Association of a GNAS1 gene variant with hypertension and diabetes mellitus.

Previous studies have shown that the T allele of the GNAS1 T393C polymorphism is associated with poor responsiveness to beta-blockade and that the T393C polymorphism interacts with cigarette smoking and alcohol consumption in the pathogenesis of hypertension. Thus, the T393C polymorphism is likely to interact with beta-adrenoceptor (beta-AR) stimulation in the pathogenesis of hypertension. Although this interaction might be caused by a direct effect of Gs proteins on the cardiovascular system, it could also result from an indirect effect of Gs proteins mediated by glucose metabolism. Moreover, association studies are often irreproducible. We therefore examined the possible interaction between the T393C polymorphism and gamma-glutamyl transpeptidase (GGT), which is an established biomarker of alcohol consumption, in the association with glucose metabolism as well as with hypertension in a Japanese population. Genotyping for GNAS1 was performed by using the polymerase chain reaction-restriction fragment length polymorphism method in all 821 samples. The present study showed a significant interaction between the T393C polymorphism and GGT in the association with hypertension (p =0.033). This interaction was even more significant after adjustment for all confounding factors (p =0.0025). In contrast, analysis of the possible interaction of the T393C polymorphism with GGT in the association with diabetes mellitus or fasting plasma glucose failed to show a significant result. These results did not support the hypothesis that the interaction between the T393C polymorphism and GGT in the association with hypertension could be caused by an indirect effect of Gs proteins mediated by glucose metabolism.     

GNAS1基因T393C多态性与特发性室性心律失常的相关分析

目的分析Gs蛋白α亚基基因（GNAS1）T393C单核苷酸多态性（SNP）与特发性室性心律失常的相关性。方法分别选取特发性室性心律失常患者165例及健康对照162例,采用PCR-RFLP分析GNAS1基因T393C等位基因型及等位基因频率分布。结果两组基因型频率分布均符合Hardy-Weinberg平衡（P值分别为0.545 4和0.663 5）。T393C多态性等位基因型频率和等位基因频率在两组间比较具有显著性差异（P〈0.01）,CC基因型及393C等位基因的频率在病例组中显著增高。结论GNAS1基因T393C多态性与特发性室性心律失常有相关性。     

Effects of dopamine receptor type 1 and Gs protein alpha subunit gene polymorphisms on blood pressure at rest and in response to stress

BACKGROUND: Exaggerated blood pressure (BP) response to behavioral stress has been recognized as an independent predictor of increased BP levels in human subjects. The coupling of dopamine receptor type 1 (DRD1) with stimulatory G-proteins plays an important role in BP regulation. Therefore, we investigated whether the A-48G polymorphism of the DRD1 gene and the T393C polymorphism of the Gs protein alpha subunit (GNAS) gene influenced BP levels at rest and in response to stress. METHODS: A total of 912 white and African American (44.5%) twin subjects (17.4 +/- 3.4 years) were genotyped. Systolic and diastolic BP were measured at rest and during two 10-min stress tasks (a social competence interview and a virtual reality car driving simulation test). Regular association analyses and sibpair transmission disequilibrium tests were performed. The two polymorphisms, A-48G (DRD1) and T393C (GNAS), were genotyped by polymerase chain reaction with restriction digestion enzymes. RESULTS: A dominant BP-lowering effect of the -48G allele was observed on diastolic BP at rest (P = .032) and in response to the car driving simulation test (P = .046). The 393C allele was associated with higher systolic BP levels during the social competence interview (P = .024) and the car driving simulation test (P = .016). There were no statistical significances between the two loci for systolic and diastolic BP at rest and during stress. CONCLUSIONS: Our findings suggest that DRD1 and GNAS loci contribute to BP regulation at rest, and in particular, in response to behavioral stress. The BP measurement during behavioral stress may have added value for gene association studies.     

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.     

