antihypertensive medication). Out of 51 SNPs, four significantly and independently predicted the risk of progression of home hypertension, even after adjustment for possible confounding factors, including baseline home BP value. These were rs3767489 near the regulator of G-protein signaling 2 (RGS2), rs4961 in adducin 1 (ADD1), rs2236957 in the calcium channel, voltage-dependent, alpha-2/delta-subunit 2 (CACNA2D2) and rs769214 in catalase (CAT). Accumulation of these SNPs significantly improved the predictive values for the development of home hypertension. In conclusion, this longitudinal study, which was based on home BP measurement, showed that accumulation of common polymorphisms reliably predicted the risk of future hypertension in the Japanese general population.

Asymptomatic cerebral microbleeds seen in healthy subjects have a strong association with asymptomatic lacunar infarction.

BACKGROUND: Cerebral microbleed (CMB), which is conspicuous on gradient-echo T2-weighted magnetic resonance imaging, is a risk factor of intracerebral hemorrhage (ICH). CMBs have been detected even in neurologically healthy persons, who also seem prone to be affected by stroke, not only ICH but also cerebral infarction. METHODS AND RESULTS: The presence of CMB was investigated in brain dock participants, making reference to silent lacunar infarction (SLI). Participants comprised 377 neurologically healthy persons and 21 (5.6%) had CMB detected, which was associated with a high incidence of hypertension, other conventional risk factors having no significant correlation with CMB. In a simple correlation analysis, CMB showed a positive association with age and systolic blood pressure (SBP). Logistic regression analysis revealed that SLI was the factor most strongly associated with CMB. Moreover, individuals who had both CMB and SLI had higher SBP than other groups. CONCLUSIONS: The etiology of CMB is similar to that of SLI.

PPARgamma Pro12Ala Pro/Pro and resistin SNP-420 G/G genotypes are synergistically associated with plasma resistin in the Japanese general population.

OBJECTIVE: The Ala allele of the Pro12Ala polymorphism (rs1801282) of peroxisome proliferator-activated receptor gamma (PPARgamma) is protective against type 2 diabetes (T2DM). Resistin, secreted from adipocytes, causes insulin resistance in rodents. Resistin gene expression is reduced by the PPARgamma ligand. We previously reported that subjects with the G/G genotype of a resistin gene single nucleotide polymorphism (SNP) at -420 (rs1862513) had the highest circulating resistin levels, followed by C/G and C/C. The aim of this study was to determine the relationship among PPARgamma Pro12Ala polymorphism, resistin SNP-420, and plasma resistin. DESIGN, PATIENTS AND MEASUREMENTS: We cross-sectionally analysed 2077 community-dwelling subjects attending an annual medical check-up. Genotypes were determined by TaqMan analysis. Fasting plasma resistin was measured using ELISA. RESULTS: Plasma resistin appeared to be higher in subjects with the Pro/Pro genotype of PPARgamma than those with Pro/Ala and Ala/Ala genotypes (mean +/- SE, 11.6 +/- 0.2 vs. 10.4 +/- 0.5 microg/l). Multiple regression analysis, adjusted for age, gender, BMI, and resistin SNP-420, revealed that the Pro/Pro genotype was a positive predictor of plasma resistin (PPARgamma , Pro/Pro vs. Pro/Ala + Ala/Ala, unstandardized regression coefficient (beta) = 1.03, P = 0.0384). The effects of the Pro/Pro genotype of PPARgamma (Pro/Pro vs. Pro/Ala + Ala/Ala) and the G/G genotype of resistin SNP-420 (G/G vs. C/C) on plasma resistin were synergistic (beta = 4.76, P = 0.011). CONCLUSIONS: The PPARgamma Pro12Ala Pro/Pro and resistin SNP-420 G/G genotypes were synergistically associated with plasma resistin, when adjusted for age, gender, and BMI, in the Japanese general population.

Identification of hypertension-susceptibility genes and pathways by a systemic multiple candidate gene approach: the millennium genome project for hypertension.

