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Background: Recent studies showed that eating behaviors such as disinhibition, emotional and external eating, and snacking mediate genetic susceptibility to obesity. It remains unknown if diet quality and intake of specific food groups also mediate the genetic susceptibility to obesity., Objective: This study aimed to assess if diet quality and intakes of specific food groups mediate the association between a polygenic risk score (PRS) for BMI and BMI and waist circumference (WC). We hypothesized that poor diet quality, high intakes of energy-dense food groups, and low intakes of nutrient-dense food groups mediate the genetic susceptibility to obesity., Methods: This cross-sectional study included 750 participants (56.3% women, aged 41.5 ± 14.9 y, BMI 27.8 ± 7.5 kg/m2) from the Quebec Family Study. A PRSBMI based on >500,000 genetic variants was calculated using LDpred2. Dietary intakes were assessed with a 3-d food record from which a diet quality score (i.e. Nutrient Rich Food Index 6.3) and food groups were derived. Mediation analyses were conducted using a regression-based and bootstrapping approach., Results: The PRSBMI explained 25.7% and 19.8% of the variance in BMI and WC, respectively. The association between PRSBMI and BMI was partly mediated by poor diet quality (β = 0.33 ± 0.12; 95% CI: 0.13, 0.60), high intakes of fat and high-fat foods (β = 0.46 ± 0.16; 95% CI: 0.19, 0.79) and sugar-sweetened beverages (β = 0.25 ± 0.14; 95% CI: 0.05, 0.60), and low intakes of vegetables (β = 0.15 ± 0.08; 95% CI: 0.03, 0.32), fruits (β = 0.37 ± 0.12; 95% CI: 0.17, 0.64), and dairy products (β = 0.17 ± 0.09; 95% CI: 0.02, 0.37). The same trends were observed for WC., Conclusions: The genetic susceptibility to obesity was partly mediated by poor diet quality and intakes of specific food groups. These results suggest that improvement in diet quality may reduce obesity risk among individuals with high genetic susceptibility and emphasize the need to intervene on diet quality among these individuals., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Genome-wide association studies (GWASs) have identified several genes associated with obesity. The mechanisms through which these genes affect body weight are not fully characterized. Recent studies suggest that eating behavior (EB) traits could be involved, but only a few EB traits were investigated., Objective: This study aimed to investigate whether genetic susceptibility to obesity is mediated by EB traits (cognitive restraint, disinhibition, hunger) and their subscales. We hypothesized that EB traits, and their subscales, partly mediate this association., Design: Adult individuals (n = 768) who participated in the Quebec Family Study were included in this cross-sectional study. A genetic risk score (GRS) of obesity was calculated based on the 97 genetic variants recently identified in a GWAS meta-analysis of body mass index (BMI). EB traits and their subscales were assessed with the use of the Three-Factor Eating Questionnaire. Regression analyses with age and sex as covariates were used to investigate the associations between GRS, EB traits, BMI, and WC and whether the association between GRS and obesity is mediated by EB traits, which represents the indirect effect of GRS on obesity., Results: The GRS of obesity was positively associated with BMI (β = 0.19 ± 0.04, P < 0.0001) and WC (β = 0.46 ± 0.10, P < 0.0001). Regression analyses also revealed that the association between GRS of obesity and BMI was partly mediated by disinhibition and susceptibility to hunger (βindirect = 0.09 ± 0.03, P = 0.0007, and βindirect = 0.04 ± 0.02, P = 0.02, respectively). Habitual and situational susceptibility to disinhibition (βindirect = 0.08 ± 0.03, P = 0.002 and βindirect = 0.05 ± 0.02, P = 0.003, respectively) as well as internal and external locus of hunger (βindirect = 0.03 ± 0.02, P = 0.03 for both) were also found to mediate the association between GRS of obesity and BMI. The same trends were observed with WC., Conclusions: The results of this study indicate that the genetic susceptibility to obesity is partly mediated through undesirable EB traits, which suggests that they could be targeted in obesity treatment and prevention. This trial was registered at clinicaltrials.gov as NCT03355729.

