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Guénard, Frédéric

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Université Laval. Institut sur la nutrition et les aliments fonctionnels



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  • PublicationAccès libre
    A GWAS follow-up of obesity-related SNPs in SYPL2 reveals sexspecific association with hip circumference
    (John Wiley & Sons Inc., 2016-09-20) Guénard, Frédéric; Biron, Simon; Toro Martin, Juan de; Biertho, Laurent; Pérusse, Louis; Lescelleur, Odette; Vohl, Marie-Claude; Deshaies, Yves; Marceau, Simon; Tchernof, André
    Objective A novel single-nucleotide polymorphism (SNP) associated with morbid obesity was recently identified by exome sequencing. The purpose of this study was to follow up this low-frequency coding SNP located within the SYPL2 locus and associated with body mass index in order to reveal novel associations with obesity-related traits. Methods The body mass index-associated SNP (rs62623713 A>G [chr1:109476817/hg19]) and two tagging SNPs within the SYPL2 locus, rs9661614 T>C (chr1:109479215) and rs485660 G>A (chr1:109480810), were genotyped in the obesity (n = 3,017) and the infogene (n = 676) cohorts, which were further combined, leading to a larger cohort of 3,693 individuals. Association testing was performed by general linear models in the obesity cohort and validated by joint analysis in the combined cohort. Results rs9661614 and rs485660 were significantly associated with hip circumference (HC) in the obesity cohort, with heterozygotes exhibiting a significantly lower HC. These results were validated by joint analysis for rs9661614 (false discovery rate [FDR]-corrected P = 7.5 × 10−4) and, to a lesser extent, for rs485660 (FDR corrected P = 3.9 × 10−2). The association with HC remained significant for rs9661614 when tested independently in women (FDR-corrected P = 1.7 × 10−2), but not for rs485660 (FDR-corrected P = 0.2). Both associations were absent in men. Conclusions This study reveals strong evidence for a novel association between rs9661614 (T>C) and HC in women, which likely reflects a preferential association of SYPL2 to a gynoid profile of fat distribution. The study findings support a clinical significance of SYPL2 worth considering when assessing risk factors associated with obesity.
  • PublicationAccès libre
    Epigenetic changes in blood leukocytes following an omega-3 fatty acid supplementation
    (BiomedCentral, 2017-04-26) Guénard, Frédéric; Rudkowska, Iwona; Lemieux, Simone; Tremblay, Bénédicte L.; Vohl, Marie-Claude; Couture, Patrick
    Background: Omega-3 polyunsaturated fatty acids (n-3 FAs) have several beneficial effects on cardiovascular (CV) disease risk factors. These effects on CV risk profile may be mediated by several factors, including epigenetic modifications. Our objective is to investigate, using genome-wide DNA methylation analyses, methylation changes following an n-3 FA supplementation in overweight and obese subjects and to identify specific biological pathways potentially altered by the supplementation. Results: Blood leukocytes genome-wide DNA methylation profiles of 36 overweight and obese subjects before and after a 6-week supplementation with 3 g of n-3 FAs were compared using GenomeStudio software. After supplementation, 308 CpG sites, assigned to 231 genes, were differentially methylated (FDR-corrected Diffscore ≥│13│~ P ≤ 0.05). Using Ingenuity Pathway Analysis system, a total of 55 pathways were significantly overrepresented following supplementation. Among these pathways, 16 were related to inflammatory and immune response, lipid metabolism, type 2 diabetes, and cardiovascular signaling. Changes in methylation levels of CpG sites within AKT3, ATF1, HDAC4, and IGFBP5 were correlated with changes in plasma triglyceride and glucose levels as well as with changes in the ratio of total cholesterol/HDL-cholesterol following the supplementation. Conclusions: These data provide key differences in blood leukocytes DNA methylation profiles of subjects following an n-3 FA supplementation, which brings new, potential insights on metabolic pathways underlying the effects of n-3 FAs on CV health.