Association of GNAS1 gene variant with hypertension depending on smoking status

The beta-adrenoceptor (beta-AR) G(s) protein system has been shown to have important roles in the cardiovascular system. The gene encoding the alpha-subunit of G(s) proteins (GNAS1) is a candidate genetic determinant for hypertension. We studied the GNAS1 T393C polymorphism in >2000 Japanese individuals. chi(2) test showed a marginally significant difference in the frequencies of the alleles (P=0.036) and genotypes (P=0.094) between hypertensives and normotensives. Because hypertension is considered to be a complex disorder resulting from interactions between genetic and environmental factors, we further analyzed the T393C polymorphism, with consideration of interactions between the polymorphism and confounding factors in regression models. These analyses showed a significant interaction between the polymorphism and cigarette smoking in the pathogenesis of hypertension (P=0.0005). The interaction was reflected in a significant association of the polymorphism with hypertension in nonheavy smokers (P=0.0028; odds ratio, 1.52; 95% confidence interval, 1.16 to 2.00). A significant interaction between the polymorphism and aging in the pathogenesis of hypertension was also shown in nonheavy smokers. These findings may be helpful in conducting further molecular and biological studies on the relationship among cigarette smoking, the beta-AR-G(s) protein system, and hypertension.     

Aldosterone synthase gene T-344C polymorphism, sodium and blood pressure in a free-living population: a community-based study.

There have been few epidemiological studies on the gene-environmental interaction between the aldosterone synthase gene (CYP11B2) T-344C polymorphism and sodium in relation to blood pressure in a free-living general population. We hypothesized a priori that persons with the T allele of CYP11B2 would have elevated blood pressure levels in response to a higher sodium intake, and thus the association between the T-344C polymorphism and blood pressure would be more evident among persons with a high sodium intake than among those with a low sodium intake. Study subjects were 2,823 men and women aged 30-74 in a Japanese community. We examined the associations between the T-344C polymorphism and blood pressure levels, stratified by sodium variables estimated by 24-h urinary sodium excretion and a dietary questionnaire. There was no significant difference in blood pressure levels among the CC, TC and TT groups for either or both sexes. However, among persons with higher sodium excretion, mean systolic blood pressure levels tended to be higher in those with the TC (+3.0 mmHg, p=0.06) and TT (+2.9 mmHg, p=0.07) genotypes than in those with the CC genotype, but this tendency was not seen among those with lower sodium excretion (-4.0 mmHg, p=0.03 for TC vs. CC; -3.0 mmHg, p=0.11 for TT vs. CC; p for interaction =0.006). In conclusion, we found no association between CYP11B2 and blood pressure for total subjects or for persons with a higher sodium intake. However, a possible gene-blood pressure association among persons with higher sodium intake needs to be explored further.     

C-344T polymorphism of the aldosterone synthase gene and blood pressure in the elderly: a population-based study

OBJECTIVES: Whether the C-344T polymorphism of the aldosterone synthase gene is important for blood pressure control remains controversial. It has been proposed that an association between this polymorphism and blood pressure might be evident in elderly subjects. The aim of the present study was to test this hypothesis in an epidemiological context. DESIGN: A cross-sectional epidemiological evaluation of a highly homogeneous unselected general population of elderly Caucasians. METHODS: Lifestyle, medical history, anthropometrics, skinfold thickness, supine blood pressure, heart rate and biochemical measures were recorded in 437 subjects aged > or = 65 years living in a secluded valley. All were genotyped for C-344T allele status and underwent measurements of plasma aldosterone and renin. RESULTS: The C-344T genotypic frequency did not deviate from Hardy-Weinberg equilibrium. The aldosterone to renin ratio was 19% lower in the CC than in the TT genotype. Systolic blood pressure was significantly lower in subjects with the CC genotype, higher in the TT (+9.6 mmHg versus CC) and intermediate in the CT (+7.9 mmHg versus CC). Adjustment for age, gender, smoking and antihypertensive treatment did not affect this association. Diastolic blood pressure did not differ across genotypes. A significant increase of systolic blood pressure with increasing age and with increasing skinfold thickness was observed in the TT homozygotes but not in the C-carriers. CONCLUSIONS: These data support the concept that the C-344T polymorphism plays a role in controlling systolic blood pressure and the age-related increase in systolic blood pressure in response to age and to body fat, possibly through differences in modulation of aldosterone synthesis.     