A multiple candidate-gene approach was used to investigate not only candidate genes, but also candidate pathways involved in the regulation of blood pressure. We evaluated 307 single nucleotide polymorphisms (SNPs) in 307 genes and performed an association study between 758 cases and 726 controls. Genes were selected from among those encoding components of signal transduction pathways, including receptors, soluble carrier proteins, binding proteins, channels, enzymes, and G-proteins, that are potentially related to blood pressure regulation. In total, 38 SNPs were positively (p<0.05) associated with hypertension. Replication of the findings and possible polygenic interaction was evaluated in five G-protein-related positive genes (GNI2, GNA14, RGS2, RGS19, RGS20) in a large cohort population (total n=9,700, 3,305 hypertensives and 3,827 normotensive controls). In RGS20 and GNA14, dominant models for the minor allele were significantly associated with hypertension. Multiple dimension reduction (MDR) analysis revealed the presence of gene-gene interaction between GNA14 and RGS20. The MDR-proved combination of two genotypes showed a significant association with hypertension (chi2=9.93, p=0.0016) with an odds ratio of the high-risk genotype of 1.168 (95% confidence interval [CI] [1.061-1.287]). After correction for all possible confounding parameters, the MDR-proved high-risk genotype was still a risk for hypertension (p=0.0052). Furthermore, the high-risk genotype was associated with a significantly higher systolic blood pressure (133.08+/-19.46 vs. 132.25+/-19.19 mmHg, p=0.04) and diastolic blood pressure (79.65+/-11.49 vs. 79.01+/-11.32 mmHg, p=0.019) in the total population. In conclusion, a systemic multiple candidate gene approach can be used to identify not only hypertension-susceptibility genes but also hypertension-susceptibility pathways in which related genes may synergistically collaborate through gene-gene interactions to predispose to hypertension.

No association between INSIG2 Gene rs7566605 polymorphism and being overweight in Japanese population.

Obesity is a complex trait reflecting numerous genetic and environmental factors. Recently, a common genetic polymorphism (rs7566605) associated with a higher BMI was found in proximity to the insulin induced protein 2 (INSIG2 ) gene, with replication in four unrelated populations living in Western countries. We investigated the susceptibility to the polymorphism amongst the general Japanese population (n = 1976). The frequency of appearance of the single-nucleotide polymorphism (SNP) in the Japanese (G allele; 0.652, C allele; 0.348) was not different from that found in subjects of European origin as reported previously. However, the BMI levels in each of these genotypes did not differ significantly (GG; 23 +/- 3, GC; 24 +/- 3, CC; 24 +/- 3 kg/m(2), P = 0.906). In a separate analysis according to sex (male; P = 0.462, female; P = 0.879), age decade (40s; P = 0.057, 50s; P = 0.998, 60s; P = 0.622, 70s; 0.425, respectively), and tertiles of the BMI (1st; P = 0.409, 2nd; P = 0.088, 3rd; P = 0.780), the differences did not achieve statistical significance. The frequency of obesity did not differ among the genotypes (25 kg/m(2); 30.3, 30.8, 28.2%, P = 0.729, 30 kg/m(2); 2.9, 3.8, 2.8%, P = 0.549). No associations were also observed for related plasma markers; high-molecular weight (HMW) adiponectin (P = 0.510), high-sensitive C-reactive protein (P = 0.788), resistin (P = 0.937) and homeostasis of minimal assessment of insulin resistance (P = 0.634). These results indicate a lack of association between SNP rs7566605 and being overweight among the Japanese (in the middle-aged and elderly population).

Reduced high-molecular-weight adiponectin and elevated high-sensitivity C-reactive protein are synergistic risk factors for metabolic syndrome in a large-scale middle-aged to elderly population: the Shimanami Health Promoting Program Study.

