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Personne :
Ruchat, Stéphanie-May

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Ruchat

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Stéphanie-May

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CHU de Québec-Université Laval. Centre de recherche

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ncf11853290

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Associations between glucose tolerance, insulin sensitivity and insulin secretion phenotypes and polymorphisms in adiponectin and adiponectin receptor genes in the Quebec Family Study

2008-02-19, Ruchat, Stéphanie-May, Loos, Ruth, Bouchard, Claude, Rankinen, Tuomo, Pérusse, Louis, Weisnagel, John, Vohl, Marie-Claude, Després, Jean-Pierre

Aims:  Studies suggest that adiponectin (APM1) and its receptors 1 and 2 (AdipoR1 and AdipoR2) play an important role in the development of insulin resistance (IR). Our objective was to examine associations between APM1 (+45T>G, +276G>T and –3971A>G), AdipoR1 (−100G>T and −3882T>C) and AdipoR2 (−35361A>G and –1352G>A) genes single‐nucleotide polymorphisms (SNPs) and adiponectin plasma levels, indicators of glucose tolerance, insulin sensitivity (IS) and insulin secretion. Methods:  Six hundred and twenty‐two non‐diabetic subjects from the Quebec Family Study (QFS) underwent a 75‐g oral glucose tolerance test (OGTT), with measurement of fasting adiponectin, glucose, insulin and C‐peptide levels. Indices of glucose tolerance, IS and insulin secretion were derived from fasting and OGTT measurements. Results:  Significant evidence of association was found between indices of IS and APM1 and AdipoR1 SNPs. The APM1 –3971G/G homozygotes exhibited a reduced area under the curve of insulin during the OGTT (P = 0.007) and higher Cederholm index (P = 0.01) compared to the A/A homozygotes. The APM1 +45T>G variant was also associated with fasting (P = 0.002) and 2‐h (P = 0.007) glucose values as well as with higher Cederholm index (P = 0.04) and disposition index (P = 0.02). Finally, the AdipoR1 −3882T>C SNP was associated with fasting glucose (P = 0.03), the homeostasis model assessment for insulin resistance (P = 0.04) and an index of insulin secretion (P30/G30, P = 0.02). No evidence of association was found with plasma adiponectin levels. Conclusions:  These results provide evidence for an influence of common SNPs in the APM1 and AdipoR1 genes on different phenotypes of glucose and insulin metabolism associated with increased risk of type 2 diabetes.

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Association between insulin secretion, insulin sensitivity and type 2 diabetes susceptibility variants identified in genome-wide association studies

2008-12-10, Ruchat, Stéphanie-May, Elks, Cathy E., Bouchard, Claude, Loos, Ruth, Pérusse, Louis, Weisnagel, John, Vohl, Marie-Claude, Rankinen, Tuomo

Several single nucleotide polymorphisms (SNPs) for type 2 diabetes mellitus (T2DM) risk have been identified by genome wide association studies (GWAS). The objective of the present study was to investigate the impact of these SNPs on T2DM intermediate phenotypes in order to clarify the physiological mechanisms through which they exert their effects on disease etiology. We analysed 23 SNPs in 9 T2DM genes (CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8, TCF2, TCF7L2 and WFS1) in a maximum of 712 men and women from the Quebec Family Study. The participants underwent a 75 g oral glucose tolerance test (OGTT) and were measured for glucose, insulin and C-peptide levels. Indices of insulin sensitivity and insulin secretion were derived from fasting and OGTT measurements. We confirmed the significant associations of variants in CDKAL1, CDKN2B, HHEX/IDE, KCNJ11 and TCF7L2 with insulin secretion and also found associations of some of these variants with insulin sensitivity and glucose tolerance. IGF2BP2 and SLC30A8 SNPs were not associated with insulin secretion but were with insulin sensitivity and glucose tolerance (0.002 B P B 0.02). To examine the joint effects of these variants and their contribution to T2DM endophenotypes variance, stepwise regression models were used and the model R2 was computed. The variance in the phenotypes explained by combinations of variants ranged from 2.0 to 8.5%. Diabetes-associated variants in CDKAL1, CDKN2B, HHEX/IDE, IGF2BP2, KCNJ11, SLC30A8 and TCF7L2 are associated with physiological alterations leading to T2DM, such as glucose intolerance, impaired insulin secretion or insulin resistance, supporting their role in the disease aetiology. These variants were found to account for 2.0–8.5% of the variance of T2DM-related traits.

