Personne : Thériault, Sébastien
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Université Laval. Département de biologie moléculaire, de biochimie médicale et de pathologie
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- PublicationRestreintLipoprotein-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, GeorgeBackground 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.
- PublicationAccès libreGenetic association analyses highlight IL6, ALPL, and NAV1 as three new susceptibility genes underlying calcific aortic valve stenosis(American Heart Association, 2019-10-15) Gaudreault, Nathalie; Dina, Christian; Thériault, Sébastien; Messika-Zeitoun, David; Arsenault, Benoit; Le Scouarnec, Solena; Capoulade, Romain; Boureau, Anne-Sophie; Bossé, Yohan; Rigade, Sidwell; Lamontagne, Maxime; Li, Zhonglin; Pibarot, Philippe; Simonet, Floriane; Clavel, Marie-Annick; Dagenais, François.; Mathieu, Patrick; Lecointe, Simon; Baron, Estelle; Bonnaud, Stéphanie; Karakachoff, Matilde; Charpentier, Eric; Fellah, Imen; Roussel, Jean-Christian; Verhoye, Jean Philippe; Baufreton, Christophe; Probst, Vincent; Roussel, Ronan; Redon, Richard; Le Tourneau, Thierry; Schott, Jean-JacquesBackground: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD, have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. Methods: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. Results: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. Conclusions: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.
- PublicationAccès libreLipoprotein(a), oxidized phospholipids, and aortic valve microcalcification assessed by 18F-sodium fluoride positron emission tomography and computed tomography(ScienceDirect, 2019-04-12) Bilodeau, Anthony; Thériault, Sébastien; Nadeau, Maxime; Arsenault, Benoit; Chen, Hao Yu; Bourgeois, Raphaëlle; Shen, Mylène; Trottier, Mikaël; Tessier, Michel; Després, Audrey-Anne; Guimond, Jean; Bossé, Yohan; Engert, James; Perrot, Nicolas; Couture, Patrick; Mathieu, Patrick; Witztum, Joseph L.; Dweek, MarcBackground Lipoprotein(a) (Lp[a]) is the preferential lipoprotein carrier of oxidized phospholipids (OxPLs) and a well-established genetic risk factor for calcific aortic valve stenosis (CAVS). Whether Lp(a) predicts aortic valve microcalcification in individuals without CAVS is unknown. Our objective was to estimate the prevalence of elevated Lp(a) and OxPL levels in patients with CAVS and to determine if individuals with elevated Lp(a) but without CAVS have higher aortic valve microcalcification. Methods We recruited 214 patients with CAVS from Montreal and 174 patients with CAVS and 108 controls from Québec City, Canada. In a second group of individuals with high (≥75 nmol/L, n = 27) or low (<75 nmol/L, n = 28) Lp(a) levels, 18F-sodium fluoride positron emission tomography/computed tomography was performed to determine the difference in mean tissue-to-background ratio (TBR) of the aortic valve. Results Patients with CAVS had 62.0% higher Lp(a) (median = 28.7, interquartile range [8.2-116.6] vs 10.9 [3.6-28.8] nmol/L, P < 0.0001), 50% higher OxPL-apolipoprotein-B (2.2 [1.3-6.0] vs 1.1 [0.7-2.6] nmol/L, P < 0.0001), and 69.9% higher OxPL-apolipoprotein(a) (7.3 [1.8-28.4] vs 2.2 [0.8-8.4] nmol/L, P < 0.0001) levels compared with individuals without CAVS (all P < 0.0001). Individuals without CAVS but elevated Lp(a) had 40% higher mean TBR compared with individuals with low Lp(a) levels (mean TBR = 1.25 ± 0.23 vs 1.15 ± 0.11, P = 0.02). Conclusions Elevated Lp(a) and OxPL levels are associated with prevalent CAVS in patients studied in an echocardiography laboratory setting. In individuals with elevated Lp(a), evidence of aortic valve microcalcification by 18F-sodium fluoride positron emission tomography/computed tomography is present before the development of clinically manifested CAVS.
