Verwoert, G.C.

Does aortic stiffness improve the prediction of coronary heart disease in elderly the Rotterdam Study (Article)

2012-01-01T00:00:00Z

It has been demonstrated that aortic stiffness is an independent predictor of cardiovascular disease. We investigated whether this measure is of use in cardiovascular risk stratification in clinical practice for elderly subjects (mean age 71.5 years). Within the framework of the Rotterdam Study, we stratified subjects free of coronary heart disease (CHD) at baseline into categories of low (<10%), intermediate (10-20%) and high (>20%) 10-year risk of CHD based on Framingham risk factors. Within each risk category, we determined the percentages of subjects moving into a higher or lower risk category when adding aortic stiffness to the Framingham risk factors. Among 2849 participants, 223 CHD events occurred during a median follow-up of 7.9 years. In the low risk group, 5% of the subjects could be reclassified and in the high-risk group, 6% of the subjects could be reclassified to the intermediate-risk group. In the intermediate-risk group 3% could be reclassified to the high-risk group and 6% to the low-risk group. In a population of elderly subjects, aortic stiffness measurement in addition to Framingham risk factors leads to a limited reclassification of subjects in 10-year cardiovascular disease-risk categories. Therefore, aortic stiffness is associated with the risk of CHD in elderly, but provides no additional value in cardiovascular risk stratification.

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk (Article)

2011-10-06T00:00:00Z

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140mmg Hg systolic blood pressure ≥90mmg 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.

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure (Article)

2011-10-01T00:00:00Z

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.

Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM (Article)

2011-08-30T00:00:00Z

Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10-11and 2.7 × 10-11), which were also in strong linkage disequilibrium (r2=0.7) with each other, lie in the 23-kb long commonly shared 5′ flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10-09) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10-09)-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10-05) and Parkinson's disease pathways (P-value=3.6 × 10-05).Molecular Psychiatry advance online publication, 30 August 2011; doi:10.1038/mp.2011.101.

Measures of body composition and risk of heart failure in the elderly: The Rotterdam study (Article)

2011-05-01T00:00:00Z

Objectives: The incidence of heart failure increases with aging. Aim of the present, study was to determine whether measures body composition predict incident heart failure in older adults. Selling: Prospective community-based cohort study. 5, 868 men and women aged 55 years and older participating the Rotterdam study. Measures of body mass index and waist circumference were obtained at baseline. Information on incident heart failure was obtained during follow-up. Cox regression analyses were performed to investigate the possible association between measure of body composition and incident heart failure. Results: During a mean follow up of 10.9 (SD ±4.4) years, 765 participants had heart failure. After adjustment for age and gender, 1-standard deviation of body mass index, waist circumference and the waist-hip ratio predicted heart failure (HR 1.25; 95% CI 1.17-1.34; HR 1.26; 95% CI 1.18-1.36; and HR 1.17; 95% CI 1.08-1.27), respectively. In age-stratified analyses, 1-standard deviation of body mass index (1.17; 95% CI 1.06-1.29) and waist circumference (1.16; 95% CI 1.05-1.29) were still associated with the risk of heart failure in the oldest participants, whereas the waist-hip ratio was not (1.06; 95% CI 0.945-1.18). Conclusion: Although estimates decrease with age, measures of overall and central adiposity predict incident heart failure among community dwelling older adults.

Association of hypertension drug target genes with blood pressure and hypertension in 86 588 individuals (Article)

2011-05-01T00:00:00Z

We previously conducted genome-wide association meta-analysis of systolic blood pressure, diastolic blood pressure, and hypertension in 29 136 people from 6 cohort studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Here we examine associations of these traits with 30 gene regions encoding known antihypertensive drug targets. We find nominal evidence of association of ADRB1, ADRB2, AGT, CACNA1A, CACNA1C, and SLC12A3 polymorphisms with 1 or more BP traits in the Cohorts for Heart and Aging Research in Genomic Epidemiology genome-wide association meta-analysis. We attempted replication of the top meta-analysis single nucleotide polymorphisms for these genes in the Global BPgen Consortium (n=34 433) and the Women's Genome Health Study (n=23 019) and found significant results for rs1801253 in ADRB1 (Arg389Gly), with the Gly allele associated with a lower mean systolic blood pressure (β: 0.57 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=4.7×10), diastolic blood pressure (β: 0.36 mm Hg; SE: 0.06 mm Hg; meta-analysis: P=9.5×10), and prevalence of hypertension (β: 0.06 mm Hg; SE: 0.02 mm Hg; meta-analysis: P=3.3×10). Variation in AGT (rs2004776) was associated with systolic blood pressure (β: 0.42 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=3.8×10), as well as diastolic blood pressure (P=5.0×10) and hypertension (P=3.7×10). A polymorphism in ACE (rs4305) showed modest replication of association with increased hypertension (β: 0.06 mm Hg; SE: 0.01 mm Hg; meta-analysis: P=3.0×10). Two loci, ADRB1 and AGT, contain single nucleotide polymorphisms that reached a genome-wide significance threshold in meta-analysis for the first time. Our findings suggest that these genes warrant further studies of their genetic effects on blood pressure, including pharmacogenetic interactions.