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Association between micro-opioid receptor-1 102T>C polymorphism and intermediate type 2 diabetes phenotypes : results from the Quebec Family Study (QFS)

2008-08-01, Ruchat, Stéphanie-May, Girard, Martine, Bouchard, Claude, Pérusse, Louis, Weisnagel, John, Vohl, Marie-Claude

It has been suggested recently that molecules expressed both in the pancreas and hypothalamus, such as mu-opioid receptor 1 (OPRM1), could form an integrated brain-liver system, which may sense glucose levels and therefore contribute to the development of type 2 diabetes mellitus (T2DM). In the present study, we tested associations between OPRM1 gene polymorphisms (rs1799971, 102T/C and rs0648007G/A) and indices of glucose tolerance, insulin sensitivity (IS) and insulin secretion derived from plasma measures obtained in a fasting state and following a 75 g oral glucose tolerance test (OGTT) in 749 subjects from the Quebec Family Study (QFS). Polymorphisms were tested for association with glucose tolerance (normal vs IFG and T2DM combined) by calculating a chi(2) statistic and corresponding P values, whereas associations with quantitative measures of glucose tolerance, IS and insulin secretion were tested using mixed linear models implemented in the MIXED procedure of sas (SAS Institute, Cary, NC, USA). Associations were found between 102T/C OPRM1 and indices of glucose tolerance and IS. Compared with T/T homozygotes, carriers of the OPRM1 C-102 variant exhibited a better glucose tolerance with a lower (P = 0.006) glucose area under the curve (AUC) following the OGTT and a better IS with a higher (P = 0.03) value of the Cederholm index, a numerical index of the curve relating glucose uptake to the log(10) plasma insulin levels during the OGTT. The results of the present study reveal that the 102T/C OPRM1 gene polymorphism is associated with a better glucose tolerance and improved IS, both of which suggest a potential protective effect of this variant on T2DM risk.

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Étude des déterminants génétiques et des interactions gène-gène et gène-environnement associés à l'homéostasie glucidique

