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Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium.

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, ?=-0.075±0.012 SD/allele, P=2.8×10(-10); replication ?=-0.086±0.020 SD/allele, P=1.4×10(-6)). Combined results for rs7152623 from 11 cohorts gave ?=-0.076±0.010 SD/allele, P=3.1×10(-15). The association persisted when adjusted for mean arterial pressure (?=-0.060±0.009 SD/allele, P=1.0×10(-11)). Results were consistent in younger (<55 years, 6 cohorts, n=13 914, ?=-0.081±0.014 SD/allele, P=2.3×10(-9)) and older (9 cohorts, n=12 026, ?=-0.061±0.014 SD/allele, P=9.4×10(-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.

SUBMITTER: Mitchell GF

PROVIDER: S-EPMC3288392 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium.

Mitchell Gary F GF Verwoert Germaine C GC Tarasov Kirill V KV Isaacs Aaron A Smith Albert V AV Yasmin Rietzschel Ernst R ER Tanaka Toshiko T Liu Yongmei Y Parsa Afshin A Najjar Samer S SS O'Shaughnessy Kevin M KM Sigurdsson Sigurdur S De Buyzere Marc L ML Larson Martin G MG Sie Mark P S MP Andrews Jeanette S JS Post Wendy S WS Mattace-Raso Francesco U S FU McEniery Carmel M CM Eiriksdottir Gudny G Segers Patrick P Vasan Ramachandran S RS van Rijn Marie Josee E MJ Howard Timothy D TD McArdle Patrick F PF Dehghan Abbas A Jewell Elizabeth S ES Newhouse Stephen J SJ Bekaert Sofie S Hamburg Naomi M NM Newman Anne B AB Hofman Albert A Scuteri Angelo A De Bacquer Dirk D Ikram Mohammad Arfan MA Psaty Bruce M BM Fuchsberger Christian C Olden Matthias M Wain Louise V LV Elliott Paul P Smith Nicholas L NL Felix Janine F JF Erdmann Jeanette J Vita Joseph A JA Sutton-Tyrrell Kim K Sijbrands Eric J G EJ Sanna Serena S Launer Lenore J LJ De Meyer Tim T Johnson Andrew D AD Schut Anna F C AF Herrington David M DM Rivadeneira Fernando F Uda Manuela M Wilkinson Ian B IB Aspelund Thor T Gillebert Thierry C TC Van Bortel Luc L Benjamin Emelia J EJ Oostra Ben A BA Ding Jingzhong J Gibson Quince Q Uitterlinden André G AG Abecasis Gonçalo R GR Cockcroft John R JR Gudnason Vilmundur V De Backer Guy G GG Ferrucci Luigi L Harris Tamara B TB Shuldiner Alan R AR van Duijn Cornelia M CM Levy Daniel D Lakatta Edward G EG Witteman Jacqueline C M JC

Circulation. Cardiovascular genetics 20111108 1

<h4>Background</h4>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.<h4>Methods and results</h4>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 coh ...[more]