OBJECTIVE: In Western countries, one of the most important modifiable targets for the prevention of cardiovascular diseases is metabolic syndrome. Adiponectin is an adipose tissue-specific plasma protein that inversely associates with metabolic syndrome. Among several molecular isoforms, high-molecular-weight (HMW) complex is considered the active form. Increased serum high-sensitivity C-reactive protein (hsCRP) concentration also associates with metabolic syndrome, and adiponectin could modulate plasma C-reactive protein levels. Here, through cross-sectional investigation, we investigated whether reduced HMW adiponectin and increased hsCRP levels in plasma are synergistically associated with metabolic syndrome. Measurement of HMW complex of adiponectin is one of the novelties of this study. DESIGN: We analyzed 1845 community-dwelling middle-aged to elderly subjects (62+/-13 yr). Plasma HMW adiponectin levels were measured by ELISA. Clinical parameters were obtained from the subjects' personal health records, evaluated at their annual medical check-up. RESULTS: Each component of metabolic syndrome, except for raised blood pressure, showed significantly lower plasma HMW adiponectin concentrations for both men and women (P<0.001). In contrast, plasma hsCRP levels were significantly higher in subjects with metabolic disorders (P<0.001). After adjusting for other confounding factors, HMW adiponectin [log normalized, odds ratio 0.084 (95% confidence interval 0.050-0.142), P<0.001] and hsCRP [3.009 (2.175-4.163), P<0.001] were identified as independent determinants of metabolic syndrome. In addition to the direct associations, we also observed a synergistic effect between these two molecules (F=11.8, P<0.001). CONCLUSIONS: Reduced HMW adiponectin and elevated hsCRP are synergistically associated with the accumulation of metabolic disorders. The combination of these markers would be useful for identifying at-risk populations.

High-density association study and nomination of susceptibility genes for hypertension in the Japanese National Project.

Essential hypertension is one of the most common, complex diseases, of which considerable efforts have been made to unravel the pathophysiological mechanisms. Over the last decade, multiple genome-wide linkage analyses have been conducted using 300-900 microsatellite markers but no single study has yielded definitive evidence for 'principal' hypertension susceptibility gene(s). Here, we performed a three-tiered, high-density association study of hypertension, which has been recently made possible. For tier 1, we genotyped 80 795 SNPs distributed throughout the genome in 188 male hypertensive subjects and two general population control groups (752 subjects per group). For tier 2 (752 hypertensive and 752 normotensive subjects), we genotyped a panel of 2676 SNPs selected (odds ratio >or= 1.4 and P

Migraine is associated with enhanced arterial stiffness.

Migraine is a common subtype of headache. Epidemiological studies have revealed that migraine could be an independent risk factor for ischemic stroke even in elderly subjects. Arterial stiffness is one of the major pathophysiological bases of stroke. In the present study, we cross-sectionally investigated the possible relationship between migraine and arterial stiffness in community-dwelling subjects. The study subjects were independently recruited from two sources (Group A, n=134, 68+/-5 years; Group B, n=138, 68+/-7 years). Augmentation index (AI), the ratio of augmented pressure by the reflection pressure wave to the pulse pressure, was obtained from the radial arterial waveform as an index of arterial stiffness. Brachial blood pressure was also measured simultaneously. Migraine was diagnosed using a previously validated questionnaire. The prevalence of migraine was 5.2% (Group A) and 16.7% (Group B). Subjects with migraine had higher radial AI in both Group A (migraine, 101+/-15%; other headache, 88+/-12%; no headache, 86+/-12%, p=0.003) and Group B (95+/-11%, 90+/-11%, 91+/-14%, p=0.058). Multiple linear regression analysis revealed that migraine was an independent determinant of AI (beta=0.154, p=0.002) after adjustment for other confounding factors: age (beta=-0.024, p=0.654); sex (beta=0.141, p=0.069); body height (beta=-0.215, p=0.005); systolic blood pressure (beta=0.174, p=0.001); medication for hypertension, hyperlipidemia, and diabetes mellitus (beta=-0.014, p=0.787); and heart rate (beta=-0.539, p<0.001). In a separate analysis by sex, migraine was also a significant determinant for AI (male, beta=0.246, p=0.019; female, beta=0.159, p=0.008). Migraine in the elderly could be a clinical manifestation of enhanced arterial stiffness.