  • PublicationRestreint
    Polygenic risk score for predicting weight loss after bariatric surgery
    (American Society for Clinical Investigation, 2018-09-06) Guénard, Frédéric; Toro Martin, Juan de; Pérusse, Louis; Marceau, Simon; Vohl, Marie-Claude; Tchernof, André
    BACKGROUND. The extent of weight loss among patients undergoing bariatric surgery is highly variable. Herein, we tested the contribution of genetic background to such interindividual variability after biliopancreatic diversion with duodenal switch. METHODS. Percentage of excess body weight loss (%EBWL) was monitored in 865 patients over a period of 48 months after bariatric surgery, and 2 polygenic risk scores were constructed with 186 and 11 (PRS₁₈₆ and PRS₁₁) single nucleotide polymorphisms previously associated with BMI. RESULTS. The accuracy of the %EBWL logistic prediction model — including initial BMI, age, sex, and surgery modality, and assessed as the area under the receiver operating characteristics (ROC) curve adjusted for optimism ((AUCadj= 0.867) — significantly increased after the inclusion of PRS186 (ΔAUCadj = 0.021; 95% CI of the difference (95% CIdiff) = 0.0046–0.038) but not PRS11 (ΔAUCadj= 0.008; 95% CIdiff= –0.003–0.019). The overall fit of the longitudinal linear mixed model for %EBWL showed a significant increase after addition of PRS₁₈₆ (–2 log-likelihood = 12.3; P = 0.002) and PRS11 (–2 log-likelihood = 9.9; P = 0.007). A significant interaction with postsurgery time was found for PRS₁₈₆ (β = –0.003; P = 0.008) and PRS₁₁ (β = –0.008; P = 0.03). The inclusion of PRS₁₈₆ and PRS₁₁ into the model improved the cost-effectiveness of bariatric surgery by reducing the percentage of false negatives from 20.4% to 10.9% and 10.2%, respectively. CONCLUSION. These results revealed that genetic background has a significant impact on weight loss after biliopancreatic diversion with duodenal switch. Likewise, the improvement in weight loss prediction after addition of polygenic risk scores is cost-effective, suggesting that genetic testing could potentially be used in the presurgical assessment of patients with severe obesity.
  • PublicationAccès libre
    Influences of gestational obesity on associations between genotypes and gene expression levels in offspring following maternal gastrointestinal bypass surgery for obesity.
    (Public Library of Science, 2015-01-20) Guénard, Frédéric; Marceau, Picard; Bossé, Yohan; Lamontagne, Maxime; Cianflone, Katherine M.; Kral, John G.; Vohl, Marie-Claude; Deshaies, Yves
    Maternal obesity and excess gestational weight gain with compromised metabolic fitness predispose offspring to lifelong obesity and its comorbidities. We demonstrated that compared to offspring born before maternal gastrointestinal bypass surgery (BMS) those born after (AMS) were less obese, with less cardiometabolic risk reflected in the expression and methylation of diabetes, immune and inflammatory pathway genes. Here we examine relationships between gestational obesity and offspring gene variations on expression levels. Methods : Whole-genome genotyping and gene expression analyses in blood of 22 BMS and 23 AMS offspring from 19 mothers were conducted using Illumina HumanOmni-5-Quad and HumanHT-12 v4 Expression BeadChips, respectively. Using PLINK we analyzed interactions between offspring gene variations and maternal surgical status on offspring gene expression levels. Altered biological functions and pathways were identified and visualized using DAVID and Ingenuity Pathway Analysis. Results : Significant interactions (p ≤ 1.22x10-12) were found for 525 among the 16,060 expressed transcripts: 1.9% of tested SNPs were involved. Gene function and pathway analysis demonstrated enrichment of transcription and of cellular metabolism functions and overrepresentation of cellular stress and signaling, immune response, inflammation, growth, proliferation and development pathways. Conclusion : We suggest that impaired maternal gestational metabolic fitness interacts with offspring gene variations modulating gene expression levels, providing potential mechanisms explaining improved cardiometabolic risk profiles of AMS offspring related to ameliorated maternal lipid and carbohydrate metabolism.
  • PublicationAccès libre
    Temporal changes in gene expression profile during mature adipocyte dedifferentiation
    (Hindawi Publishing Corporation, 2017-03-19) Guénard, Frédéric; Biron, Simon; Lapointe, Marc-André; Vohl, Marie-Claude; Côté, Julie Anne; Lessard, Julie.; Tchernof, André
    Objective. To characterize changes in gene expression profile during human mature adipocyte dedifferentiation in ceiling culture. Methods. Subcutaneous (SC) and omental (OM) adipose tissue samples were obtained from 4 participants paired for age and BMI. Isolated adipocytes were dedifferentiated in ceiling culture. Gene expression analysis at days 0, 4, 7, and 12 of the cultures was performed using Affymetrix Human Gene 2.0 STvi arrays. Hierarchical clustering according to similarity of expression changes was used to identify overrepresented functions. Results. Four clusters gathered genes with similar expression between day 4 to day 7 but decreasing expression from day 7 to day 12. Most of these genes coded for proteins involved in adipocyte functions (LIPE, PLIN1, DGAT2, PNPLA2, ADIPOQ, CEBPA, LPL, FABP4, SCD, INSR, and LEP). Expression of several genes coding for proteins implicated in cellular proliferation and growth or cell cycle increased significantly from day 7 to day 12 (WNT5A, KITLG, and FGF5). Genes coding for extracellular matrix proteins were differentially expressed between days 0, 4, 7, and 12 (COL1A1, COL1A2, and COL6A3, MMP1, and TGFB1). Conclusion. Dedifferentiation is associated with downregulation of transcripts encoding proteins involved in mature adipocyte functions and upregulation of genes involved in matrix remodeling, cellular development, and cell cycle.