- PublicationAccès libreA transcriptome-wide association study identifies PALMD as a susceptibility gene for calcific aortic valve stenosis(Nature Publishing Group, 2018-03-07) Gaudreault, Nathalie; Thériault, Sébastien; Rosa, Mickael; Boulanger, Marie-Chloé; Capoulade, Romain; Messika-Zeitoun, David; Bossé, Yohan; Lamontagne, Maxime; Pibarot, Philippe; Clavel, Marie-Annick; Dagenais, François.; Mathieu, PatrickCalciﬁc aortic valve stenosis (CAVS) is a common and life-threatening heart disease and the current treatment options cannot stop or delay its progression. A GWAS on 1009 cases and 1017 ethnically matched controls was combined with a large-scale eQTL mapping study of human aortic valve tissues (n = 233) to identify susceptibility genes for CAVS. Replication was performed in the UK Biobank, including 1391 cases and 352,195 controls. A tran- scriptome-wide association study (TWAS) reveals PALMD (palmdelphin) as signiﬁcantly associated with CAVS. The CAVS risk alleles and increasing disease severity are both associated with decreased mRNA expression levels of PALMD in valve tissues. The top variant identiﬁed shows a similar effect and strong association with CAVS (P = 1.53 × 10−10) in UK Biobank. The identiﬁcation of PALMD as a susceptibility gene for CAVS provides insights into the genetic nature of this disease, opens avenues to investigate its etiology and to develop much-needed therapeutic options.
- PublicationAccès librePrédiction précoce du risque de diabète gestationnel : développement de modèles combinant facteurs cliniques et marqueurs biochimiques(2014) Thériault, Sébastien; Giguère, Yves.; Forest, JeanCe projet vise à développer un outil de prédiction précoce du risque de diabète gestationnel (DG). Il est basé sur une étude de cohorte prospective chez 7929 femmes enceintes recrutées entre 2005 et 2010 dans la ville de Québec. La validation externe de quatre modèles prédictifs a permis d’identifier des variables cliniques (ex. : antécédent de DG, indice de masse corporelle, histoire familiale de diabète) particulièrement performantes pour prédire le développement d’un DG nécessitant une insulinothérapie. Un modèle original combinant ces variables cliniques avec trois marqueurs biochimiques (HbA1c, SHBG et hsCRP entre 14 et 17 semaines de grossesse) a permis d’obtenir une aire sous la courbe ROC de 0,90 et une sensibilité de 72% à un taux de faux positifs de 10%. Ce projet a permis d’identifier des facteurs prédictifs du DG identifiables tôt en grossesse afin de permettre une meilleure prise en charge des femmes à haut risque.
- PublicationAccès libreGenetic 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, PaoloThe 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.