Plasma resistin, associated with single nucleotide polymorphism -420, is correlated with insulin resistance, lower HDL cholesterol, and high-sensitivity C-reactive protein in the Japanese general population.

OBJECTIVE: Resistin, secreted from adipocytes, causes insulin resistance in rodents. We previously reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at -420 increases type 2 diabetes susceptibility by enhancing promoter activity. We report here on the relation between plasma resistin and either SNP -420 genotype or factors related to insulin resistance. RESEARCH DESIGN AND METHODS: We cross-sectionally analyzed 2,078 community-dwelling Japanese subjects attending a yearly medical checkup. The SNP -420 genotype was determined by TaqMan analysis. Fasting plasma resistin was measured using an enzyme-linked immunosorbent assay kit. RESULTS: Plasma resistin was associated with the SNP -420 genotype (P < 0.0001), which was highest in G/G followed by C/G and C/C. Plasma resistin was higher in elderly individuals, female subjects, nondrinkers, and subjects with high blood pressure (P < 0.001, 0.003, <0.001, and 0.001, respectively). Simple regression analysis revealed that age, female sex, homeostasis model assessment of insulin resistance (HOMA-IR) index, systolic blood pressure, low HDL cholesterol, and high-sensitivity C-reactive protein (hs-CRP) were positively correlated with plasma resistin (P < 0.001, 0.003, <0.001, 0.004, <0.001, and 0.003, respectively). Multiple regression analysis adjusted for age, sex, and BMI revealed that plasma resistin was an independent factor for HOMA-IR, low HDL cholesterol, and hs-CRP (P = 0.001, <0.001, and 0.006, respectively). CONCLUSIONS: Plasma resistin was associated with SNP -420 and was correlated with insulin resistance, low serum HDL cholesterol, and high hs-CRP in the Japanese general population.

[A case of Werner syndrome with chromosomal abnormality].

A 52-year-old woman with diabetes mellitus (DM) complained of weakness of the arms and legs. She was referred to our hospital in November 2002 because of anemia, thyroid tumor and meningioma including DM. She was short in stature, juvenile bilateral cataract, intractable skin ulcers, clavus on the sole of her foot, a bird-like face and high-pitched voice. Typical physical features led to the final diagnosis of Werner's syndrome. Although the myelogram revealed no abnormal findings except erythroid hypoplasia, cytogenetic analysis of bone marrow cells showed deletion of chromosome 20 in 10% of the analyzed cells, which suggested the possibility of that myelodysplastic syndrome (MDS) or acute myeloblastic leukemia (AML) could occur. She had a thyroidectomy because both lobes of the thyroid gland were enlarged and caused hoarseness, In addition, it is common knowledge that the goiter could become malignant. We need to follow her carefully because she might be vulnerable to malignant disease, including leukemia and malignant meningioma.

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.

Orthostatic systolic hypotension and the reflection pressure wave.

Orthostatic hypotension (OH) is a potent predictor of cardiovascular frailty. Although OH is determined by changes in brachial blood pressure (BP), it has been reported that there are significant differences between central BP and peripheral BP. The prevalence of OH has been reported to be higher in subjects with isolated systolic hypertension. Since an early returning of the reflection pressure wave due to advanced arterial stiffness is one of the underlying mechanisms of systolic hypertension, a significant association between alterations of the reflection pressure wave and OH has been hypothesized. To explore this hypothesis, the orthostatic changes in carotid BP and arterial waveform were evaluated. The study subjects were 155 community residents (69 +/- 7 years old). Carotid and brachial BP were measured simultaneously in the supine position and 1 min after standing using a cuff-oscillometric and tonometric method. The carotid augmentation index (AIx) was obtained from the pressure waveform. The orthostatic decline of BP was more prominent in the carotid artery than the brachial artery. Nine subjects were diagnosed with orthostatic systolic hypotension (OSH) from brachial BP, while 21 subjects were diagnosed from carotid BP (p < 0.001). The orthostatic change in carotid systolic BP was significantly associated with that in carotid AIx (r = 0.361, p < 0.001). The decline of the reflection component of carotid pulse pressure (-4.0 +/- 8.4 mmHg) was more prominent than that of the incident component (-1.2 +/- 9.9 mmHg, p = 0.002). These results indicate that evaluation of brachial BP may not represent the orthostatic changes in central BP. Alteration of the reflection pressure wave could be one of the underlying mechanisms of OSH in the central artery.