  • PublicationAccès libre
    Network Analysis of the potential role of DNA methylation in the relationship between plasma carotenoids and lipid profile
    (MDPI, 2019-06-04) Guénard, Frédéric; Pérusse, Louis; Lamarche, Benoît; Tremblay, Bénédicte L.; Vohl, Marie-Claude
    Abstract: Variability in plasma carotenoids may be attributable to several factors including genetic variants and lipid profile. Until now, the impact of DNA methylation on this variability has not been widely studied. Weighted gene correlation network analysis (WGCNA) is a systems biology method used for finding gene clusters (modules) with highly correlated methylation levels and for relating them to phenotypic traits. The objective of the present study was to examine the role of DNA methylation in the relationship between plasma total carotenoid concentrations and lipid profile using WGCNA in 48 healthy subjects. Genome-wide DNA methylation levels of 20,687 out of 472,245 CpG sites in blood leukocytes were associated with total carotenoid concentrations. Using WGCNA, nine co-methylation modules were identified. A total of 2734 hub genes (17 unique top hub genes) were potentially related to lipid profile. This study provides evidence for the potential implications of gene co-methylation in the relationship between plasma carotenoids and lipid profile. Further studies and validation of the hub genes are needed.
  • PublicationAccès libre
    Genetic regulation of differentially methylated genes in visceral adipose tissue of severely obese men discordant for the metabolic syndrome
    (Elsevier, 2017-02-01) Guénard, Frédéric; Biron, Simon; Biertho, Laurent; Pérusse, Louis; Lescelleur, Odette; Vohl, Marie-Claude; Marceau, Simon (***WMS); Deshaies, Yves; Tchernof, André
    A genetic influence on methylation levels has been reported and methylation quantitative trait loci (meQTL) have been identified in various tissues. The contribution of genetic and epigenetic factors in the development of the metabolic syndrome (MetS) has also been noted. To pinpoint candidate genes for testing the association of SNPs with MetS and its components, we aimed to evaluate the contribution of genetic variations to differentially methylated CpG sites in severely obese men discordant for MetS. A genome-wide differential methylation analysis was conducted in visceral adipose tissue (VAT) of 31 severely obese men discordant for MetS (16 with and 15 without MetS) and identified ∼17,800 variable CpG sites. The genome-wide association study conducted to identify the SNPs (meQTL) associated with methylation levels at variable CpG sites revealed 2292 significant associations (P < 2.22 × 10−11) involving 2182 unique meQTLs regulating the methylation levels of 174 variable CpG sites. Two meQTLs disrupting CpG sites located within the collagen-encoding COL11A2 gene were tested for associations with MetS and its components in a cohort of 3021 obese individuals. Rare alleles of these meQTLs showed association with plasma fasting glucose levels. Further analysis conducted on these meQTL suggested a biological impact mediated through the disruption of transcription factor (TF)–binding sites based on the prediction of TF-binding affinities. The current study identified meQTL in the VAT of severely obese men and revealed associations of two COL11A2 meQTL with fasting glucose levels.
  • PublicationAccès libre
    The challenge of stratifying obesity : attempts in the Quebec family study
    (Frontiers Research Foundation, 2019-10-10) Guénard, Frédéric; Bouchard, Claude; Toro Martin, Juan de; Pérusse, Louis; Tremblay, Angelo; Vohl, Marie-Claude
    Background and aims: Obesity is a major health problem worldwide. Given the heterogeneous obesity phenotype, an optimal obesity stratification would improve clinical management. Since obesity has a strong genetic component, we aimed to develop a polygenic risk score (PRS) to stratify obesity according to the genetic background of the individuals. Methods: A total of 231 single nucleotide polymorphisms (SNP) significantly associated to body mass index (BMI) from 21 genome-wide association studies were genotyped or imputed in 881 subjects from the Quebec Family Study (QFS). The population was randomly split into discovery (80%; n = 704) and validation (20%; n = 177) samples with similar obesity (BMI ≥ 30) prevalence (27.8% and 28.2%, respectively). Family-based associations with obesity were tested for every SNP in the discovery sample and a weighed and continuous PRS231 was constructed. Generalized linear mixed effects models were used to test the association of PRS231 with obesity in the QFS discovery sample and validated in the QFS replication sample. Furthermore, the Fatty Acid Sensor (FAS) Study (n = 141; 27.7% obesity prevalence) was used as an independent sample to replicate the results. Results: The linear trend test demonstrated a significant association of PRS231 with obesity in the QFS discovery sample (ORtrend = 1.19 [95% CI, 1.14-1.24]; P = 2.0x10-16). We also found that the obesity prevalence was significantly greater in the higher PRS231 quintiles compared to the lowest quintile. Significant and consistent results were obtained in the QFS validation sample for both the linear trend test (ORtrend = 1.16 [95% CI, 1.07-1.26]; P = 6.7x10-4), and obesity prevalence across quintiles. These results were partially replicated in the FAS sample (ORtrend = 1.12 [95% CI, 1.02-1.24]; P = 2.2x10-2). PRS231 explained 7.5%, 3.2%, and 1.2% of BMI variance in QFS discovery, QFS validation, and FAS samples, respectively. Conclusions: These results revealed that genetic background in the form of a 231 BMI-associated PRS has a significant impact on obesity, but a limited potential to accurately stratify it. Further studies are encouraged on larger populations.
