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Article ; Online: A dataset of proteomic changes during human heat stress and heat acclimation

Daniel Gagnon / Hadiatou Barry / Amina Barhdadi / Essaid Oussaid / Ian Mongrain / Louis-Philippe Lemieux Perreault / Marie-Pierre Dubé

Scientific Data, Vol 10, Iss 1, Pp 1-

2023 Volume 6

Abstract: Abstract Hotter climates have important impacts on human health and performance. Yet, the cellular and molecular responses involved in human heat stress and acclimation remain understudied. This dataset includes physiological measurements and the plasma ... ...

Abstract	Abstract Hotter climates have important impacts on human health and performance. Yet, the cellular and molecular responses involved in human heat stress and acclimation remain understudied. This dataset includes physiological measurements and the plasma concentration of 2,938 proteins collected from 10 healthy adults, before and during passive heat stress that was performed both prior to and after a 7-day heat acclimation protocol. Physiological measurements included body temperatures, sweat rate, cutaneous vascular conductance, blood pressure, and skin sympathetic nerve activity. The proteomic dataset was generated using the Olink Explore 3072 assay, enabling a high-multiplex antibody-based assessment of protein changes based on proximity extension assay technology. The data need to be interpreted in the context of the moderate level of body hyperthermia attained and the specific demographic of young, healthy adults. We have made this dataset publicly available to facilitate research into the cellular and molecular mechanisms involved in human heat stress and acclimation, crucial for addressing the health and performance challenges posed by rising temperatures.
Keywords	Science ; Q
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The associations of hostility and defensiveness with telomere length are influenced by sex and health status

Louisia Starnino / Gilles Dupuis / Lambert Busque / Vincent Bourgoin / Marie-Pierre Dubé / David Busseuil / Bianca D’Antono

Biology of Sex Differences, Vol 12, Iss 1, Pp 1-

2021 Volume 13

Abstract: Abstract Background Shorter telomere length (TL) may indicate premature cellular aging and increased risk for disease. While there is substantial evidence for shorter TL in individuals suffering from psychiatric disorders, data is scarce on maladaptive ... ...

Abstract	Abstract Background Shorter telomere length (TL) may indicate premature cellular aging and increased risk for disease. While there is substantial evidence for shorter TL in individuals suffering from psychiatric disorders, data is scarce on maladaptive personality traits related to coronary artery disease (CAD). The purpose of this study was to evaluate the association of TL with hostility and defensiveness in individuals with CAD or other non-cardiovascular illnesses and whether associations were moderated by CAD status and sex. Methods One thousand thirty-six individuals (M age = 65.40 ± 6.73 years) with and without CAD completed the Marlowe-Crowne Social Desirability Scale and the Cook–Medley Hostility Scale. Relative TL was measured via quantitative polymerase chain reaction of total genomic DNA samples. Analyses involved hierarchical regressions on TL, performed separately for hostility and defensiveness, controlling for pertinent sociodemographic, behavioural, and medical risk factors. Separate analyses were performed on 25 healthy participants. Results A hostility by sex interaction emerged (β = − .08, p = .006) in the patient groups, where greater hostility was associated with shorter TL in women only (p < .01). A Defensiveness by CAD status interaction (β = − .06, p = .049) revealed longer TL in more defensive CAD patients only (p = .06). In healthy men, shorter TL was observed in those with greater defensiveness (β = .52, p = .006) but lower hostility (β = − .43, p = .049). Conclusion Hostility and defensiveness are differentially associated with TL as a function of sex and health status. The implication of these results for health remains to be determined, but propose an additional pathway through which the effect of maladaptive personality traits may contribute to CV and other disease.
Keywords	Telomere length ; Hostility ; Defensiveness ; Cardiovascular disease ; Sex and age ; Medicine ; R ; Physiology ; QP1-981
Subject code	150
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Females present higher dose‐adjusted drug concentrations of metoprolol and allopurinol/oxypurinol than males

Jessica Hindi / Marc‐Olivier Pilon / Maxime Meloche / Grégoire Leclair / Essaïd Oussaïd / Isabelle St‐Jean / Martin Jutras / Marie‐Josée Gaulin / Ian Mongrain / David Busseuil / Jean Lucien Rouleau / Jean‐Claude Tardif / Marie‐Pierre Dubé / Simon deDenus

Clinical and Translational Science, Vol 16, Iss 5, Pp 872-

2023 Volume 885

Abstract: Abstract Females present a higher risk of adverse drug reactions. Sex‐related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation of females in clinical trials. The aim of ... ...

