Oldgren J

References (2)

Title : Genetic determinants of dabigatran plasma levels and their relation to bleeding - Pare_2013_Circulation_127_1404
Author(s) : Pare G , Eriksson N , Lehr T , Connolly S , Eikelboom J , Ezekowitz MD , Axelsson T , Haertter S , Oldgren J , Reilly P , Siegbahn A , Syvanen AC , Wadelius C , Wadelius M , Zimdahl-Gelling H , Yusuf S , Wallentin L
Ref : Circulation , 127 :1404 , 2013
Abstract : BACKGROUND: Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in the prevention of stroke in atrial fibrillation patients compared with warfarin. We hypothesized that genetic variants could contribute to interindividual variability in blood concentrations of the active metabolite of dabigatran etexilate and influence the safety and efficacy of dabigatran. METHODS AND RESULTS: We successfully conducted a genome-wide association study in 2944 Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) participants. The CES1 single-nucleotide polymorphism rs2244613 was associated with trough concentrations, and the ABCB1 single-nucleotide polymorphism rs4148738 and the CES1 single-nucleotide polymorphism rs8192935 were associated with peak concentrations at genome-wide significance (P<9x10(-8)) with a gene-dose effect. Each minor allele of the CES1 single-nucleotide polymorphism rs2244613 was associated with lower trough concentrations (15% decrease per allele; 95% confidence interval, 10-19; P=1.2x10(-8)) and a lower risk of any bleeding (odds ratio, 0.67; 95% confidence interval, 0.55-0.82; P=7x10(-5)) in dabigatran-treated participants, with a consistent but nonsignificant lower risk of major bleeding (odds ratio, 0.66; 95% confidence interval, 0.43-1.01). The interaction between treatment (warfarin versus all dabigatran) and carrier status was statistically significant (P=0.002), with carriers having less bleeding with dabigatran than warfarin (hazard ratio, 0.59; 95% confidence interval, 0.46-0.76; P=5.2x10(-)5) in contrast to no difference in noncarriers (hazard ratio, 0.96; 95% confidence interval, 0.81-1.14; P=0.65). There was no association with ischemic events, and neither rs4148738 nor rs8192935 was associated with bleeding or ischemic events. CONCLUSIONS: Genome-wide association analysis identified that carriage of the CES1 rs2244613 minor allele occurred in 32.8% of patients in RE-LY and was associated with lower exposure to active dabigatran metabolite. The presence of the polymorphism was associated with a lower risk of bleeding. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.
ESTHER : Pare_2013_Circulation_127_1404
PubMedSearch : Pare_2013_Circulation_127_1404
PubMedID: 23467860

Title : Collaborative meta-analysis of individual participant data from observational studies of Lp-PLA2 and cardiovascular diseases - Ballantyne_2007_Eur.J.Cardiovasc.Prev.Rehabil_14_3
Author(s) : Ballantyne C , Cushman M , Psaty B , Furberg C , Khaw KT , Sandhu M , Oldgren J , Rossi GP , Maiolino G , Cesari M , Lenzini L , James SK , Rimm E , Collins R , Anderson J , Koenig W , Brenner H , Rothenbacher D , Berglund G , Persson M , Berger P , Brilakis E , McConnell JP , Sacco R , Elkind M , Talmud P , Cannon CP , Packard C , Barrett-Connor E , Hofman A , Kardys I , Witteman JC , Criqui M , Corsetti JP , Rainwater DL , Moss AJ , Robins S , Bloomfield H , Collins D , Wassertheil-Smoller S , Ridker P , Danesh J , Gu D , Nelson JJ , Thompson S , Zalewski A , Zariffa N , Di Angelantonio E , Kaptoge S , Thompson A , Walker M , Watson S , Wood A
Ref : Eur J Cardiovasc Prev Rehabil , 14 :3 , 2007
Abstract : BACKGROUND: A large number of observational epidemiological studies have reported generally positive associations between circulating mass and activity levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) and the risk of cardiovascular diseases. Few studies have been large enough to provide reliable estimates in different circumstances, such as in different subgroups (e.g., by age group, sex, or smoking status) or at different Lp-PLA2 levels. Moreover, most published studies have related disease risk only to baseline values of Lp-PLA2 markers (which can lead to substantial underestimation of any risk relationships because of within-person variability over time) and have used different approaches to adjustment for possible confounding factors. OBJECTIVES: By combination of data from individual participants from all relevant observational studies in a systematic 'meta-analysis', with correction for regression dilution (using available data on serial measurements of Lp-PLA2), the Lp-PLA2 Studies Collaboration will aim to characterize more precisely than has previously been possible the strength and shape of the age and sex-specific associations of plasma Lp-PLA2 with coronary heart disease (and, where data are sufficient, with other vascular diseases, such as ischaemic stroke). It will also help to determine to what extent such associations are independent of possible confounding factors and to explore potential sources of heterogeneity among studies, such as those related to assay methods and study design. It is anticipated that the present collaboration will serve as a framework to investigate related questions on Lp-PLA2 and cardiovascular outcomes. METHODS: A central database is being established containing data on circulating Lp-PLA2 values, sex and other potential confounding factors, age at baseline Lp-PLA2 measurement, age at event or at last follow-up, major vascular morbidity and cause-specific mortality. Information about any repeat measurements of Lp-PLA2 and potential confounding factors has been sought to allow adjustment for possible confounding and correction for regression dilution. The analyses will involve age-specific regression models. Synthesis of the available observational studies of Lp-PLA2 will yield information on a total of about 15 000 cardiovascular disease endpoints.
ESTHER : Ballantyne_2007_Eur.J.Cardiovasc.Prev.Rehabil_14_3
PubMedSearch : Ballantyne_2007_Eur.J.Cardiovasc.Prev.Rehabil_14_3
PubMedID: 17301621
Gene_locus related to this paper: human-PLA2G7