Genetic Markers Enhance Coronary Risk Prediction in Men: The MORGAM Prospective Cohorts

WOS:000306806600029Peer reviewe

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Polymorphisms in the promoter region of the dimethylarginine dimethylaminohydrolase 2 gene are associated with prevalence of hypertension

Infusion of the endogenous nitric oxide synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) causes an elevation of blood pressure and depression of cardiac output. Polymorphisms in the promoter region of the ADMA-degrading enzyme dimethylarginine dimethylaminohydrolase 2 (DDAH2) gene have been associated with elevated ADMA concentrations and adverse outcomes in critically ill patients. We hypothesized that two DDAH2 promoter - 1151 A/C and -449 G/C polymorphisms (rs805304 and rs805305) will be associated with blood pressure levels, hypertension prevalence and measures of cardiac structure and function in the general population. Methods and results: We genotyped rs805304 and rs805305 in 783 participants of the population-based Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) Augsburg S3 study. Plasma ADMA concentrations did not differ by rs805304 and rs805305 genotypes. Both polymorphisms were associated with a higher prevalence of hypertension. The odds ratio (adjusted for age, gender and body mass index) for hypertension was 1.70 (95%CI: 1.22-2.36: p=0.002) for those homozygous (n=348) for the -1151A allele and 1.80 (95%CI: 1.29-2.49, p<0.001) for individuals homozygous for the -449G allele (n=350). However, both polymorphisms were not related to measures of cardiac structure and function (left ventricular [LV] mass, LV wall thickness, LV end-diastolic diameter, ejection fraction, E/A ratio, isovolumetric relaxation time) in multivariable-adjusted models. Conclusion: The present study indicates that the -1151 A/C and -449 G/C polymorphisms in the DDAH2 promoter region are not related to plasma ADMA levels or measures of cardiac structure and function but are associated with an increased prevalence of hypertension. The mechanisms of this association need further investigation

Long-term pattern of brain natriuretic peptide and N-terminal pro brain natriuretic peptide and its determinants in the general population: contribution of age, gender, and cardiac and extra-cardiac factors

AIMS: The natriuretic peptides BNP and NT-proBNP are potent cardiac markers, but knowledge of long-term changes is sparse. We thus quantified determinants of change in BNP and NT-proBNP in a study of south German residents (KORA). METHODS AND RESULTS: A total of 1005 men and women (age 25-74 years, mean 48 years) underwent physical examination and echocardiography at baseline and at follow-up after 10 years. The current analysis comprised 877 subjects with dual measurements of BNP and NT-proBNP. Both markers increased in both sexes (P < 0.001) during the 10-year follow-up, and higher levels in women persisted across time (P for sex difference <0.001). Among baseline covariates, predictors for 10-year change of NT-proBNP, BNP, or both were age, sex, diabetes status, and heart rate (multivariable regression analysis, each P < 0.05). However, changes of covariates over the 10-year follow-up were much stronger determinants. Specifically, incident myocardial infarction, new beta-blocker medication, and increased cardiac parameters (left atrial diameter, LV end-diastolic diameter, and LV mass index) were associated with increasing BNP, NT-proBNP, or both, whereas increased heart rate, haematocrit, and body mass index (BMI) were associated with decreasing BNP and NT-proBNP (all P < 0.05). CONCLUSION: Next to ageing and sex, a variety of changes in covariates reflecting the sequelae of cardiac remodelling as well as myocardial infarction and diabetes influence long-term changes of BNP and NT-proBNP. Of note, diabetes and increased BMI exert opposite effects. For interpretation of individual marker concentrations, a host of covariates needs to be considered, especially in subjects without prevalent or incident cardiac disease

Variation in Body Composition Determines Long-Term Blood Pressure Changes in Pre-Hypertension The MONICA/KORA (Monitoring Trends and Determinants on Cardiovascular Diseases/Cooperative Research in the Region of Augsburg) Cohort Study

Objectives We studied the relationship between changes in body composition and changes in blood pressure levels. Background The mechanisms underlying the frequently observed progression from pre-hypertension to hypertension are poorly understood. Methods We examined 1,145 subjects from a population-based survey at baseline in 1994/1995 and at follow-up in 2004/2005. First, we studied individuals pre-hypertensive at baseline who, during 10 years of follow-up, either had normalized blood pressure (PreNorm, n = 48), persistently had pre-hypertension (PrePre, n = 134), or showed progression to hypertension (PreHyp, n = 183). In parallel, we studied predictors for changes in blood pressure category in individuals hypertensive at baseline (n = 429). Results After 10 years, the PreHyp group was characterized by a marked increase in body weight (+5.71% [95% confidence interval (CI): 4.60% to 6.83%]) that was largely the result of an increase in fat mass (+17.8% [95% CI: 14.5% to 21.0%]). In the PrePre group, both the increases in body weight (+1.95% [95% CI: 0.68% to 3.22%]) and fat mass (+8.09% [95% CI: 4.42% to 11.7%]) were significantly less pronounced than in the PreHyp group (p < 0.001 for both). The PreNorm group showed no significant change in body weight (-1.55% [95% CI: -3.70% to 0.61%]) and fat mass (+0.20% [95% CI: -6.13% to 6.52%], p < 0.05 for both, vs. the PrePre group). Conclusions After 10 years of follow-up, hypertension developed in 50.1% of individuals with pre-hypertension and only 6.76% went from hypertensive to pre-hypertensive blood pressure levels. An increase in body weight and fat mass was a risk factor for the development of sustained hypertension, whereas a decrease was predictive of a decrease in blood pressure. (J Am Coll Cardiol 2010; 56: 65-76) (C) 2010 by the American College of Cardiology FoundationGerman Research Foundation (Deutsche Forschungsgemeinschaft [DFG][DFG Schu 672/12-1]Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung [BMBF][NGFN2 [FKZ-01GS0418]Competence Network of Heart Failure[BMBF-01GI0205]University of Lubeck Medical School[A39-2005]Helmholtz Zentrum MunchenFederal Ministry of Education and ResearchBavarian Ministry of Financ