Abstract	Abstract Females present a higher risk of adverse drug reactions. Sex‐related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation of females in clinical trials. The aim of this study was to investigate whether anthropometric and socioeconomic factors and comorbidities could explain sex‐related differences in concentrations and dosing for metoprolol and oxypurinol, the active metabolite of allopurinol. We conducted an analysis of two cross‐sectional studies. Participants were self‐described “White” adults taking metoprolol or allopurinol selected from the Montreal Heart Institute Hospital Cohort. A total of 1007 participants were included in the metoprolol subpopulation and 459 participants in the allopurinol subpopulation; 73% and 86% of the participants from the metoprolol and allopurinol subpopulations were males, respectively. Females presented higher age‐ and dose‐adjusted concentrations of both metoprolol and oxypurinol (both p < 0.03). Accordingly, females presented higher unadjusted and age‐adjusted concentration:dose ratio of both metoprolol and allopurinol/oxypurinol compared to males (all p < 3.0 × 10−4). Sex remained an independent predictor of metoprolol concentrations (p < 0.01), but not of oxypurinol concentrations, after adjusting for other predictors. In addition to sex, age, daily dose, use of moderate to strong CYP2D6 inhibitors, weight, and CYP2D6 genotype‐inferred phenotype were associated with concentrations of metoprolol (all p < 0.01). Daily dose, weight, estimated glomerular filtration rate (eGFR), and employment status were associated with oxypurinol concentrations (all p < 0.01). Females present higher dose‐adjusted concentrations of metoprolol and oxypurinol than males. This suggests the need for sex‐specific dosing requirements for these drugs, although this hypothesis should be validated in prospective studies.
Keywords	Therapeutics. Pharmacology ; RM1-950 ; Public aspects of medicine ; RA1-1270
Subject code	590
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Construction of a femininity score in the UK Biobank and its association with angina diagnosis prior to myocardial infarction

Anna Levinsson / Simon de Denus / Johanna Sandoval / Louis-Philippe Lemieux Perreault / Joëlle Rouleau / Jean-Claude Tardif / Julie Hussin / Marie-Pierre Dubé

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 9

Abstract: Abstract Gender captures social components beyond biological sex and can add valuable insight to health studies in populations. However, assessment of gender typically relies on questionnaires which may not be available. The aim of this study is to ... ...

Abstract	Abstract Gender captures social components beyond biological sex and can add valuable insight to health studies in populations. However, assessment of gender typically relies on questionnaires which may not be available. The aim of this study is to construct a gender metric using available variables in the UK Biobank and to apply it to the study of angina diagnosis. Proxy variables for femininity characteristics were identified in the UK Biobank and regressed on sex to construct a composite femininity score (FS) validated using tenfold cross-validation. The FS was assessed as a predictor of angina diagnosis before incident myocardial infarction (MI) events. The FS was derived for 315,937 UK Biobank participants. In 3059 individuals with no history of MI at study entry who had an incident MI event, the FS was a significant predictor of angina diagnosis prior to MI (OR 1.24, 95% CI 1.10–1.39, P < 0.001) with a significant sex-by-FS interaction effect (P = 0.003). The FS was positively associated with angina diagnosis prior to MI in men (OR 1.37, 95% CI 1.19–1.57, P < 0.001), but not in women. We have provided a new tool to conduct gender-sensitive analyses in observational studies, and applied it to study of angina diagnosis prior to MI.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Leveraging large observational studies to discover genetic determinants of drug concentrations

Maxime Meloche / Grégoire Leclair / Martin Jutras / Essaïd Oussaïd / Marie‐Josée Gaulin / Ian Mongrain / David Busseuil / Jean‐Claude Tardif / Marie‐Pierre Dubé / Simon deDenus

Clinical and Translational Science, Vol 15, Iss 4, Pp 1063-

A proof‐of‐concept study

2022 Volume 1073

Abstract: Abstract Large, observational genetic studies are commonly used to identify genetic factors associated with diseases and disease‐related traits. Such cohorts have not been commonly used to identify genetic predictors of drug dosing or concentrations, ... ...