Association of the GNAS1 T393C polymorphism with tumor stage and survival in gastric cancer

AIM: To analyze the impact of the GNAS1 T393C polymorphism on prognosis and histopathology of gastric cancer.METHODS: Genomic DNA was extracted from paraffinembedded tissues of 122 patients with primary gastric carcinoma and from the blood of 820 healthy white individuals. Allelic discrimination was performed by quantitative real-time polymerase chain reaction. Genotyping was correlated with histopathologic parameters and with overall survival according to the Kaplan- Meier approach and with multivariate analysis by multiple stepwise regression. RESULTS: Thirty-nine (32%) patients displayed a CC genotype, 57 (46.7%) a CT genotype and 26 (21.3%) a TT genotype. The frequency of the C allele (fC) in the patient group was 0.55, which was not significantly different from that of healthy blood donors. The distribution was compatible with the Hardy-Weinberg equilibrium.Analysis of clinicopathological parameters did not show any significant correlation of the T393C genotype with gender (P = 0.50), differentiation (P = 0.29),pT-category (P = 0.19), pN-category (P = 0.30), pMcategory (P = 0.25), R-category (P = 0.95), the classifications Goseki (P = 1.00) and Ming (P = 0.74). Dichotomization between C+ (CC+CT) and C-genotypes (TT), however, revealed significantly more advanced tumor stages (P = 0.023) and lower survival rates (P = 0.043) for C allele carriers.CONCLUSION: The present study provides strong evidence to suggest that the GNAS1 T393C allele carrier status influences tumor progression and survival in gastric cancer with higher tumor stages and a worse outcome for C allele carriers.     

Lack of association of human G-protein beta 3 subunit variant with hypertension in Japanese workers

OBJECTIVE: To examine the association between hypertension and the C825T polymorphism in the G-protein beta 3 subunit gene in Japanese workers. METHODS: This study used logistic regression analysis and multiple regression analyses to investigate whether the C825T polymorphism was associated independently with hypertension or blood pressure when factors such as age, body mass index, blood chemistry and lifestyle were taken into consideration. The target subjects were 1452 male and 1169 female workers selected from 3834 male and 2591 female workers in a single company. Hypertension was defined as a systolic blood pressure > or = 140 mmHg and/or diastolic blood pressure > or = 90 mmHg, or taking antihypertensive medication. The power of the study was estimated as 83% for males and 41% for females based on allelic frequencies in Caucasians. RESULTS: Genotype distributions for C825T in hypertensive males (CC = 58, CT = 135, TT = 63) and females (CC = 20, CT = 36, TT = 20) were not significantly different from normotensive males (CC = 300, CT = 614, TT = 282) or females (CC = 274, CT = 602, TT = 217), respectively. Allele distributions were not significantly different in either sex. Multiple logistic regression analysis showed that genotype was not associated significantly with hypertension, whereas there was a significant relationship between hypertension and age, family history of hypertension, body mass index, hematocrit, platelet count, gamma-glutamyl transpeptidase (gamma-GTP) and uric acid. Data analysis using one-way analysis of variance and multiple regression showed that the C825T allele had no significant influence on either systolic, diastolic or mean blood pressure. CONCLUSIONS: This study indicates that the C825T polymorphism is not a significant factor for hypertension or blood pressures in Japanese people. Targeting of this polymorphism is therefore unlikely to be beneficial when attempting to prevent hypertension in the general Japanese population.     