Association of dopamine beta-hydroxylase polymorphism with hypertension through interaction with fasting plasma glucose in Japanese.

Dopamine-beta-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine and is released from sympathetic neurons into the circulation. Several lines of evidence, including the finding of elevated plasma DBH activity in essential hypertension, suggest an important role of DBH in hypertension. Recently, a novel polymorphism (-1021C/T) in the 5' flanking region of the DBH gene has been shown to account for 35-52% of the variation in plasma DBH activity. We therefore investigated the possible association between the DBH -1021C/T polymorphism and hypertension in a large Japanese population. Moreover, because the development of hypertension is considered to be due at least partly to gene-environmental interactions, we also investigated the possible interactions between the DBH -1021C/T polymorphism and environmental factors. Consequently, we found a significant interaction between the DBH -1021C/T polymorphism and fasting plasma glucose (FPG) in the association with hypertension. CC homozygotes showed a steeper increase in probability of hypertension with FPG than T allele carriers. We also found a marginally significant trend suggesting the presence of an interaction between the DBH -1021C/T polymorphism and FPG in the association with blood pressure. Consistent with the presence of the interaction, we found that a 19 bp sequence containing the DBH -1021C/T polymorphism includes two palindromic non-canonical E boxes separated by 5 bps, and closely resembles the glucose response element of the L-type pyruvate kinase gene. These findings could be helpful in conducting further molecular and biological studies on the relationship among glucose metabolism, the sympathetic nervous system, and hypertension.

Endothelial nitric oxide synthase gene polymorphism (Glu298Asp) in patients with coexistent hypertrophic cardiomyopathy and coronary spastic angina.

Coronary vasospasm appears to play a significant role in the etiology of myocardial ischemia in patients with hypertrophic cardiomyopathy (HCM). Furthermore, the management of patients with coexistent HCM and coronary spastic angina (CSA) presents a therapeutic challenge. The purpose of this study was to examine the Glu298Asp variant of the endothelial nitric oxide synthase (eNOS) gene to determine whether this polymorphism was associated with susceptibility to CSA in patients with HCM. The eNOS gene polymorphism (Glu298Asp) was genotyped in 150 HCM patients by the TaqMan chemical method. Patients were classified into group A (n=12) if they had CSA provoked by intracoronary acetylcholine, and group B (n=138) if they did not. In group A, the frequency of Glu/Glu, Glu/Asp, and Asp/Asp genotypes was 5 (41.7%), 6 (50%), and 1 (8.3%), respectively. In group B, it was 119 (86.2%), 17 (12.3%), and 2 (1.5%), respectively. The frequency of the Asp298 variant was significantly higher in group A than in group B (P<0.001). Multivariate logistic regression analysis showed that the Asp298 variant was a significant risk factor for CSA (odds ratio 11.8; P<0.001) that was independent of age, gender, smoking status or body mass index. Significantly more drugs were used by the patients in group A than those in group B and the patients with the Asp298 variant were treated with significantly more drugs than those without it. In conclusion, the Asp298 variant of the eNOS gene may be associated with CSA in HCM patients. HCM patients with CSA or the Asp298 variant may need more drugs to relieve their symptoms.

Effect of genetic polymorphism of OATP-C (SLCO1B1) on lipid-lowering response to HMG-CoA reductase inhibitors.