Abstract	Abstract Large, observational genetic studies are commonly used to identify genetic factors associated with diseases and disease‐related traits. Such cohorts have not been commonly used to identify genetic predictors of drug dosing or concentrations, perhaps because of the heterogeneity in drug dosing and formulation, and the random timing of blood sampling. We hypothesized that large sample sizes relative to traditional pharmacokinetic studies would compensate for this variability and enable the identification of pharmacogenetic predictors of drug concentrations. We performed a cross‐sectional, proof‐of‐concept association study to replicate the well‐established association between metoprolol concentrations and CYP2D6 genotype‐inferred metabolizer phenotypes in participants from the Montreal Heart Institute Hospital Cohort undergoing metoprolol therapy. Plasma concentrations of metoprolol and α‐hydroxymetoprolol (α‐OH‐metoprolol) were measured in samples collected randomly regarding the previous metoprolol dose. A total of 999 individuals were included. The metoprolol daily dose ranged from 6.25 to 400 mg (mean 84.3 ± 57.1 mg). CYP2D6‐inferred phenotype was significantly associated with both metoprolol and α‐OH‐metoprolol in unadjusted and adjusted models (all p < 10−14). Models for metoprolol daily dose showed consistent results. Our study suggests that randomly drawn blood samples from biobanks can serve as a new approach to discover genetic associations related to drug concentrations and dosing, with potentially broader implications for genomewide association studies on the pharmacogenomics of drug metabolism.
Keywords	Therapeutics. Pharmacology ; RM1-950 ; Public aspects of medicine ; RA1-1270
Subject code	610
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: An association study of ABCG2 rs2231142 on the concentrations of allopurinol and its metabolites

Marc‐Olivier Pilon / Grégoire Leclair / Essaïd Oussaïd / Isabelle St‐Jean / Martin Jutras / Marie‐Josée Gaulin / Ian Mongrain / David Busseuil / Jean Lucien Rouleau / Jean‐Claude Tardif / Marie‐Pierre Dubé / Simon deDenus

Clinical and Translational Science, Vol 15, Iss 8, Pp 2024-

2022 Volume 2034

Abstract: Abstract ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid‐ ... ...

Abstract	Abstract ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid‐lowering agent used to treat this condition. It has also been suggested that oxypurinol, the primary active metabolite of allopurinol, is a substrate of the BCRP. We thus hypothesized that carrying the rs2231142 variant would be associated with decreased oxypurinol concentrations, which would explain the lower reduction in uric acid. We performed a cross‐sectional study to investigate the association between the ABCG2 rs2231142 variant and oxypurinol, allopurinol, and allopurinol riboside concentrations in 459 participants from the Montreal Heart Institute Hospital Cohort. Age, sex, weight, use of diuretics, and estimated glomerular filtration rate were all significantly associated with oxypurinol plasma concentration. No association was found between rs2231142 and oxypurinol, allopurinol and allopurinol riboside plasma concentrations. Rs2231142 was not significantly associated with daily allopurinol dose in the overall population, but an association was observed in men, with T carriers receiving higher doses. Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites. The underlying mechanism of the association between rs2231142 and allopurinol efficacy requires further investigation.
Keywords	Therapeutics. Pharmacology ; RM1-950 ; Public aspects of medicine ; RA1-1270
Subject code	610
Language	English
Publishing date	2022-08-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Population Pharmacokinetics of Candesartan in Patients with Chronic Heart Failure

Imad Kassem / Steven Sanche / Jun Li / Guillaume Bonnefois / Marie‐Pierre Dubé / Jean‐Lucien Rouleau / Jean‐Claude Tardif / Michel White / Jacques Turgeon / Fahima Nekka / Simon deDenus

Clinical and Translational Science, Vol 14, Iss 1, Pp 194-

2021 Volume 203

Abstract: Heart failure (HF) causes pathological changes in multiple organs, thus affecting the pharmacokinetics (PK) of drugs. The aim of this study was to investigate the PK of candesartan in patients with HF while examining significant covariates and their ... ...

