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Thériault, Sébastien

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Thériault

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Sébastien

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Université Laval. Département de biologie moléculaire, de biochimie médicale et de pathologie

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ncf11873324

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  • PublicationRestreint
    Polygenic risk score for coronary artery disease improves the prediction of early-onset myocardial infarction and mortality in men
    (Lippincott Williams & Wilkins, 2021-10-21) Manikpurage, Hasanga D.; Eslami, Aida; Perrot, Nicolas; Li, Zhonglin; Couture, Christian; Mathieu, Patrick; Bossé, Yohan; Arsenault, Benoit; Thériault, Sébastien
    BACKGROUND: Several risk factors for coronary artery disease (CAD) have been described, some of which are genetically determined. The use of a polygenic risk score (PRS) could improve CAD risk assessment, but predictive accuracy according to age and sex is not well established. METHODS: A PRS$_\textup{CAD}$ including the weighted effects of >1.14 million single nucleotide polymorphisms associated with CAD was calculated in UK Biobank (n=408 422), using LDpred. Cox regressions were performed, stratified by age quartiles and sex, for incident myocardial infarction (MI) and mortality, with a median follow-up of 11.0 years. Improvement in risk prediction of MI was assessed by comparing PRS$_\textup{CAD}$ to the pooled cohort equation with categorical net reclassification index using a 2% threshold (NRI$^\textup{0.02}$) and continuous NRI (NRI$^\textup{>0}$). RESULTS: From 7746 incident MI cases and 393 725 controls, hazard ratio for MI reached 1.53 (95% CI, 1.49–1.56; P=2.69×10⁻²⁹⁶) per SD increase of PRS$_\textup{CAD}$. PRS$_\textup{CAD}$ was significantly associated with MI in both sexes, with a stronger association in men (interaction P=0.002), particularly in those aged between 40 and 51 years (hazard ratio, 2.00 [95% CI, 1.86–2.16], P=1.93×10⁻⁷²). This group showed the highest reclassification improvement, mainly driven by the up-classification of cases (NRI$^\textup{0.02}$, 0.199 [95% CI, 0.157–0.248] and NRI$^\textup{>0}$, 0.602 [95% CI, 0.525–0.683]). From 23 982 deaths, hazard ratio for mortality was 1.08 (95% CI, 1.06–1.09; P=5.46×10⁻³⁰) per SD increase of PRS$_\textup{CAD}$, with a stronger association in men (interaction P=1.60×10⁻⁶). CONCLUSIONS: Our PRS$_\textup{CAD}$ predicts MI incidence and all-cause mortality, especially in men aged between 40 and 51 years. PRS could optimize the identification and management of individuals at risk for CAD.
  • PublicationRestreint
    Lipoprotein-associated phospholipase A2 activity, genetics and calcific aortic valve stenosis in humans
    (BMJ Pub. Group, 2020-08-26) Thériault, Sébastien; Arsenault, Benoit; Rigade, Sidwell; Capoulade, Romain; Chen, Hao Yu; Bossé, Yohan; Dina, Christian; Pibarot, Philippe; Martinsson, Andreas; Perrot, Nicolas; Boekholdt, Matthijs; Clavel, Marie-Annick; Mathieu, Patrick; Le Tourneau, Thierry; Messika-Zeitoun, David; Engert, James; Wareham, Nicholas J.; Smith, J. Gustav; Schott, Jean Jacques; Thanassoulis, George
    Background Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity has been shown to predict calcific aortic valve stenosis (CAVS) outcomes. Our objective was to test the association between plasma Lp-PLA2 activity and genetically elevated Lp-PLA2 mass/activity with CAVS in humans. Methods and results Lp-PLA2 activity was measured in 890 patients undergoing cardiac surgery, including 476 patients undergoing aortic valve replacement for CAVS and 414 control patients undergoing coronary artery bypass grafting. After multivariable adjustment, Lp-PLA2 activity was positively associated with the presence of CAVS (OR=1.21 (95% CI 1.04 to 1.41) per SD increment). We selected four single nucleotide polymorphisms (SNPs) at the PLA2G7 locus associated with either Lp-PLA2 mass or activity (rs7756935, rs1421368, rs1805017 and rs4498351). Genetic association studies were performed in eight cohorts: Quebec-CAVS (1009 cases/1017 controls), UK Biobank (1350 cases/349 043 controls), European Prospective Investigation into Cancer and Nutrition-Norfolk (504 cases/20 307 controls), Genetic Epidemiology Research on Aging (3469 cases/51 723 controls), Malmö Diet and Cancer Study (682 cases/5963 controls) and three French cohorts (3123 cases/6532 controls), totalling 10 137 CAVS cases and 434 585 controls. A fixed-effect meta-analysis using the inverse-variance weighted method revealed that none of the four SNPs was associated with CAVS (OR=0.99 (95% CI 0.96 to 1.02, p=0.55) for rs7756935, 0.97 (95% CI 0.93 to 1.01, p=0.11) for rs1421368, 1.00 (95% CI 1.00 to 1.01, p=0.29) for rs1805017, and 1.00 (95% CI 0.97 to 1.04, p=0.87) for rs4498351). Conclusions Higher Lp-PLA2 activity is significantly associated with the presence of CAVS and might represent a biomarker of CAVS in patients with heart disease. Results of our genetic association study suggest that Lp-PLA2 is however unlikely to represent a causal risk factor or therapeutic target for CAVS.