The effect of genetic polymorphism of human organic anion transporting polypeptide C (OATP-C) on the lipid-lowering response to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors was assessed. A retrospective study was conducted on 66 patients who underwent treatment of hyperlipidemia with HMG-CoA reductase inhibitors in a municipal hospital in a community-based cohort of Ehime prefecture in the southern part of Japan. Plasma lipid concentrations before and after administration were analyzed in patients in relation to the 521T/C (Val-174-->Ala) polymorphism in the OATP-C gene (TT: n=44 (66.7%), TC: n=20 (30.3%), CC: n=0 (0.0%), undetermined: n=2 (3.0%)). Total cholesterol level was significantly lowered after treatment with HMG-CoA reductase inhibitors in all patients (p<0.001); moreover, subjects with the 521C allele showed an attenuated total-cholesterol-lowering effect compared with those homozygous for the 521T allele (-22.3+/-8.7% vs. -16.5+/-10.5%, p<0.05). These data suggest that the 521T/C polymorphism of the OATP-C gene modulates the lipid-lowering efficacy of HMG-CoA reductase inhibitors.

Microalbuminuria and arterial stiffness in a general population: the Shimanami Health Promoting Program (J-SHIPP) study.

Microalbuminuria is an early marker of renal damage and has been shown to predict future cardiovascular mortality and morbidity in patients with diabetes or hypertension, as well as in subjects in the general population. In this study, we investigated the hypothesis that the presence of microalbuminuria reflects the advancement of arterial stiffness by using a study group of 136 community residents who had no cardiovascular diseases except for hypertension and who were not taking any medications. Urinary albumin concentration was determined by the standard method and corrected by creatinine. Microalbuminuria was defined as a urinary albumin/creatinine ratio of 2.0-30.0 mg/mmol creatinine. Arterial stiffness was evaluated by pulse wave velocity (PWV) determined at three points: from the heart to the carotid artery, to the brachial artery, and to the ankle. Carotid arterial pressure was determined using a tonometric sensor. Carotid ultrasonography was performed to measure carotid intima-media thickness (IMT) and carotid arterial internal dimension. Subjects with microalbuminuria had higher blood pressure and wider pulse pressure not only in the brachial artery but also in the carotid artery. Microalbuminuria was associated with significantly higher PWV compared with that of normoalbuminuric subjects at all sites studied (mean PWV: 821.2+/-137.4 cm/s vs. 933.8+/-137.5 cm/s, p<0.0001). Stepwise regression analysis revealed that the presence of mircroalbuminuria (p=0.047) was a significant independent predictor of PWV in addition to age, sex, and systolic blood pressure. These findings suggest that microalbuminuria is associated with advanced atherosclerosis in the general population. Underlying arterial stiffness may explain the high cardiovascular mortality in subjects with microalbuminuria. Hypertension may be the mechanism linking microalbuminuria and arterial stiffness in the general population.

Association of GNB3 gene with pulse pressure and clustering of risk factors for cardiovascular disease in Japanese.

Heterotrimeric guanine nucleotide-binding proteins (G proteins) mediate many pathways including the beta-adrenergic signaling pathway. The C825T polymorphism in the gene coding for the beta3 subunit of G proteins (GNB3) has been shown to be associated with several phenotypes such as hypertension, obesity, and diabetes mellitus comprising the metabolic syndrome. The GNB3 C825T polymorphism may therefore be associated with many atherosclerosis-related phenotypes. On these grounds, we studied the C825T polymorphism in relation to atherosclerosis-related phenotypes in a large Japanese population. Analyses in general linear models showed that T carriers had a significantly wider pulse pressure (P=0.0089) as well as a significantly higher systolic blood pressure (P=0.026). In contrast, analyses in logistic regression models showed that the C825T polymorphism was not significantly associated with each of the four major classical risk factors for cardiovascular and cerebrovascular disease (obesity, hypertension, hypertriglyceridemia, and diabetes mellitus). However, a significantly higher percentage of subjects had none of the four disorders in CC homozygotes than in T carriers (P=0.026). Thus, the C825T polymorphism was significantly associated with clustering of these four risk factors. Although the effect of the gene on each phenotype appears to be weak, considering the combined impact of the effects of the C825T polymorphism on risk factors, the GNB3 gene may be an important gene for human health.