2009, Ruchat, Stéphanie-May, Pérusse, Louis, Weisnagel, John

Le diabète de type 2 constitue aujourd'hui un problème majeur de santé publique à l'échelle mondiale. Une meilleure compréhension de l'étiologie de la maladie, en étudiant notamment les facteurs de susceptibilité génétiques ainsi que les interactions gène-gène et gène-environnement, est nécessaire pour développer des stratégies préventives et thérapeutiques efficaces. Dans cette thèse, différentes approches ont été utilisées afin de mieux caractériser l'implication des facteurs génétiques dans l'homéostasie glucidique. Un criblage génomique a été effectué sur les niveaux circulants d'adiponectine, d'interleukine 6 (IL6), du facteur de tumeur nécrosant-α (tumor necrosis factor α ou TNFα) et de la protéine C réactive (CRP). Plusieurs régions chromosomiques ont été identifiées incluant 15q21.1, 3q13.33, 20q13.2 et 14q32.2 pour l'adiponectine, 12p11.23 et 12q15 pour CRP et 14q12 pour IL6. Par ailleurs, plusieurs gènes candidats du diabète de type 2 ont été étudiés pour vérifier leur association avec des phénotypes liés à l'homéostasie glucidique. Un variant fonctionnel (Asn40Asp) au sein du gène codant pour le récepteur mu 1 aux opioïdes (OPRM1) a été associé avec la sensibilité à l'insuline et la tolérance au glucose. Aussi, les gènes de susceptibilité au diabète, identifiés et confirmés par l'approche du gène candidat ou par les études à grande échelle du génome humain (genome-wide association studies, GWAS), soit CDKAL1 (CDK5 regulatory subunit associated protein I-like 1), CDKN2A/2B (cyclin-dependent kinase inhibitor 2A/2B), HHEX/IDE (haematopoietically expressed homeobox/insulin-degrading enzyme), HNF1B (hepatocyte nuclear factor 1 β), IGF2BP2 (insulin-like growth factor 2 mRNA-binding protein 2), KCNJ11 (potassium inward rectifier channel Kir6.2), SLC30A8 (solute carrier family 30, member 8), TCF7L2 (transcription factor 7 like 2) et WFS1 (wolframin 1) ont été associés à la sensibilité à l'insuline, à la sécrétion d'insuline et/ou à la tolérance au glucose. Aussi, des effets significatifs d'interaction entre certains de ces gènes (CDKN2A/2B, IGF2BP2, KCNJ11 et TCF7L2) et l'apport en matière grasse ont été observés pour des paramètres liés à l'adiposité et à l'homéostasie glucidique. Nous avons également voulu tester si des gènes de susceptibilité au diabète (CDKAL1, CDKN2A/2B, HHEX/IDE, IGF2BP2, KCNJ11, PPARG et TCF7L2) pouvaient influencer les changements du profil glucidique suite à un programme d'entraînement. Notre étude a démontré que le variant Pro12Ala de PPARG (peroxisome proliferator activated receptor-y) modulait la réponse à un programme d'entraînement en endurance d'une durée de 20 semaines, les porteurs de l'allèle Ala ayant davantage amélioré leur profil glucidique que les porteurs du génotype Pro/Pro. Aucune association n'a été observée avec les autres gènes. En plus d'interagir avec l'exercice, le variant Pro12Ala de PPARG interagit aussi avec le variant Gly482Ser de PPARGC1A (co-activateur de PPARG). Les porteurs de la combinaison génotypique Gly/+-Ala/+ présentaient une résistance à l'insuline plus importante que les porteurs de la combinaison génotypique Ser/Ser-Ala/+, alors que l'effet du variant Gly482Ser de PPARGC1A n'était pas différent parmi les Pro/Pro de PPARG. Un autre gène candidats du diabète, le gène HNF4A, a été étudié en association avec l'homéostasie glucidique, de manière indépendante et en interaction avec l'activité physique. Les individus ayant rapporté un niveau d'activité physique élevé durant l'année écoulée (> 2 heures/semaine) présentaient une meilleure tolérance au glucose s'ils étaient homozygotes A/A pour le variant rsl 885088 et une sécrétion d'insuline plus faible s'ils étaient homozygotes T/T pour le variant rs745975. Finalement, la création d'un modèle de prédiction de la détérioration glycémique, incluant des marqueurs génétiques et des facteurs de risque traditionnels du diabète, a permis de démontrer que la combinaison de facteurs génétiques et non génétiques a le potentiel d'améliorer la prédiction du risque de pré-diabète et de diabète. Les résultats de ces travaux de recherche suggèrent que des gènes candidats du diabète de type 2 peuvent influencer l'étiologie de la maladie via différents mécanismes physiologiques et qu'ils peuvent interagir entre eux ou avec des facteurs environnementaux pour moduler le profil de risque en plus de contribuer à prédire le risque de la maladie.

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Evidence of interaction between type 2 diabetes susceptibility genes and dietary fat intake for adiposity and glucose homeostasis-related phenotypes

2010-03-09, Ruchat, Stéphanie-May, Elks, Cathy E., Bouchard, Claude, Loos, Ruth, Pérusse, Louis, Weisnagel, John, Vohl, Marie-Claude, Rankinen, Tuomo

Background/Aims: Genome-wide association studies have led to the identification of several susceptibility genes for type 2 diabetes mellitus (T2DM). The objective of this study was to test the hypothesis that the associations between single nucleotide polymorphisms (SNPs) in these genes and adiposity and glucose homeostasis-related phenotypes are influenced by dietary fat intake. Methods: Thirty-three SNPs in 9 T2DM genes (CDKAL1, CDKN2A/B, HHEX, HNF1B, IGF2BP2, KCNJ11, SLC30A8, TCF7L2 and WFS1) were tested in a maximum of 669 subjects from the Quebec Family Study. Subjects were measured for several adiposity indices and underwent a 75-gram oral glucose tolerance test. Total fat intake was estimated from a 3-day dietary record. Results: We observed 13 significant (p ^ 0.01) SNP-dietary fat interactions. Among them, IGF2BP2 rs4402960, alone or in interaction with dietary fat intake, influenced abdominal total fat (ATF: SNP effect, p = 0.006, interaction effect, p = 0.009) and abdominal visceral fat (AVF: SNP effect, p = 0.007, interaction effect, p = 0.01). Similarly, TCF7L2 rs12573128 alone or in interaction with dietary fat intake, influenced insulin sensitivity (SNP effect and interaction effect, p ^ 0.008) and glucose tolerance (SNP effect p ^ 0.009 and interaction effect, p ^ 0.01). Conclusion: These results suggest that gene-dietary fat interactions may influence glucose homeostasis-related phenotypes and play an important role in determining the increased risk of diabetes associated with the T2DM susceptibility genes.