Arterial stiffness as determinant of increased amino terminal pro-B-type natriuretic peptide levels in individuals with and without cardiovascular disease - The Rotterdam Study (Article)

2010-10-01T00:00:00Z

Objective: Large artery stiffening has adverse effects on cardiac structure and function and, therefore, may be associated with elevated circulating levels of amino-terminal pro-B-type natriuretic peptide (NT-proBNP). Methods: In a large community-dwelling older population (n = 6211, mean age 69.2 years), serum NT-proBNP, brachial pulse pressure (PP) and carotid-femoral pulse wave velocity (cfPWV) were measured. Results: In individuals without cardiovascular disease (CVD), median NT-proBNP was 6.7 pmol/l in men (n = 2073) and 10.1 pmol/l in women (n = 3085) (P < 0.001). In these individuals, indices of arterial stiffness correlated with NT-proBNP with beta-coefficients for brachial PP and cfPWV of 0.315 and 0.255 in men and 0.233 and 0.232 in women (all P < 0.001). After multivariable adjustment (age, weight, height, mean arterial pressure, heart rate, smoking, diabetes, estimated glomerular filtration rate, total and high-density lipoprotein-cholesterol and use of lipid-lowering and antihypertensive medication), these associations remained significant for brachial PP and cfPWV in men and for brachial PP in women. In multivariable-adjusted models, brachial PP explained 20.3% and cfPWV 10.7% of the variation of NT-proBNP in men and, respectively, 10.8 and 9.4% in women. In patients with prevalent CVD, indices of arterial stiffness and NT-proBNP were unrelated in multivariable-adjusted models. Conclusion: Our findings show that arterial stiffness is independently associated with elevated NT-proBNP levels in individuals without prevalent CVD. The association between vascular stiffness and NT-proBNP is stronger in men than in women and absent in individuals with prevalent CVD.

Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six loci influencing serum magnesium levels (Article)

2010-08-01T00:00:00Z

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using ~2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p<5×10-8) or suggestive associations (p<4×10-7) were evaluated for replication in an additional 8,463 subjects of European descent. The association of common variants at six genomic regions (in or near MUC1, ATP2B1, DCDC5, TRPM6, SHROOM3, and MDS1) with serum magnesium levels was genome-wide significant when meta-analyzed with the replication dataset. All initially significant SNPs from the CHARGE Consortium showed nominal association with clinically defined hypomagnesemia, two showed association with kidney function, two with bone mineral density, and one of these also associated with fasting glucose levels. Common variants in CNNM2, a magnesium transporter studied only in model systems to date, as well as in CNNM3 and CNNM4, were also associated with magnesium concentrations in this study. We observed no associations with serum sodium or potassium levels exceeding p<4×10-7. Follow-up studies of newly implicated genomic loci may provide additional insights into the regulation and homeostasis of human serum magnesium levels.

Inflammation and incident-isolated systolic hypertension in older adults: The Rotterdam study (Article)

2010-05-01T00:00:00Z

Objectives: Previous cross-sectional studies found an association between inflammatory markers and measures of arterial stiffness. Recently, some studies investigated whether patients with genotypes associated with high levels of circulating C-reactive protein had high arterial stiffness. These studies reported an association between C-reactive protein levels and measures of arterial stiffness, but no association between polymorphisms in the C-reactive protein gene and arterial stiffness, suggesting that C-reactive protein may have no causal role in the development of arterial stiffness. To further investigate the nature of the association between inflammatory markers and arterial stiffness, we prospectively examined the association of high-specificity C-reactive protein with incident-isolated systolic hypertension, as a model of arterial stiffness, in a large population-based study. Methods and Results: The present study included 1637 apparently healthy participants from the Rotterdam study. The mean age of the participants was 64 ± 6.4 years. During follow-up, 252 participants developed isolated systolic hypertension. Logistic regression analyses were performed. One standard deviation of high-specificity C-reactive protein was associated with incident-isolated systolic hypertension [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.01-1.41]. Conclusion: The findings of the present study support a role of C-reactive protein in the development of isolated systolic hypertension in apparently healthy older adults.

Genome-wide association study of PR interval (Article)

2010-02-01T00:00:00Z

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P 5 × 10 8. At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium (Article)

2009-11-01T00:00:00Z

Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 × 10 8 to 7 × 10 86). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.

Genome-wide association study of blood pressure and hypertension (Article)

2009-06-01T00:00:00Z

Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P 4 × 10 7. The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P 5 × 10 8) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.

Orthostatic hypotension and risk of cardiovascular disease in elderly people: The Rotterdam study (Article)

2008-10-01T00:00:00Z

OBJECTIVES: To determine the prognostic role of orthostatic hypotension for cardiovascular disease (CVD) and all-cause mortality in elderly people. DESIGN: Prospective study. SETTING: Community based. PARTICIPANTS: Five thousand sixty-four subjects from the Rotterdam study aged 55 and older. MEASUREMENTS: Orthostatic hypotension was measured using a Dinamap automatic blood pressure recorder. Orthostatic hypotension is defined as a decline in systolic blood pressure of 20 mmHg or more or a decline in diastolic blood pressure of 10 mmHg or more from supine to standing position at any of three measurements taken 1, 2, and 3 minutes after standing. RESULTS: At baseline, 901 subjects had orthostatic hypotension. During follow-up, 668 subjects had coronary heart disease (CHD) (mean follow-up 6.0 ± 3.5 years), and 1,835 subjects died (mean follow-up period 7.8 ± 3.8 years). Orthostatic hypotension increased the risk of CHD (hazard ratio (HR)=1.31, 95% confidence interval (CI)=1.08-1.57) and all-cause mortality (HR=1.22, 95% CI=1.09-1.36), in models adjusted for age and sex. The risk was slightly lower after additional adjustment for cardiovascular risk factors. In analyses stratified for age, the HRs for all-cause mortality were 1.80 (95% CI 1.25-2.60), 1.13 (0.89-1.42), and 1.27 (95% CI=1.11-1.44), in the first, second, and third tertile of age, respectively. CONCLUSION: Orthostatic hypotension increases the risk of CHD and all-cause mortality in elderly people. The risk of CVD and mortality is strongest in younger and very old subjects.