Abstract	Heart failure (HF) causes pathological changes in multiple organs, thus affecting the pharmacokinetics (PK) of drugs. The aim of this study was to investigate the PK of candesartan in patients with HF while examining significant covariates and their related impact on estimated clearance using a population PK (Pop‐PK) modeling approach. Data from a prospective, multicenter study were used. Modeling and simulations were conducted using Nonlinear Mixed‐Effects Modeling (NONMEM) and R software. A total of 281 white patients were included to develop the Pop‐PK model. The final model developed for apparent oral clearance (CL/F) included weight, estimated glomerular filtration rate (eGFR), and diabetes, which partly explained its interindividual variability. The mean CL/F value estimated was 7.6 L/h (1.7–22.6 L/h). Simulations revealed that an important decrease in CL/F (> 25%) is obtained with the combination of the factors retained in the final model. Considering these factors, a more individualized approach of candesartan dosing should be investigated in patients with HF.
Keywords	Therapeutics. Pharmacology ; RM1-950 ; Public aspects of medicine ; RA1-1270
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A genetic model of ivabradine recapitulates results from randomized clinical trials.

Marc-André Legault / Johanna Sandoval / Sylvie Provost / Amina Barhdadi / Louis-Philippe Lemieux Perreault / Sonia Shah / R Thomas Lumbers / Simon de Denus / Benoit Tyl / Jean-Claude Tardif / Marie-Pierre Dubé

PLoS ONE, Vol 15, Iss 7, p e

2020 Volume 0236193

Abstract: Background Naturally occurring human genetic variants provide a valuable tool to identify drug targets and guide drug prioritization and clinical trial design. Ivabradine is a heart rate lowering drug with protective effects on heart failure despite ... ...

Abstract	Background Naturally occurring human genetic variants provide a valuable tool to identify drug targets and guide drug prioritization and clinical trial design. Ivabradine is a heart rate lowering drug with protective effects on heart failure despite increasing the risk of atrial fibrillation. In patients with coronary artery disease without heart failure, the drug does not protect against major cardiovascular adverse events prompting questions about the ability of genetics to have predicted those effects. This study evaluates the effect of a variant in HCN4, ivabradine's drug target, on safety and efficacy endpoints. Methods We used genetic association testing and Mendelian randomization to predict the effect of ivabradine and heart rate lowering on cardiovascular outcomes. Results Using data from the UK Biobank and large GWAS consortia, we evaluated the effect of a heart rate-reducing genetic variant at the HCN4 locus encoding ivabradine's drug target. These genetic association analyses showed increases in risk for atrial fibrillation (OR 1.09, 95% CI: 1.06-1.13, P = 9.3 ×10-9) in the UK Biobank. In a cause-specific competing risk model to account for the increased risk of atrial fibrillation, the HCN4 variant reduced incident heart failure in participants that did not develop atrial fibrillation (HR 0.90, 95% CI: 0.83-0.98, P = 0.013). In contrast, the same heart rate reducing HCN4 variant did not prevent a composite endpoint of myocardial infarction or cardiovascular death (OR 0.99, 95% CI: 0.93-1.04, P = 0.61). Conclusion Genetic modelling of ivabradine recapitulates its benefits in heart failure, promotion of atrial fibrillation, and neutral effect on myocardial infarction.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A sex-specific evolutionary interaction between ADCY9 and CETP

Isabel Gamache / Marc-André Legault / Jean-Christophe Grenier / Rocio Sanchez / Eric Rhéaume / Samira Asgari / Amina Barhdadi / Yassamin Feroz Zada / Holly Trochet / Yang Luo / Leonid Lecca / Megan Murray / Soumya Raychaudhuri / Jean-Claude Tardif / Marie-Pierre Dubé / Julie Hussin

eLife, Vol

2021 Volume 10

Abstract: Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction ...