Interaction between the C(-344)T polymorphism of CYP11B2 and age in the regulation of blood pressure and plasma aldosterone levels: cross-sectional and longitudinal findings of the Olivetti Prospective Heart Study

OBJECTIVE: To study the interaction between the C(-344)T polymorphism and known determinants (age, body mass and dietary sodium) of blood pressure and plasma aldosterone. DESIGN: Cross-sectional and longitudinal (1980-1995) survey of male workers in southern Italy. SETTING: Medical centre of the Olivetti factories. PARTICIPANTS: In 1995, the C(-344)T polymorphism was characterized in 811 untreated men. A subgroup of 280 participants already seen in 1980 was the object of longitudinal analysis. MAIN OUTCOME MEASURES: Blood pressure, demographic, anthropometric and biochemical variables (serum and urinary electrolytes and plasma aldosterone) and frequency of the C(-344)T polymorphism. RESULTS: In the whole population, there was no difference among genotypes for any of the variables examined. However, multiple regression showed a significant interaction between age (but not body mass or sodium intake) and genotype with regard to systolic (P = 0.03) and diastolic ( P= 0.02) pressure variability independently of covariates. Diastolic pressure increased linearly with age in carriers of the T allele (TT, P<0.001 and TC, P= 0.005), but not in CC homozygotes ( P= 0.848). In T carriers - but not in CC homozygotes - blood pressure and serum potassium increased and plasma aldosterone and serum sodium decreased across quintiles of age (P< 0.001 for all trends). In the longitudinal study, diastolic pressure increased significantly over time only in T carriers (TC+TT: +2.6 +/- 0.6, versus CC: -0.4 +/- 1.5 mmHg, P= 0.04). CONCLUSION: Inter-individual variation of blood pressure and plasma aldosterone is affected by the interaction of C(-344)T polymorphism and ageing, thus supporting a role for this variant in mechanisms affecting blood pressure regulation.     

Association of a functional polymorphism in the CYP4A11 gene with systolic blood pressure in survivors of myocardial infarction

OBJECTIVE: Survivors of myocardial infarction (MI) are known to have a high prevalence of arterial hypertension which, at the same time, imposes a major risk to such patients. Genetic variants of the arachidonic acid monooxygenase CYP4A11 may result in decreased synthesis of 20-hydroxyeicostatetraenoic acid (20-HETE), experimental hypertension and elevated blood pressure levels in humans. The present study aimed to investigate the impact of the functionally relevant T8590C polymorphism of this gene on blood pressure and the prevalence of hypertension in MI patients. METHODS: Survivors of MI from the MONICA Augsburg MI registry (n = 560) were studied after a mean of 5.6 years after the acute event. Participants were examined by standardized anthropometric and echocardiographic measurements, as well as genotyping for CYP4A11 T8590C allele status. RESULTS: Genotype frequencies in MI patients (TT = 71.8%, CT = 26.2%, CC = 2.0%) did not differ from those in population-based controls (n = 1363; TT = 75.4%, CT = 22.5% and CC = 2.1%, P = 0.22). MI survivors with the CC genotype displayed higher systolic blood pressure levels (CC: 143.4 +/- 4.9 mmHg versus CT: 134.5 +/- 1.3 mmHg and TT: 131.1 +/- 0.8 mmHg; P = 0.02) and a non-significant trend towards higher diastolic blood pressure levels (CC: 88.4 +/- 3.0 mmHg versus CT: 84.9 +/- 0.8 mmHg and TT: 83.9 +/- 0.5 mmHg; P = 0.17) in multivariate models. Accordingly, the C allele was related to elevated odds ratios for hypertension in a recessive [4.14; 95% confidence interval (CI) = 1.07-15.96, P = 0.04] and in a dominant model (1.50; 95% CI = 1.03-2.20, P = 0.04), respectively. No blood pressure-independent association of the T8590C polymorphism with echocardiographic parameters of left ventricular function and/or geometry was found. CONCLUSION: The data obtained in the present study strengthen the evidence of an association of the CYP4A11 T8590C polymorphism with blood pressure levels and hypertension prevalence. Particularly, the risk of arterial hypertension is substantially higher in MI patients homozygous for the CC allele. By contrast, no evidence was obtained for an association between this genotype and MI.     