  • PublicationRestreint
    Sex-specific associations of genetically predicted circulating Lp(a) (Lipoprotein(a)) and hepatic LPA gene expression levels with cardiovascular outcomes : mendelian randomization and observational analyses
    (Lippincott Williams & Wilkins, 2021-07-19) Guertin, Jakie; Kaiser, Yannick; Manikpurage, Hasanga D.; Perrot, Nicolas; Bourgeois, Raphaëlle; Couture, Christian; Wareham, Nicholas J.; Bossé, Yohan; Pibarot, Philippe; Stroes, Erik S.; Mathieu, Patrick; Clavel, Marie-Annick; Thériault, Sébastien; Boekholdt, Matthijs; Arsenault, Benoit
    Background: Elevated Lp(a) (Lipoprotein(a)) levels are associated with coronary artery disease (CAD), ischemic stroke (IS), and calcific aortic valve stenosis (CAVS). Studies investigating the association between Lp(a) levels and these diseases in women have yielded inconsistent results. Methods: To investigate the association of Lp(a) with sex-specific cardiovascular outcomes, we determined the association between genetically predicted Lp(a) levels (using 27 single nucleotide polymorphisms at the LPA locus) and hepatic LPA expression (using 80 single nucleotide polymorphisms at the LPA locus associated with LPA mRNA expression in liver samples from the Genotype-Tissue Expression dataset) on CAD, IS, and CAVS using individual participant data from the UK Biobank: 408 403 participants of European ancestry (37 102, 4283, and 2574 with prevalent CAD, IS, and CAVS, respectively). The long-term association between Lp(a) levels and incident CAD, IS, and CAVS was also investigated in European Prospective Investigation into Cancer and Nutrition-Norfolk: 18 721 participants (3964, 846, and 424 with incident CAD, IS, and CAVS, respectively). Results: Genetically predicted plasma Lp(a) levels were positively and similarly associated with prevalent and incident CAD and CAVS in men and women. Genetically predicted plasma Lp(a) levels were associated with prevalent and incident IS when we studied men and women pooled together, and in men only. Genetically predicted LPA expression levels were associated with prevalent CAD and CAVS in men and women but not with IS. Conclusions: Genetically predicted blood Lp(a) and hepatic LPA gene expression as well as serum Lp(a) levels predict the risk of CAD and CAVS in men and in women. Whether RNA interference therapies aiming at lowering Lp(a) levels could be useful in reducing cardiovascular disease risk in both men and women with high Lp(a) levels needs to be determined in large-scale cardiovascular outcomes trials.
  • PublicationAccès libre
    Genetic and in vitro inhibition of PCSK9 and calcific aortic valve stenosis
    (Elsevier, 2020-07-01) Thériault, Sébastien; Valerio, Vincenza; Arsenault, Benoit; Moschetta, Donato; Capoulade, Romain; Boekholdt, S. Matthijs; Bossé, Yohan; Dina, Christian; Pibarot, Philippe; Chen, Hao Yu; Perrot, Nicolas; Abner, Erik; Clavel, Marie-Annick; Martinsson, Andreas; Mathieu, Patrick; Manikpurage, Hasanga D.; Rigade, Sidwell; Mass, Elvira; Le Tourneau, Thierry; Messika-Zeitoun, David; Wareham, Nicholas J.; Engert, James; Polvani, Gianluca; Esko, Tõnu; Smith, J. Gustav; Thanassoulis, George; Schott, Jean-Jacques; Camera, Marina; Poggio, Paolo
    The authors investigated whether PCSK9 inhibition could represent a therapeutic strategy in calcific aortic valve stenosis (CAVS). A meta-analysis of 10 studies was performed to determine the impact of the PCSK9 R46L variant on CAVS, and the authors found that CAVS was less prevalent in carriers of this variant (odds ratio: 0.80 [95% confidence interval: 0.70 to 0.91]; p ¼ 0.0011) compared with noncarriers. PCSK9 expression was higher in the aortic valves of patients CAVS compared with control patients. In human valve interstitials cells submitted to a pro-osteogenic medium, PCSK9 levels increased and a PCSK9 neutralizing antibody significantly reduced calcium accumulation. (J Am Coll Cardiol Basic Trans Science 2020;5:649–61) © 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.