The Aging Process of the Heart: Obesity Is the Main Risk Factor for Left Atrial Enlargement During Aging The MONICA/KORA (Monitoring of Trends and Determinations in Cardiovascular Disease/Cooperative Research in the Region of Augsburg) Study

Objectives This prospective study evaluated the association of obesity and hypertension with left atrial (LA) volume over 10 years. Background Although left atrial enlargement (LAE) is an independent risk factor for atrial fibrillation, stroke, and death, little information is available about determinants of LA size in the general population. Methods Participants (1,212 men and women, age 25 to 74 years) originated from a sex-and age-stratified random sample of German residents of the Augsburg area (MONICA S3). Left atrial volume was determined by standardized echocardiography at baseline and again after 10 years. Left atrial volume was indexed to body height (iLA). Left atrial enlargement was defined as iLA >= 35.7 and >= 33.7 ml/m in men and women, respectively. Results At baseline, the prevalence of LAE was 9.8%. Both obesity and hypertension were independent predictors of LAE, obesity (odds ratio [OR]: 2.4; p < 0.001) being numerically stronger than hypertension (OR: 2.2; p < 0.001). Adjusted mean values for iLA were significantly lower in normal-weight hypertensive patients (25.4 ml/m) than in obese normotensive individuals (27.3 ml/m; p = 0.016). The highest iLA was found in the obese hypertensive subgroup (30.0 ml/m; p < 0.001 vs. all other groups). This group also presented with the highest increase in iLA (+6.0 ml/m) and the highest incidence (31.6%) of LAE upon follow-up. Conclusions In the general population, obesity appears to be the most important risk factor for LAE. Given the increasing prevalence of obesity, early interventions, especially in young obese individuals, are essential to prevent premature onset of cardiac remodeling at the atrial level. (J Am Coll Cardiol 2009; 54: 1982-9) (C) 2009 by the American College of Cardiology FoundationFederal Ministry of Education and Research[FKZ 01GI0205]Deutsche Forschungsgemeinschaft (DFG)[Schu 672/9-1]Deutsche Forschungsgemeinschaft (DFG)[Schu 672/10-1]Deutsche Forschungsgemeinschaft (DFG)[Schu 672/12-1]Bundesministerium fur Forschung und Technologie (BMBF)Medical Faculty, University of Lubeck[A39-2005]European-Union[LSH-2005-037593]HelmholtzZentrum Munchen-German Research Centre for Environmental HealthGerman Federal Ministry of Education, Science, Research, and TechnologyState of Bavari

Effects of smoking on arterial distensibility, central aortic pressures and left ventricular mass

BACKGROUND: The effects of smoking on central aortic pressures and the age-related increase in left ventricular mass (LVM) are largely unknown. We studied the relationship between smoking, arterial distensibility, central aortic pressures and left ventricular mass in two population-based studies. METHODS: Data was obtained from two German population-based studies (KORA and SHIP, participants&#39; ages 25-84years). We identified 114 normotensive current smokers and 185 normotensive all-time non-smokers in KORA as well as 400 and 588 such individuals in SHIP. Echocardiographic LVM was obtained at baseline (T0) and follow-up after ten years (T1) in KORA and at follow-up (T1) in SHIP. Additionally, pulse-wave analysis-based central aortic pressure and augmentation index (AIx) were measured at T1 in KORA. RESULTS: Cross-sectional analysis, using KORA T0 and SHIP T1, revealed in both studies a higher covariate-adjusted LVM and left ventricular mass index (LVMI) in smokers as compared with non-smokers. Moreover, in the KORA T1 examination, the smokers demonstrated a more pronounced increase, relative to baseline, of LVM (+13.5%) and LVMI (+13.4%) compared to non-smokers (+8.59% and +8.65%; p=0.036 and 0.042, respectively). Additionally, at KORA T1 smokers had a higher central systolic blood pressure and higher AIx than non-smokers (p=0.012 and p=0.001, respectively). CONCLUSIONS: The difference in central aortic pressure due to enhanced and more prolonged wave reflection may explain our finding of a further pronounced increase in left ventricular wall thickness and mass over time in smokers