Association of the T8590C polymorphism of CYP4A11 with hypertension in the MONICA Augsburg echocardiographic substudy

Genetic variants of the arachidonic acid monooxygenase CYP4A11 result in decreased synthesis of 20-hydroxyeicostatetraenoic acid and experimental hypertension. Moreover, in humans, the T8590C polymorphism of CYP4A11 displayed association with arterial hypertension. The aim of the present study was to further investigate this association in a large population-based sample. Therefore, the participants of the echocardiographic substudy of the third MONICA (MONitoring trends and determinants In CArdiovascular disease) survey (n=1397) were studied by standardized anthropometric, echocardiographic, and biochemical measurements as well as genotyping for CYP4A11 T8590C allele status. Individuals with the CC genotype have higher systolic (CC 141.4+/-3.17 mm Hg versus CT 134.2+/-0.97 mm Hg and TT 134.3+/-0.53 mm Hg; P=0.03) and diastolic blood pressure levels (CC 85.4+/-2.06 mm Hg versus CT 80.3+/-0.63 mm Hg and TT 80.7+/-0.34 mm Hg; P=0.02). Accordingly, the odds ratio (adjusted for age, body mass index, and gender) of the CC genotype versus the CT and TT genotypes for hypertension was 3.31 (95% confidence interval [CI]), 1.38 to 7.96; P=0.016) in the entire study population, with similar trends in men (4.30 [95% CI, 1.08 to 17.15]) and women (2.93 [95% CI, 0.88 to 9.84]). Consistent with the renal effects of the gene, no blood pressure-independent association between the T8590C polymorphism and echocardiographic parameters of left ventricular function and geometry was found. In conclusion, our data strengthen the association between the T8590C polymorphism of CYP4A11 and hypertension and suggest a recessive mode of inheritance. In contrast, we found no blood pressure-independent modulatory effect of CYP4A11 T8590C on cardiac size, structure, and function.     

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.     

The CC genotype of the GNAS T393C polymorphism is associated with obesity and insulin resistance in women with polycystic ovary syndrome

OBJECTIVE: Variants in the Gs protein alpha subunit gene (GNAS1) are known to be involved in the pathogenesis of several endocrine and metabolic disorders. To understand genetic determinants of androgen excess, insulin resistance, and obesity in polycystic ovary syndrome (PCOS), we investigated the effect of the common GNAS1 T393C polymorphism on the phenotype of German PCOS women. DESIGN: Two hundred and seventy-eight PCOS women and 820 Caucasian controls were genotyped for the common T393C polymorphism in GNAS1. To this end, genomic DNA was amplified by PCR with specific oligonucleotides and genotypes were determined using the restriction enzyme FokI. In addition, we evaluated whether the T393C polymorphism had an influence on the response to 6 months metformin treatment in a subgroup of 105 PCOS women. METHODS: Anthropometric variables, metabolic parameters including indices of insulin resistance measured by oral glucose tolerance testing, and endocrine biochemical as well as clinical parameters were measured in all PCOS subjects. RESULTS: GNAS1 genotype distributions were not significantly different between PCOS women and controls. In PCOS women, no significant differences in endocrine clinical and biochemical variables were found between the genotypes. However, the C-allele carrier group had significantly higher mean body weight, body mass index, leptin levels, and higher indices of insulin resistance compared with women with GNAS1 TT-genotype. Metformin treatment significantly improved hyperandrogenism, menstrual cyclicity, body weight, and insulin resistance independent of GNAS1 genotype. The major determinant of weight loss was body weight before treatment. CONCLUSION: The T393C polymorphism is not associated with PCOS in Caucasian women, but may represent a genetic marker for increased susceptibility for obesity in this cohort.     

