A. Venezia

Aldosterone synthase gene (CYP11B2) C-344T polymorphism, plasma aldosterone, renin activity and blood pressure in a multi-ethnic population

Background The aldosterone synthase gene (CYP1B2) locus is a candidate region involved in the development of hypertension. Objective To study the relationship between the C-344T CYP1B2 polymorphism, plasma aldosterone, renin activity and blood pressure in a multi-ethnic population. Design Population-based, cross-sectional study of 1313 middle-aged men and women (456 white, 441 of African origin and 416 South Asian). Anthropometry, blood pressure, biochemistry, questionnaire data and timed urine collections were taken with standardized techniques. All were genotyped for the C-344T CYP11B2 polymorphism. Results The frequency of the C allele was significantly lower in people of African origin (0.21) than in white (0.46) and South Asian (0.43) (P < 0.001). After adjustment for age, sex and ethnicity the TT genotype was associated with 14% higher plasma aldosterone levels, 3.7 mmHg higher systolic and 2.1 mmHg higher diastolic blood pressure than CC (P for linear trend < 0.05). No significant interactions with age, sex, ethnicity, body mass index (BMI) and fractional excretion of sodium were found in the associations between genotype and both blood pressure and aldosterone levels. In a sub-sample of participants in which plasma renin activity was measured (n = 457), a significant excess of T alleles was found in those with a raised (⩾ 750) aldosterone-to-renin ratio (ARR). Conclusion In this multi-ethnic population, the C-344T CYP1B2 polymorphism is associated with blood pressure, plasma aldosterone levels and ARR. Although significant differences in allele frequencies were found between groups, ethnicity does not explain the results.

Comparisons of spot vs 24-h urine samples for estimating population salt intake: Validation study in two independent samples of adults in Britain and Italy

OBJECTIVES To assess the reliability and reproducibility of estimations of group mean 24-h urinary sodium (Na) excretion through timed spot urines compared to 24 h urinary Na output in two independent cross-sectional population samples including men and women and different ethnic groups. METHODS AND RESULTS Study 1 was carried out in Britain and included 915 untreated 40-59 yrs male and female participants (297 white, 326 of black African origin and 292 South Asian). Study 2 was carried out in Italy and included 148 white men (mean age 58.3 yrs). All participants provided both a 24-h urine collection and a timed urine sample as part of population surveys. Na, creatinine (Cr) and volume (V) were measured in all samples. Age, body mass index (BMI) and blood pressure (BP) were also measured. We compared the daily Na excretion through 24-h urine (gold standard) with its estimate from timed urine samples with two methods: Tanakas predictions and Arithmetic extrapolations, and assessed them with correlation coefficients, Bland-Altman plot, prediction of quintile position and Receiver Operating Characteristic (ROC) Areas Under the Curve (AUC) for a cut-off of <100 mmol of Na/day. In Study 1 (discovery study) with the Tanaka method there were poor correlations between predicted and measured 24-h Na excretions in different ethnic groups and genders (r Spearman from 0.055 [R(2) = 0.003] in black women to 0.330 [R(2) = 0.11] in white women). The Bland-Altman plots indicated consistent bias with overestimate for low and underestimate for high intakes. ROC AUCs varied from 0.521 to 0.652 with good sensitivity (95-100%) but very poor specificity (0-9%). With the Arithmetic extrapolations correlations varied from 0.116 [R(2) = 0.01] to 0.367 [R(2) = 0.13]. Bias was detected with both Bland-Altman plots and through quintile analyses (underestimate at low levels and overestimate at high levels). Finally, ROC AUCs varied from 0.514 to 0.640 with moderate sensitivity (64-70%) but low specificity (20-53%). In Study 2 (validation study) results were consistent with the discovery phase in white men. CONCLUSION Based on these results, 24-h urinary collection for the measurement of Na excretion remains the preferred tool for assessing salt intake when compared with reported methods based on timed spot urine samples.

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 CYP11B2 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 CYP11B2 C(−344)T polymorphism and ageing, thus supporting a role for this variant in mechanisms affecting blood pressure regulation.

