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The associations of the β-adducin C1797T polymorphism with blood pressure (BP) and various indexes of sodium homeostasis were investigated in 388 men and 456 women, aged 18 to 60 years, recruited from three European populations (Cracow, Poland, n = 300; Novosibirsk, Russian Federation, n = 274; Mirano, Italy; n = 270). Phenotypes included 24-h ambulatory BP and urinary excretion of electrolytes and aldosterone. Subjects were genotyped for the β-adducin polymorphism. Both a population-based association study and a family-based analysis were performed. Urinary sodium excretion was higher in Cracow than in Mirano (241 v 185 mmol/24 h, P < .05) and intermediate in Novosibirsk (206 mmol/24 h). The β-adducin T allele (15.2% v 9.1%, P < .0001) was more prevalent in Mirano than in the two Slavic centers. In both population-based and family-based association analyses, there was significant heterogeneity between Slavic and Italian subjects in the phenotype–genotype relationships with β-adducin. In the Slavic centers, 24-h systolic BP was higher in T allele carriers than in CC homozygotes (122.3 v 119.7 mm Hg, P = .03), whereas this was not the case in Mirano (121.8 v 122.9 mm Hg, P = .42). In Slavic (212.6 v 233.1 mmol/24 h) as well as in Italian (166.1 v 191.5 mmol/24 h) participants, 24-h sodium excretion was lower (P = .01) in T allele carriers than in CC homozygotes. These results were confirmed in the family-based analysis of offspring using a quantitative transmission disequilibrium test. In conclusion, the frequency of the β-adducin T allele and salt intake differ across European populations. Thus, both variation in genetic background and salt intake may explain the observed heterogeneity in the phenotype–genotype relationships. Genetic determinants of complex quantitative traits such as BP can only be investigated within their epidemiologic context. [Copyright &y& Elsevier]

Objective: Data on the contribution of ambulatory blood pressure (ABP) components to the risk of developing atrial fibrillation (AF) are limited. We prospectively tested the hypothesis that ABP may represent a potentially modifiable risk factor for the development of AF in a European population study., Methods: We recorded daytime blood pressure (BP) in 3956 subjects randomly recruited from the general population in five European countries. Of these participants, 2776 (70.2%) underwent complete 24-hour ABP monitoring. Median follow-up was 14 years. We defined daytime systolic BP load as the percentage BP readings above 135 mm Hg. The incidence of AF was assessed from ECGs obtained at baseline and follow-up and from records held by general practitioners and/or hospitals., Results: Overall, during 58 810 person-years of follow-up, 143 participants experienced new-onset AF. In adjusted Cox models, each SD increase in baseline 24 hours, daytime and night-time systolic BP was associated with a 27% (P=0.0056), 22% (P=0.023) and 20% (P=0.029) increase in the risk for incident AF, respectively. Conventional systolic BP was borderline associated with the risk of AF (18%; P=0.06). As compared with the average population risk, participants in the lower quartile of daytime systolic BP load (<3%) had a 51% (P=0.0038) lower hazard for incident AF, whereas in the upper quartile (>38%), the risk was 46% higher (P=0.0094)., Conclusions: Systolic ABP is a significant predictor of incident AF in a population-based cohort. We also observed that participants with a daytime systolic BP load >38% had significantly increased risk of incident AF., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Different diagnostic criteria limit comparisons between populations in the prevalence of diastolic left ventricular (LV) dysfunction. We aimed to compare across populations age-specific echocardiographic criteria for diastolic LV dysfunction as well as their correlates and prevalence., Methods: We measured the E and A peaks of transmitral blood flow by pulsed wave Doppler and the e' and a' peaks of mitral annular velocities by tissue Doppler imaging (TDI) in 2 cohorts randomly recruited in Belgium (n = 782; 51.4% women; mean age, 51.1 years) and in Italy, Poland and Russia (n = 476; 55.7%; 44.5 years)., Results: In stepwise regression, the multivariable-adjusted correlates of the transmitral and TDI diastolic indexes were similar in the 2 cohorts and included sex, age, body mass index, blood pressure and heart rate. Similarly, cut-off limits for the E/A ratio (2.5th percentile) and E/e' ratio (97.5th percentile) in 338 and 185 reference subjects free from cardiovascular risk factors respectively selected from both cohorts were consistent within 0.02 and 0.26 units (median across 5 age groups). The rounded 2.5th percentile of the E/A ratio decreased by ~0.10 per age decade in these apparently healthy subjects. The reference subsample provided age-specific cut-off limits for normal E/A and E/e' ratios. In the 2 cohorts combined, diastolic dysfunction groups 1 (impaired relaxation), 2 (possible elevated LV filling pressure) and 3 (elevated E/e' and abnormally low E/A) encompassed 114 (9.1%), 135 (10.7%), and 40 (3.2%) subjects, respectively., Conclusions: The age-specific criteria for diastolic LV dysfunction were highly consistent across the study populations with an age-standardized prevalence of 22.4% vs. 25.1%.