β2肾上腺素能受体基因+491C/T多态性与新疆哈萨克族原发性高血压的关联研究

目的研究新疆哈萨克族人β2肾上腺素能受体（β2-AR）基因＋491C／T多态性与原发性高血压（EH）的关系,旨在从分子水平探讨哈萨克族人EH易感机制。方法采用人群为基础的病例．对照研究方法,选择507例30-60岁哈萨克族人（289例EH者与218例血压正常者）为研究对象,酚／氯仿法提取外周血白细胞基因组DNA,应用PCR—RFLP技术,检测＋491C／T基因型,并观察各基因型和等位基因频率在该人群中EH组和正常血压组的分布及其差异。结果该人群β2-AR基因＋491C／T位点检测出两种基因型CC、CT,分布频率分别为98．82％、1．18％,等位基因C、T频率为99．41％、0．59％,符合Hardy-Weinberg平衡（x^2=0．018,P=0．893）。两种基因型频率在EH组分别为：97．92％、2．08％,在正常血压组中未发现CT基因型;两组中等位基因C、T分布频率分别为98．96％、1．04％和100％、0％;两组基因型、等位基因频率的分布差异均有统计学意义（P均为0．04）。各基因型间收缩压、舒张压差异无统计学意义（P〉0．05）,但根据性别进行分层后,各基因型间收缩压差异有统计学意义（P=0．046）。结论β2-AR基因＋491C／T多态性与新疆哈萨克族人尤其是男性哈萨克族人EH相关联,提示该多态性可能是哈萨克族人EH的易感因素。     

Ambulatory blood pressure and left ventricular structure and function in relation to the G-protein beta3-subunit polymorphism C825T in White Europeans

The 825T allele of the G-protein beta(3)-subunit is associated with increased intracellular signalling. Its association with hypertension is inconsistent. We, therefore, studied the C825T polymorphism in relation to ambulatory blood pressure as well as left ventricular structure and function in two European populations. We genotyped 248 parents and 318 offspring, enrolled in the European Project on Genes in Hypertension in Cracow, Poland (n=286) and in Novosibirsk, Russian Federation (n=280). The 24-h ambulatory blood pressure was recorded using oscillometric SpaceLabs 90207 monitors. Within each centre, a single observer performed two-dimensionally guided M-mode echocardiography and Doppler sonography to measure left ventricular structure (American Society of Echocardiography conventions) and diastolic function: early (E) and late (A) peak diastolic inflow velocities. We used analysis of covariance and generalized estimating equations to allow for covariables and nonindependence among related subjects. Genotype frequencies were similar (P=0.25) in Cracow and Novosibirsk and amounted to 44.7% for CC, 47.2% for CT, and 8.1% for TT. Among parents (mean age: 51.3 years)-but not among offspring (mean age 25.1 years)-24-h, daytime and night time systolic blood pressures were 5-6 mmHg higher in TT homozygotes than in C allele carriers. In TT homozygous parents (-8.2 cm/sec, P=0.004) as well as in TT homozygous offspring (-7.5 cm/sec, P=0.02), the E-wave was significantly reduced, which in offspring also resulted in a lower E/A ratio (-0.25, P=0.002). Neither in parents nor in offspring, left ventricular mass index was associated with the C825T polymorphism. In conclusion, in TT homozygotes of both generations, early left ventricular relaxation was reduced. In TT homozygous parents, the latter observation might be because of the higher systolic pressure associated with the TT genotype.     

Gene by environment interaction: the -159C/T polymorphism in the promoter region of the CD14 gene modifies the effect of alcohol consumption on serum IgE levels