  • PublicationAccès libre
    Genome-wide association study of dietary pattern scores
    (MDPI, 2017-06-23) Guénard, Frédéric; Bouchard-Mercier, Annie; Rudkowska, Iwona; Lemieux, Simone; Vohl, Marie-Claude; Couture, Patrick
    Dietary patterns, representing global food supplies rather than specific nutrients or food intakes, have been associated with cardiovascular disease (CVD) incidence and mortality. The contribution of genetic factors in the determination of food intakes, preferences and dietary patterns has been previously established. The current study aimed to identify novel genetic factors associated with reported dietary pattern scores. Reported dietary patterns scores were derived from reported dietary intakes for the preceding month and were obtained through a food frequency questionnaire and genome-wide association study (GWAS) conducted in a study sample of 141 individuals. Reported Prudent and Western dietary patterns demonstrated nominal associations (p < 1 × 10−5) with 78 and 27 single nucleotide polymorphisms (SNPs), respectively. Among these, SNPs annotated to genes previously associated with neurological disorders, CVD risk factors and obesity were identified. Further assessment of SNPs demonstrated an impact on gene expression levels in blood for SNPs located within/near BCKDHB (p = 0.02) and the hypothalamic glucosensor PFKFB3 (p = 0.0004) genes, potentially mediated through an impact on the binding of transcription factors (TFs). Overrepresentations of glucose/energy homeostasis and hormone response TFs were also observed from SNP-surrounding sequences. Results from the current GWAS study suggest an interplay of genes involved in the metabolic response to dietary patterns on obesity, glucose metabolism and food-induced response in the brain in the adoption of dietary patterns.
  • PublicationAccès libre
    Prevention of potential adverse metabolic effects of a supplementation with omega-3 fatty acids using a genetic score approach
    (Karger, 2019-11-29) Franck, Maximilien; Guénard, Frédéric; Toro Martin, Juan de; Rudkowska, Iwona; Lamarche, Benoît; Lemieux, Simone; Vohl, Marie-Claude; Couture, Patrick
    Introduction: The consumption of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) has been reported to have beneficial health effects, notably, by reducing plasma triglyceride levels. Nonetheless, a concomitant decrease in insulin sensitivity has also been observed, but is highly variable among subjects. Herein, we aimed to determine the importance of the genetic background in the interindividual variability of the insulin sensitivity response following an n-3 PUFA supplementation. Methods: A total of 210 participants completed a 6-week n-3 PUFA supplementation with 5 g/day of fish oil (providing 1.9–2.2 g of eicosapentaenoic acid + 1.1 g of docosahexaenoic acid). Insulin resistance was estimated by the homeostatic model assessment (HOMA-IR), and participants were further classified as high-risk or low-risk depending on their HOMA-IR change following the n-3 PUFA supplementation, as compared to pre-supplementation values. Genome-wide genotyping data were obtained for 138 participants using HumanOmni-5-Quad BeadChips containing 4,301,331 single nucleotide polymorphisms. A genome-wide association analysis (GWAS) was carried out between high-risk and low-risk participants. The population study was split into training (60%) and testing (40%) datasets to assess the predictive accuracy of a genetic risk score (GRS) constructed by summing the number of risk alleles. Results: Following the n-3 PUFA supplementation, 32 participants had increased HOMA-IR as compared to initial values and were classified as high risk (23.2%), whereas remaining subjects were classified as low risk (n = 106, 76.8%). A total of 8 loci had frequency differences between high-risk and low-risk participants at a suggestive GWAS association threshold (p value <1 × 10–5). After applying 10-fold cross validation, the GRS showed a significant association with the risk of increased HOMA-IR in the testing dataset (OR = 3.16 [95% CI, 1.85–7.14]), with a predictive accuracy of 0.85, and explained 40% of variation in HOMA-IR change. Conclusions: These results suggest that the genetic background has a relevant role in the interindividual variability observed in the insulin sensitivity response following an n-3 PUFA supplementation. Subjects being at risk of insulin sensitivity lowering following an n-3 PUFA supplementation may be identified using genetic-based precision nutrition approaches