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  • 1
    Keywords: RECEPTOR ; T-CELL ; PROMOTER ; BLOOD-PRESSURE ; protein expression ; GENOME-WIDE ASSOCIATION ; INDEPENDENT PREDICTOR ; ARTERIAL STIFFNESS ; AORTIC STIFFNESS ; HYPERTENSIVE PATIENTS
    Abstract: BACKGROUND: Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events. METHODS AND RESULTS: We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20 634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3'-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency=0.42, beta=-0.075+/-0.012 SD/allele, P=2.8x10(-10); replication beta=-0.086+/-0.020 SD/allele, P=1.4x10(-6)). Combined results for rs7152623 from 11 cohorts gave beta=-0.076+/-0.010 SD/allele, P=3.1x10(-15). The association persisted when adjusted for mean arterial pressure (beta=-0.060+/-0.009 SD/allele, P=1.0x10(-11)). Results were consistent in younger (〈55 years, 6 cohorts, n=13 914, beta=-0.081+/-0.014 SD/allele, P=2.3x10(-9)) and older (9 cohorts, n=12 026, beta=-0.061+/-0.014 SD/allele, P=9.4x10(-6)) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio=1.05; confidence interval=1.02-1.08; P=0.0013) and heart failure (hazard ratio=1.10, CI=1.03-1.16, P=0.004). CONCLUSIONS: Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor 1 or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.
    Type of Publication: Journal article published
    PubMed ID: 22068335
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  • 2
    Keywords: POPULATION ; HEALTH ; RISK FACTOR ; BLOOD-PRESSURE ; DISORDERS ; hyperthyroidism ; HYPOTHYROIDISM ; ARTERIAL STIFFNESS ; SUBCLINICAL THYROID-DYSFUNCTION ; ENDOTHELIUM-DEPENDENT VASODILATATION
    Abstract: Background: Recent data from a population-based study in children and adolescents suggest that serum thyrotropin (TSH) levels are associated with arterial blood pressure and hypertension. These results are in agreement with some but not all population-based studies in adults. Discrepancies in results might be explained by drug intake, different iodine supplies, and sizes of populations investigated. In addition, it is not clear whether an association between TSH and hypertension exists longitudinally or only cross-sectionally. Thus, our aim was to investigate cross-sectional and longitudinal associations between thyroid function and arterial blood pressure in a large consortium of cohort studies in adults. Methods: Data from five population-based studies were pooled resulting in 17,023 individuals being available for cross-sectional and 10,048 individuals for longitudinal analyses. Associations of baseline TSH with baseline blood pressure or hypertension were analyzed by multivariable median or logistic regression models. Multivariable median or Poisson regression models were used to investigate associations of baseline TSH with five-year change in arterial blood pressure or incident hypertension. Results: There was a cross-sectional positive association of TSH with arterial blood pressure (p〈0.001) and hypertension (odds ratio [OR]=1.76 [confidence interval (CI) 1.24-2.50], p=0.002). Likewise, hypothyroidism was associated with systolic (beta=1.1 [CI 0.1-2.1], p=0.040) and diastolic blood pressure (beta=1.4 [CI 0.7-2.0], p〈0.001). TSH, however, was not consistently associated with a five-year change in blood pressure or incident hypertension. Conclusions: High serum TSH levels were associated with current hypertension and blood pressure but not with a five-year change in blood pressure and incident hypertension. This argues for only a short-term effect of thyroid hormone levels on arterial blood pressure or a spurious association that needs further evaluation in population-based studies.
    Type of Publication: Journal article published
    PubMed ID: 23427935
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  • 3
    Keywords: INHIBITOR ; RISK ; TRIAL ; EVENTS ; SERUM-LEVELS ; ARTERY-DISEASE ; MENDELIAN RANDOMIZATION ; HEALTHY-MEN ; EPIC-NORFOLK ; ACUTE CORONARY SYNDROMES
    Abstract: OBJECTIVES: This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease. BACKGROUND: Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. METHODS: We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable. RESULTS: PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. CONCLUSIONS: Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
    Type of Publication: Journal article published
    PubMed ID: 23916927
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