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Interaction between HNF4A polymorphisms and physical activity in relation to type 2 diabetes-related traits : results from the Quebec Family Study

2009-04-29, Ruchat, Stéphanie-May, Bouchard, Claude, Rankinen, Tuomo, Pérusse, Louis, Weisnagel, John, Vohl, Marie-Claude

Aims : To test for associations between type 2 diabetes mellitus (T2DM)-related traits and polymorphisms (SNPs) in the hepatocyte nuclear factor 4-α gene (HNF4A) in the Quebec Family Study cohort, and determine whether these associations are modulated by physical activity (PA). Methods : Two HNF4A SNPs (rs1885088 G > A; rs745975 C > T), previously reported to be associated with T2DM, were studied in 528 non-diabetic subjects who underwent a 75 g oral glucose tolerance test (OGTT). Glucose, insulin and C-peptide plasma levels, measured in the fasting state and during the OGTT, were used in the analysis. The amount (hours per week) of PA was assessed by questionnaire. Results : The HNF4A rs1885088 SNP was not independently associated with T2DM-related traits, whereas the rs745975 was associated with fasting insulin, HOMA-IR and 2-h glucose levels (p < 0.05 for all). Genotype by PA interactions were found for glucose homeostasis (p < 0.0001) and insulin secretion (p ≤ 0.03). When subjects were stratified by PA level (according to the median value), we found that high level of PA (>2 h/week) was associated with smaller glucose area under the curve (AUC) and 2-h glucose levels in rs1885088 A/A homozygotes and with lower fasting C-peptide and insulin AUC in rs745975 T/T homozygotes. Conclusion : These results indicate that the associations of HNF4A rs1885088 with glucose tolerance and rs745975 with insulin secretion are modulated by PA. Our finding therefore suggests that the effect of HNF4A polymorphisms on the risk of T2DM is influenced by PA.

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Evidence for interaction between PPARG Pro12Ala and PPARGC1A Gly482Ser polymorphisms in determining type 2 diabetes intermediate phenotypes in overweight subjects

2009-06-17, Ruchat, Stéphanie-May, Bouchard, Claude, Pérusse, Louis, Rankinen, Tuomo, Weisnagel, John, Vohl, Marie-Claude

Background: The peroxisome proliferator-activated receptor-γ (PPARG) Pro12Ala and the PPARG co-activator-1α (PPARGC1A) Gly482Ser polymorphisms (SNPs) have been associated with type 2 diabetes mellitus (T2DM) risk. We hypothesized that independent and interactive effects of the PPARG Pro12Ala and PPARGC1A Gly482Ser polymorphisms influence T2DM intermediate phenotypes. Material and Methods: PPARG Pro12Ala and PPARGC1A Gly482Ser SNPs were studied in 680 non diabetic subjects who underwent a 75 g oral glucose tolerant test (OGTT). Glucose and insulin plasma levels in the fasting state and derived from the OGTT were included in the present study. Results: We found significant independent effects of the PPARG and PPARGC1A variants on fasting insulin levels (p=0.02 for both), HOMA-IR (p=0.03 and p=0.02, respectively), insulin area under the curve (AUC) (p=0.007 and p=0.006, respectively) and 2-h glucose levels (p=0.02 for PPARGC1A). Furthermore, significant gene-gene interactions were found for fasting insulin, HOMA-IR and insulin AUC (p=0.03 for all). Carriers of the PPARGC1A Gly allele who were also PPARG Ala-carriers had higher fasting insulin levels (p=0.02), HOMA-IR (p=0.01) and insulin AUC (p=0.01) compared to the Ser/Ser-Ala+genotype combination, whereas no differences between the PPARGC1A genotypes among the PPARG Pro/Pro carriers were observed. Conclusion: Together, these results showed that PPARG Pro12Ala and PPARGC1A Gly482Ser variants are associated, alone and in interaction, with insulin and glucose homeostasis and suggest that gene-gene interactions should be taken into account in candidate gene studies of T2DM to identify subjects with markedly different risks of developing the disease.