- PublicationAccès libreGenetic Variation in LPA, calcific aortic valve stenosis in patients undergoing cardiac surgery, and familial risk of aortic valve microcalcification(JAMA Network, 2019-07-01) Bilodeau, Anthony; Thériault, Sébastien; Dina, Christian; Nadeau, Maxime; Chen, Hao Yu; Arsenault, Benoit; Boekholdt, Stefan Matthijs; Trottier, Mikaël; Rigade, Sidwell; Capoulade, Romain; Després, Audrey-Anne; Guimond, Jean; Bossé, Yohan; Le Tourneau, Thierry; Pibarot, Philippe; Messika-Zeitoun, David; Perrot, Nicolas; Clavel, Marie-Annick; Tessier, Michel; Mathieu, Patrick; Engert, James; Khaw, Kay-Tee; Wareham, Nicholas J.; Dweck, Marc; Schott, Jean-Jacques; Thanassoulis, GeorgeIMPORTANCE: Genetic variants at the LPA locus are associated with both calcific aortic valve stenosis (CAVS) and coronary artery disease (CAD). Whether these variants are associated with CAVS in patients with CAD vs those without CAD is unknown. OBJECTIVE: To study the associations of LPA variants with CAVS in a cohort of patients undergoing heart surgery and LPA with CAVS in patients with CAD vs those without CAD and to determine whether first-degree relatives of patients with CAVS and high lipoprotein(a) (Lp[a]) levels showed evidence of aortic valve microcalcification. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study included patients undergoing cardiac surgery from the Genome-Wide Association Study on Calcific Aortic Valve Stenosis in Quebec (QUEBEC-CAVS) study and patients with CAD, patients without CAD, and control participants from 6 genetic association studies: the UK Biobank, the European Prospective Investigation of Cancer (EPIC)-Norfolk, and Genetic Epidemiology Research on Aging (GERA) studies and 3 French cohorts. In addition, a family study included first-degree relatives of patients with CAVS. Data were collected from January 1993 to September 2018, and analysis was completed from September 2017 to September 2018. EXPOSURES: Case-control studies. MAIN OUTCOMES AND MEASURES: Presence of CAVS according to a weighted genetic risk score based on 3 common Lp(a)-raising variants and aortic valve microcalcification, defined as the mean tissue to background ratio of 1.25 or more, measured by fluorine 18-labeled sodium fluoride positron emission tomography/computed tomography. RESULTS: This study included 1009 individuals undergoing cardiac surgery and 1017 control participants in the QUEBEC-CAVS cohort; 3258 individuals with CAVS and CAD, 41 100 controls with CAD, 2069 individuals with CAVS without CAD, and 380 075 control participants without CAD in the UK Biobank, EPIC-Norfolk, and GERA studies and 3 French cohorts combined; and 33 first-degree relatives of 17 patients with CAVS and high Lp(a) levels (≥60 mg/dL) and 23 control participants with normal Lp(a) levels (<60 mg/dL). In the QUEBEC-CAVS study, each SD increase of the genetic risk score was associated with a higher risk of CAVS (odds ratio [OR], 1.35 [95% CI, 1.10-1.66]; P = .003). Each SD increase of the genetic risk score was associated with a higher risk of CAVS in patients with CAD (OR, 1.30 [95% CI, 1.20-1.42]; P < .001) and without CAD (OR, 1.33 [95% CI, 1.14-1.55]; P < .001). The percentage of individuals with a tissue to background ratio of 1.25 or more or CAVS was higher in first-degree relatives of patients with CAVS and high Lp(a) (16 of 33 [49%]) than control participants (3 of 23 [13%]; P = .006). CONCLUSIONS AND RELEVANCE: In this study, a genetically elevated Lp(a) level was associated with CAVS independently of the presence of CAD. These findings support further research on the potential usefulness of Lp(a) cascade screening in CAVS.
- PublicationRestreintSex-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, BenoitBackground: 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 libreVariability of high-sensitivity troponin T concentrations in emergency settings : impact for the diagnosis of myocardial infarction.(American Society for Clinical Pathology, 2018-04-28) Thériault, Sébastien; Douville, PierreObjectives To assess biological variation of troponin T in emergency settings and establish limits for interpretation of serial results. Methods We studied 6,557 consecutive patients with troponin measurements. A stable reference subset was selected to estimate biological variation and threshold limits. Results The first troponin level was elevated in 32% of patients, and 2,490 had a second troponin level with a myocardial infarction (MI) prevalence of 16.2%. In the stable reference group with at least one abnormal value, the 99th percentile of the absolute delta between the first two samples was 16 ng/L. For MI diagnosis, the area under the receiver operating characteristic curve was 0.85 (confidence interval [CI], 0.83-0.87) for the first troponin level and 0.94 (CI, 0.93-0.95) for the absolute delta. Conclusions An absolute delta of 16 ng/L has good specificity in the emergency setting. This threshold is valid for any sex, age, and sampling interval between 3 and 24 hours and is higher than published limits found in healthy outpatients.