Background: As arteries become stiffer with ageing, reflected waves move faster and augment late systolic pressure. We investigated the age dependency of peripheral and central systolic pressure, pressure amplification (peripheral systolic blood pressure - central systolic blood pressure), and peripheral and central systolic augmentation (maximal systolic pressure minus the first peak of the pressure wave)., Methods: We randomly recruited 1420 White Europeans (mean age, 41.7 years). peripheral systolic blood pressure and central systolic blood pressure were measured by means of an oscillometric sphygmomanometer and pulse wave analysis, respectively., Results: In cross-sectional analyses (731 women, 689 men), central systolic blood pressure and central systolic augmentation increased more with age than peripheral systolic blood pressure and peripheral systolic augmentation. These age-related increases were greater in women than men. The age-related decrease in pressure amplification was similar in both sexes. In longitudinal analyses (208 women, 190 men), the annual increases in central systolic blood pressure and central systolic augmentation were steeper (p < 0.001) than those in peripheral systolic blood pressure and peripheral systolic augmentation with no sex differences (p ≥ 0.068), except for peripheral systolic augmentation, which was larger in women (p = 0.002). Longitudinally, pressure amplification decreased more with age in women than men (p = 0.012). In multivariable-adjusted analyses, age was the overriding determinant of peripheral systolic blood pressure and central systolic blood pressure., Conclusion: With ageing, peripheral systolic blood pressure approximates to central systolic blood pressure. This might explain why in older subjects peripheral systolic blood pressure becomes the main predictor of cardiovascular complications.

Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P=1.032 · 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.

Earlier studies showed association of the human SAH (Spontaneously hypertensive rat-clone A-Hypertension associated) gene with hypertension and obesity. Left ventricular mass index (LVMI) increases with blood pressure and body mass index. In a family-based population study (54.5% women; mean age, 43.1 years), we measured LVMI, mean wall thickness (MWT) and the left ventricular internal diameter (LVID) at end-diastole in 699 non-Slavic and 493 Slavic participants. In multivariable-adjusted analyses, we investigated phenotype-genotype associations (SAH G-1606A and -962ins/del polymorphisms), while accounting for confounders and relatedness. Non-Slavic -1606GG homozygotes had a slightly greater LVID than -1606A allele carriers (48.6 vs. 48.0 mm; P=0.08). However, the between-family component of the variance in LVID was significant (P=0.005), suggesting that population stratification might explain the latter finding. Non-Slavic -962del carriers had higher LVMI (91.1 vs. 88.5 g m(-2); P=0.03) and MWT (9.61 vs. 9.44 mm; P=0.03) than -962ins homozygotes. Transmission of the -962del to non-Slavic offspring was also associated with higher MWT (P=0.03). In Slavic participants, in the absence of population stratification (P>or=0.69), -1606GG homozygotes had lower LVMI (96.5 vs. 102.3 g m(-2); P=0.004) and lower MWT (10.1 vs. 10.5 mm; P=0.003) than -1606A carriers. Sensitivity analyses showed that the latter associations were confined to founders. Transmission of the -962del allele to Slavic offspring was associated with lower MWT (P=0.007). In conclusion, LVMI and MWT, two phenotypes that are jointly influenced by blood pressure and obesity, might be related to variation in the human SAH gene.