Combination of Renin-Angiotensin System Polymorphisms Is Associated With Altered Renal Sodium Handling and Hypertension

Abstract—Genes of the renin-angiotensin–aldosterone system (RAAS) are natural candidates for sodium homeostasis and blood pressure regulation. To investigate the effect of a combination of polymorphisms of RAAS genes on renal sodium handling and blood pressure, 918 participants to the Olivetti Heart Study were genotyped for the following polymorphisms: I/D of angiotensin converting enzyme (ACE), M235T of angiotensinogen (AGT), A1166C of angiotensin II type-1 receptor (AT1R), and C-344T of aldosterone synthase (CYP11B2). The segmental renal sodium handling was evaluated by the fractional excretions of exogenous lithium (FE-Li), uric acid (FE-UA), and sodium (FE-Na). Twenty-eight carriers of triple homozygosity for M (AGT), A (AT1R), and C (CYP11B2) in the presence of the D allele of ACE (DD/ID) showed lower FE-Li (20.0%±5.9% versus 25.0%±7.5%; P =0.004; mean±sD), FE-UA (6.3%±2.0% versus 8.2%±2.7%; P =0.001), and FE-Na (0.96%±0.41% versus 1.22%±0.61%; P =0.004) as compared with all other allelic combinations (n=890), independently from age and body mass, suggesting an enhanced rate of proximal tubular sodium reabsorption. The carriers of the MM, AA, CC, DD/ID combination showed a substantially higher probability of being hypertensive (OR: 3.4 [(99% CI: 1.1 to 10.1]), independently of age and body mass. This relatively rare combination of allelic variants of candidate genes of the RAAS is associated with a significant alteration in proximal renal sodium handling and with higher risk of hypertension, suggesting that a combination of polymorphic variants at different candidate loci may affect phenotypic expression even in the absence of detectable effects of each variant at any single locus.

Incidence of hypertension in individuals with different blood pressure salt-sensitivity: results of a 15-year follow-up study

Objective To evaluate the incidence of hypertension and the rate of decline in renal function in a sample of 47 Olivetti Heart Study (OHS) participants whose blood pressure (BP) salt-sensitivity and renal tubular sodium handling had been assessed in 1987–88. Methods During the 2002–04 OHS follow-up examination, medical history, physical examination and blood and urine sampling were performed in 36 of the 47 participants to the baseline study (age 60 ± 6 years; average follow-up = 15.1 ± 0.6 years). The renal length was measured in 23 participants by kidney ultrasonography. Based on the baseline salt-sensitivity evaluation, the subjects were classified into a lower salt-sensitivity (LSS, n = 20) and a higher salt-sensitivity group (HSS, n = 16). Results In comparison with the LSS group, HSS participants had a significantly higher incidence of hypertension (87.5 versus 50.0%, P = 0.02), a higher glomerular filtration rate (median, first to fourth quartile: 81.9, 72.3–95.2 versus 72.3, 59.9–81.2 ml/min; P = 0.03) and greater kidney length (median, first to fourth quartile: 68.2, 63.3–72.1 versus 61.9, 58.7–62.7 mm/m of height; P = 0.003). The incidence of hypertension remained significantly higher in HSS individuals after adjustment for age, intercurrent changes in body mass index and baseline blood pressure on low sodium diet (P = 0.04). Conclusion Our findings indicate that individuals with higher BP salt-sensitivity have a higher rate of incident hypertension and suggest an altered renal tubular sodium handling involving a trend to increased glomerular filtration rate and blood pressure over time as a possible mechanism.

Analysis of Gly40Ser polymorphism of the glucagon receptor (GCGR) gene in different ethnic groups

Analysis of Gly40Ser polymorphism of the glucagon receptor (GCGR) gene in different ethnic groups

ROLE OF DIFFERENT METABOLIC SYNDROME COMPONENTS ON THE RISK TO DEVELOP SLEEP APNOEA: PP.32.275

Objective: In various clinical studies, apnoea sleep disorders have been associated with different cardiovascular and metabolic abnormalities. The aim of this analysis was to assess the relation between a multivariable apnoea prediction index, metabolic syndrome (MS) and its single components in an unselected sample of adult male population. Design and Method: The relationship between MS (AHA 2005 criteria) and a high apnoea risk (HAR) evaluated by a multivariable apnoea prediction index higher than 0.5, was investigated in 612 (mean age ± SD = 59.7 ± 6.4 years) participants at the 2002–04 Olivetti Heart Study follow-up. Results: The prevalence of MS and of HAR were respectively 36.6% (n = 224) and 60.8% (n = 372). MS and HAR were strongly associated (χ2 = 26.3; p < 0.0001). The prevalence of HAR increased gradually with increasing number of MS components. (χ2 = 36.4; p < 0.0001), the higher the MS score, the higher the prevalence of HAR. Using a logistic regression analysis with apnoea risk as dependent variable and MS components and age as independent factors, hypertension (blood pressure > 130/85 mmHg or treatment) and central adiposity (waist circumference > 102 cm) remained the only determinants of HAR with odds ratio (95%CI) of respectively 2.57 (1.53 to 4.33) and 3.84 (2.47 to 5.98). Conclusion: In this sample of adult male population the prevalence of high apnoea risk was related to both presence and severity of metabolic syndrome. Among different components of MS, blood pressure and central adiposity were the factors more strongly associated to the risk to be affected by sleep apnoea disturbances.