BACKGROUND: Serum IgE is increased in heavy drinkers. Endotoxin mediates most of the immunological alterations associated with heavy drinking. The -159C/T polymorphism in the promoter region of the gene encoding CD14 (an endotoxin receptor) is associated with serum IgE levels in different populations. AIM: To investigate the possible interaction between alcohol intake and the -159C/T polymorphism in the promoter region of the CD14 gene for serum IgE levels. METHODS: A total of 415 individuals (51.6% males, median age 50 years, range 18-92 years) were studied. A total of 140 individuals were alcohol abstainers, 112 were moderate drinkers (1-280 g/week), and 163 were heavy drinkers (>280 g/week). Main determinations included the CD14/-159C/T genotype, a panel of skin prick tests, total serum IgE, and specific serum IgE against common aeroallergens (Phadiatop test). RESULTS: Heavy drinking was associated with increased total serum IgE values and with positive specific serum IgE to common aeroallergens, but the association was stronger in carriers of the CD14/-159C allele (either CC homozygotes or CT heterozygotes) than in CD14/-159TT homozygotes. Both additive and multiplicative interactions between heavy drinking and the CD14/-159C allele for total and specific serum IgE values was still present after adjusting for potential confounders. Neither alcohol consumption nor the CD14/-159 genotype was associated with skin prick test positivity. CONCLUSIONS: The CD14/-159C/T polymorphism modifies the effect of alcohol consumption on serum IgE levels.     

Galectin-2 (LGALS2) 3279C/T Polymorphism may be Independently Associated with Diastolic Blood Pressure in Patients with Rheumatoid Arthritis

The galectin-2 (LGALS2) 3279 C/T single nucleotide polymorphism (SNP) has recently been associated with myocardial infarction (MI). Although hypertension, a very prevalent entity in rheumatoid arthritis (RA), is one of the greatest risk factors for MI, the possible association of LGALS2 3279 C/T and hypertension has not been investigated. We genotyped 386 RA patients, 272 hypertensives and 114 normotensives. Diastolic blood pressure (DBP) was significantly lower in TT compared to CC homozygotes (?4.11 mmHg, p?=?0.044) even when adjusted for multiple confounders (?4.28 mmHg, p?=?033). Further studies are required to replicate the potential association of LGALS2 3279 C/T with DBP, and examine whether this SNP could be used as a marker of increased risk for future cardiovascular events in RA populations.     

Polymorphisms of genes encoding components of the sympathetic nervous system but not the renin-angiotensin system as risk factors for orthostatic hypotension

OBJECTIVE: The genetic background of orthostatic hypotension, an important risk factor for future cardiovascular morbidity and mortality, was investigated. DESIGN AND METHODS: The study subjects comprised 415 community-dwelling individuals, who were free from any cardiovascular complications, aged 50 years or older (mean age 70.5 +/- 9 years). Basal systolic blood pressure (SBP) was measured twice in supine posture after resting for more than 10 min. The orthostatic change in SBP was determined at 1 min and 3 min after standing up. The maximum change in SBP after standing was determined. Orthostatic hypotension was defined as a decline in SBP greater than 20 mmHg. The polymorphisms of genes encoding components of the renin-angiotensin system and sympathetic nervous system, which play pivotal roles in postural change in blood pressure regulation, were determined. RESULTS: There were no significant associations between the maximum change in SBP, the prevalence of orthostatic hypotension and gene polymorphisms of angiotensin-converting enzyme I/D, angiotensinogen M235T and angiotensin II type 1 receptor A1166C. On the contrary, polymorphism of the Gs protein alpha-subunit (GNAS1) T131C was significantly associated with the maximum change in SBP after standing [1.9 +/- 16 versus -3.6 +/- 16 mmHg (TT + TC versus CC), P = 0.008]. The prevalence of orthostatic hypotension was significantly different among GNAS1 genotypes (chi squared = 10.12, P = 0.011) and G-protein beta 3 subunit (GNB3) genotypes (chi squared = 6.12, P = 0.020). Multiple logistic regression analysis showed that both GNAS1 CC genotype [odds ratio (OR) = 2.79, 95% confidence interval (CI) 1.35-5.79, P = 0.006] and GNB3 C allele (OR = 1.78, 95% CI 1.06-3.00, P = 0.030) were independent risks for orthostatic hypotension. CONCLUSIONS: These findings indicate that genes encoding sympathetic nervous components could be involved in the predisposition for orthostatic hypotension.