Background: The regulator of G-protein signalling-2 (RGS2) is a key factor in adipogenesis. We hypothesized that the metabolic syndrome, of which obesity is an important component, might be related to genetic variation in RGS2., Methods and Results: We screened the human RGS2 gene. We tested the functionality of a common genetic variant in vitro, ex vivo, and in epidemiological study involving six European populations. The C to G substitution at position -391 in the RGS2 promoter was associated with enhanced RGS2 expression in vitro in transfected 3T3-L1 adipocytes and Chinese hamster cells and ex vivo in adipocytes from male, but not female, volunteers. In 2732 relatives from 512 families and 348 unrelated individuals, randomly recruited from six European populations, the prevalence of GG homozygosity was 54.1%. The metabolic syndrome score, a composite of six continuous traits making up this clinical entity, was 0.27 standardized units higher (P < 0.001) in 795 GG homozygous men compared with 683 men carrying the C allele. Transmission of the -391 G allele to male offspring was associated with a 0.20 unit increase in the score (P=0.039). These epidemiological relations were not significant in 1602 women., Conclusions: The C to G substitution at position -391 in the RGS2 promoter increases RGS2 expression in adipocytes and is associated with the metabolic syndrome in white European men. Further experimental and clinical research should establish whether this common polymorphism might be a target for preventive or therapeutic intervention.

Sympathetic tone increases with stimulation of the renin-angiotensin system and is under the influence of salt intake. In the European Project On Genes in Hypertension (EPOGH), we investigated whether polymorphisms in the genes encoding aldosterone synthase (CYP11B2 C-344T) and the type-1 angiotensin II receptor (AT1R A1166C) affect the autonomic modulation of heart rate at varying levels of salt intake. We measured the low frequency (LF) and high frequency (HF) components of heart rate variability and their ratio (LF:HF) in the supine and standing positions in 1797 participants (401 families and 320 unrelated subjects) randomly selected from 6 European populations, whose average urinary sodium excretion ranged from 163 to 245 mmol/d. In multivariate analyses with sodium excretion analyzed as a continuous variable, we explored the phenotype-genotype associations using generalized estimating equations and quantitative transmission disequilibrium tests. Across populations, there was no heterogeneity in the phenotype-genotype relations. The genotypic effects differed according to sodium excretion. In subjects with sodium excretion <190 mmol/d (median), supine heart rate, LF, and LF:HF increased and HF decreased with the number of CYP11B2 -344T alleles, and the orthostatic changes in LF, HF, and LF:HF were blunted in carriers of the AT1R 1166C allele. In subjects with sodium excretion >190 mmol/d, these associations with the CYP11B2 and AT1R polymorphisms were nonsignificant or in the opposite direction, respectively. Thus, CYP11B2 C-344T and AT1R A1166C polymorphisms affect the autonomic modulation of heart rate, but these genetic effects depend on sodium excretion.

The associations of the beta-adducin C1797T polymorphism with blood pressure (BP) and various indexes of sodium homeostasis were investigated in 388 men and 456 women, aged 18 to 60 years, recruited from three European populations (Cracow, Poland, n = 300; Novosibirsk, Russian Federation, n = 274; Mirano, Italy; n = 270). Phenotypes included 24-h ambulatory BP and urinary excretion of electrolytes and aldosterone. Subjects were genotyped for the beta-adducin polymorphism. Both a population-based association study and a family-based analysis were performed. Urinary sodium excretion was higher in Cracow than in Mirano (241 v 185 mmol/24 h, P <.05) and intermediate in Novosibirsk (206 mmol/24 h). The beta-adducin T allele (15.2% v 9.1%, P <.0001) was more prevalent in Mirano than in the two Slavic centers. In both population-based and family-based association analyses, there was significant heterogeneity between Slavic and Italian subjects in the phenotype-genotype relationships with beta-adducin. In the Slavic centers, 24-h systolic BP was higher in T allele carriers than in CC homozygotes (122.3 v 119.7 mm Hg, P =.03), whereas this was not the case in Mirano (121.8 v 122.9 mm Hg, P =.42). In Slavic (212.6 v 233.1 mmol/24 h) as well as in Italian (166.1 v 191.5 mmol/24 h) participants, 24-h sodium excretion was lower (P =.01) in T allele carriers than in CC homozygotes. These results were confirmed in the family-based analysis of offspring using a quantitative transmission disequilibrium test. In conclusion, the frequency of the beta-adducin T allele and salt intake differ across European populations. Thus, both variation in genetic background and salt intake may explain the observed heterogeneity in the phenotype-genotype relationships. Genetic determinants of complex quantitative traits such as BP can only be investigated within their epidemiologic context.