PMID: 22068335

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Project description:BACKGROUND:In end-stage renal disease (ESRD) patients, increased arterial stiffness detected by carotid-femoral pulse wave velocity (cf-PWV) is associated with fatal cardiovascular events and all-cause mortality. Since cf-PWV is an operator-dependent technique, poor reproducibility may be a source of bias in the estimation of arterial stiffness. OBJECTIVES:We assessed the week-to-week reproducibility of cf-PWV and radial artery pulse wave analysis in healthy subjects and ESRD patients. We also determined the extent of patient eligibility, enrollment, acceptance, and comfort. METHODS:In a cohort study design, independent tonometric examinations of carotid, femoral, and radial arteries were conducted in 20 healthy subjects and 15 ESRD patients attending chronic hemodialysis treatments according to a randomized sequence by two operators on 2 days scheduled 1-week apart. cf-PWV, augmentation index (AIx@HR75) and central pulse pressure (CPP) were the outcome measures. Patients were tested at mid-week and prior to dialysis treatment. The variability on the distance measured between the suprasternal notch and femoral site using two different methods (standard vs direct) was compared. A post-examination survey assessed acceptance and comfort associated with examinations. Reproducibility was evaluated by intra-class correlations (ICCs). RESULTS:The mean age for healthy subjects and ESRD patients was 45?±?12 and 63?±?16 years, respectively. ESRD patients had higher cf-PWV (p?=?0.0002), elevated AIx@HR75 (p?=?0.003), and increased CPP (p?=?0.001) compared to healthy subjects. The mean inter-visit differences for all stiffness indices were non-significant (p?>?0.05), but the mean inter-operator differences for the cf-PWV were significant only in the healthy subject group (-0.7 m/s; p?=?0.02). The ICCs between operators and visits were higher for the ESRD group compared to the healthy subjects (between operators, 0.870 vs 0.461; between visits, 0.830 vs 0.570). Distances were longer (p?<?0.001), but less variable with the standard method compared to the direct method (healthy subjects, p?=?0.036; ESRD, p?=?0.39). There was a high rate of patient acceptance and minimal discomfort. CONCLUSIONS:Week-to-week measurements of cf-PWV and pulse wave analysis are highly reproducible in ESRD patients prior to hemodialysis treatment. The high reproducibility and minimal test-to-test variations encourage use of cf-PWV to monitor changes in arterial stiffness and the efficacy of interventions in ESRD patients. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02196610.

Project description:The arterial system in diabetic patients is characterized by generalized non-atherosclerotic alterations in the vascular extracellular matrix causing increased arterial stiffness compared with subjects without diabetes. The underlying pathophysiology remains elusive. The elastin-associated extracellular matrix protein, fibulin-1, was recently found in higher concentrations in the arterial wall and in plasma in patients with long duration type 2 diabetes. Furthermore, plasma fibulin-1 independently predicted total mortality and was associated with pulse pressure, an indirect measure of arterial stiffness. Whether plasma fibulin-1 is associated with arterial stiffness at earlier phases of type 2 diabetes has not been determined.In this cross-sectional study, we examined 90 patients with recently diagnosed type 2 diabetes (< 5 years) and 90 gender- and age-matched controls. Plasma fibulin-1 was measured immunochemically. Arterial stiffness was assessed by carotid-femoral Pulse Wave Velocity (PWV). Differences in means were assessed by t-tests. Associations were assessed by multivariate regression analyses.Plasma fibulin-1 levels were lower in the diabetic group compared with the control group, 93?±?28 vs 106?±?30 ?g/mL, p?=?0.005. In unadjusted analysis of the total study sample, plasma fibulin-1 was not associated with PWV, p?=?0.46. However, with adjustment for the confounders age, gender, mean blood pressure, heart rate, body mass index, diabetes and glomerular filtration rate, a 10 ?g/mL increase in plasma fibulin was associated with 0.09?±?0.04 m/s increase in PWV, p?<?0.05. In subgroup analysis, plasma fibulin-1 was associated with PWV in the diabetes group, (0.16?±?0.07 m/s increase in PWV per 10 ?g/mL increase in plasma fibulin-1, p<0.05), but not controls, ??=?0.021?±?0.057 m/s per 10 ?g/mL, p?=?0.70. The association remained significant in the diabetes group after adjustment for covariates, p < 0.05.Plasma fibulin-1 is independently associated with PWV. Yet, as the plasma level of fibulin-1 was lower in patients with recently diagnosed type 2 diabetes than in healthy controls, plasma fibulin-1 levels are not a simple marker of the degree of arterial stiffening. Further studies are needed to determine the exact role of fibulin-1 in arterial stiffness and cardiovascular risk in patients with type 2 diabetes.

Dataset Information

Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium.

Publications

Common genetic variation in the 3'-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium.

Similar Datasets

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