Abstract	Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of positive selection in several human populations. Furthermore, we identified a variant in CETP, rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population. The signal is mainly seen in males, a sex-specific result that is replicated in the LIMAA cohort of over 3400 Peruvians. Analyses of RNA-seq data further suggest an epistatic interaction on CETP expression levels between the two SNPs in multiple tissues, which also differs between males and females. We also detected interaction effects of the two SNPs with sex on cardiovascular phenotypes in the UK Biobank, in line with the sex-specific genotype associations found in Peruvians at these loci. We propose that ADCY9 and CETP coevolved during recent human evolution due to sex-specific selection, which points toward a biological link between dalcetrapib’s pharmacogene ADCY9 and its therapeutic target CETP.
Keywords	population genetics ; pharmacogenomics ; transcriptomics ; phenotype associations ; cardiovascular disease ; linkage disequilibrium ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	590
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Avoidance of Vitamin K−Rich Foods Is Common among Warfarin Users and Translates into Lower Usual Vitamin K Intakes

Leblanc, Cristina / Étienne Rouleau-Mailloux / Guylaine Ferland / Marie-Pierre Dubé / Mimosa Nguyen / Nancy Presse / Stéphanie Dumas / Sylvie Perreault

Academy of Nutrition and Dietetics Journal of the Academy of Nutrition and Dietetics. 2016 June, v. 116, no. 6

2016

Abstract: Warfarin users should aim for stable daily vitamin K intakes. However, some studies report that patients are often advised to avoid eating green vegetables. Whether this advice impacts vitamin K intakes is unknown.Our aim was to describe the nature and ... ...

Abstract	Warfarin users should aim for stable daily vitamin K intakes. However, some studies report that patients are often advised to avoid eating green vegetables. Whether this advice impacts vitamin K intakes is unknown.Our aim was to describe the nature and sources of vitamin K−related dietary recommendations that patients received at the initiation of warfarin therapy, assess their adherence to these recommendations, and examine whether usual vitamin K intakes vary according to these recommendations.We conducted a retrospective cohort study with patients enrolled in the Québec Warfarin Cohort Study. Patients were asked to report dietary recommendations they had received at warfarin initiation and their adherence to these recommendations. Usual vitamin K intakes were assessed using a validated semi-quantitative food frequency questionnaire.Three hundred seventeen patients aged 36 to 97 years who initiated warfarin between 2011 and 2012 and were treated for 12 months or longer with a target international normalized ratio range of 2.0 to 3.0 or 2.5 to 3.5.Patients were classified according to vitamin K−related recommendations reported: limit or avoid vitamin K−rich foods; aim for stable consumption of vitamin K−rich foods; or no vitamin K−related advice. A one-way analysis of covariance was used to compare mean usual vitamin K intakes between patients after adjustment for covariates.Most patients (68%) reported being advised to limit or avoid vitamin K−rich foods, particularly green vegetables, 10% reported being advised to aim for stable consumption of vitamin K−rich foods, and 22% did not recall receiving any vitamin K−related recommendation. Mean usual vitamin K intakes of patients adhering to the recommendation to limit or avoid vitamin K−rich foods was 35% to 46% lower than those of other patients (P<0.001), a difference resulting almost entirely (82%) from a lower consumption of green vegetables.In contrast with current dietary recommendation, most warfarin users reported avoiding vitamin K−rich foods, which translated into lower usual vitamin K intakes.
Keywords	cohort studies ; covariance ; dietary recommendations ; foods ; patients ; therapeutics ; vegetables ; vitamin K ; warfarin ; Quebec
Language	English
Dates of publication	2016-06
Size	p. 1000-1007.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	2646718-5
ISSN	2212-2672
ISSN	2212-2672
DOI	10.1016/j.jand.2015.12.023
Database	NAL-Catalogue (AGRICOLA)

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