Methods: The association of blood pressure (BP) with the beta-adducin C1797 T polymorphism was investigated in 388 men and 456 women aged 18-60 years recruited from three European populations (Cracow, Poland, n=300; Novosibirsk, Russian Federation, n=274; Mirano, Italy; n=270). Phenotypes included conventional measurements of BP obtained at the second contact with the subjects and 24-h ambulatory BP. Subjects were genotyped for the beta-adducin C1797 T polymorphism. Both a population-based association study and a family-based analysis were performed., Results: Urinary sodium excretion was higher in Cracow than in Mirano (241 versus 185 mmol/day, P<0.05) and intermediate in Novosibirsk (206 mmol/day). The beta-adducin T allele (15.2 versus 9.1%, P<0.0001) was more prevalent in Mirano than in the two Slavic centres. In both population-based and family-based association analyses, there was significant heterogeneity between Slavic and Italian subjects in the phenotype-genotype relationships with beta-adducin. Adjusted population-based analyses demonstrated that in the two Slavic centres, values of systolic pressure obtained by 24-h, daytime and night-time ambulatory monitoring, but not those measured by conventional sphygmomanometry at home, were significantly higher in T allele carriers than in CC homozygotes. These results were confirmed in the family-based analysis of offspring using a quantitative transmission disequilibrium test., Conclusions: Phenotype-genotype associations involving blood pressure are influenced by the technique and conditions of the BP measurement as well as by the overall ecogenetic context.

Objective: In a population-based sample of nuclear families recruited in the framework of the European Project on Genes in Hypertension (EPOGH), we investigated the association between heart rate (HR) and its variability (HRV), and gender, age, posture, breathing frequency, body mass index, systolic blood pressure, family history of hypertension and various lifestyle factors, such as smoking, alcohol and coffee consumption and physical activity., Methods: RR interval and respiration were registered in the supine and standing positions (15 min each) in 1208 subjects in Bucharest (Romania, n= 267), Cracow (Poland, n= 323), Mirano (Italy, n= 323) and Novosibirsk (Russian Federation, n= 295). After exclusion of 199 participants on antihypertensive treatment and/or patients with diabetes mellitus (n= 40) or myocardial infarction (n= 4), 993 subjects were eligible for analysis. We evaluated 858 participants with high-quality recordings. Using fast Fourier transform, we decomposed HRV into low-frequency (LF: 0.04-0.15 Hz) and high-frequency (HF: 0.15-0.40 Hz) components, which were expressed in normalized units., Results: Mean values were 35.3 years for age, 24.3 kg/m for body mass index (BMI) and 121.0/77.2 mmHg for blood pressure. The group included 462 (53.8%) women. Across four centres, HR and HRV were similarly and independently associated with gender, age and postural position (P <0.001). In the supine position, HR was higher in women than men (67.2 versus 63.7 bpm). Men had higher normalized LF power than women (48.8 versus 41.5), but lower HF power (40.6 versus 47.4). The normalized HF power decreased with age (r = -0.43), whereas LF power increased (r = 0.32). On standing, HR increased (83.3 versus 65.6 bpm), normalized HF power declined (19.2 versus 44.3) and LF power increased (67.4 versus 44.9). The independent effects of respiration frequency, systolic blood pressure, family history of hypertension, body mass index and lifestyle factors on HRV differed between populations, and explained no more than 8% of the total variance., Conclusions: Across four European populations, gender, age and posture were consistent and independent correlates of HR and HRV. Lifestyle seems to have small but varying influences on HR and/or HRV, probably depending on the environmental and cultural background of the population under study.