Background/aim: Total fat intake has an important impact on the low-density lipoprotein (LDL) peak particle diameter (LDL-PPD) and may interact with nutrient-sensitive single nucleotide polymorphisms (SNPs). The objective was to examine whether there is suggestive evidence of SNP × dietary fat intake interaction effects influencing the LDL-PPD in the Quebec Family Study (QFS) in order to generate hypotheses to be tested in larger studies., Methods: SNPs from a genome-wide association study (GWAS) using Illumina Human610-Quad BeadChip, total fat intake derived from a 3-day weighted food record, and SNP × total fat intake interaction effects were examined on LDL-PPD in 541 QFS subjects., Results: The GWAS analyses 29 identified independent SNP × total fat intake interaction effects on the LDL-PPD at p < 10(-5), including SNPs in the following genes: ABCG2, CPA3, FNBP1, KCNQ3, NBAS, NCALD, OPRL1, NKAIN2, SH3BGRL2, SOX5, and SUSD4., Conclusions: This observational study suggests that multiple SNPs interact with dietary fat intake to influence variation in the LDL-PPD., (© 2015 S. Karger AG, Basel.)

Unlabelled: Inflammation is an important factor linking abdominal obesity with insulin resistance and related cardiometabolic risk. A genome-wide association study of adiposity-related traits performed in the Quebec Family Study (QFS) revealed that a single-nucleotide polymorphism (SNP) in the LRRFIP1 gene (rs11680012) was associated with abdominal adiposity (P = 4.6 × 10(-6))., Objective: The objective of this study was to assess the relationship between polymorphisms in LRRFIP1 gene and adiposity (BMI, fat mass (FM), waist circumference (WC), and computed tomography-derived areas of total, subcutaneous and visceral abdominal adipose tissue) and markers of inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6))., Design and Methods: Using Sequenom, 16 tag SNPs in the LRRFIP1 gene, capturing 78% of the genetic variation, were genotyped in 926 participants of the QFS., Results: Eight SNPs (rs7575941, rs3769053, rs11689421, rs3820808, rs11680012, rs3806505, rs6739130, and rs11686141) showed evidence of association with at least two adiposity phenotypes and plasma levels of one marker of inflammation. The strongest evidence of association was observed with rs11680012, which explained 1.8-3.4% of the variance in areas of abdominal adiposity and 2.0% of the variation in CRP levels. Carriers of the rare allele of rs11680012 had ≈ 30% more abdominal adiposity (P values between 2.7 × 10(-4) and 3.8 × 10(-6)) and 75% higher CRP levels (P = 1.6 × 10(-4)) than the common allele in age and sex adjusted data. Rs11680012 is a G/C SNP converting an arginine into a threonine and this amino acid substitution may potentially alter exonic splicing., Conclusion: This gene may therefore represent a potential interesting target to investigate in further functional studies on adiposity and inflammation., (Copyright © 2012 The Obesity Society.)

Eating behaviour traits of rigid control and disinhibition have been associated with body weight in both adults and adolescents. Moreover, adults reporting a dieting history have increased levels of unhealthy eating behaviours. Against this background, the present study aimed to examine the relationship between dieting history and eating behaviour traits in adolescents. For the purpose of this research, a total of sixty adolescents (aged 15 (sem 2·4) years) from the Québec Family Study completed the Three-Factor Eating Questionnaire (TFEQ) and a questionnaire regarding eating habits. Self-reported current and past dieting were analysed against eating behaviour traits measured by the TFEQ, including all subscales. As the results revealed, few adolescents reported currently dieting (n 3). Adolescents who reported a dieting history (23·3 %) were older (16·9 v. 14·4 years, P < 0·001), were more likely to be female (78·6 v. 41·3 %, P < 0·05) but did not have a significantly higher BMI z-score (1·5 v. 0·9, P = 0·10), although they were more likely to be either overweight or obese (P < 0·01). After correcting for sex, BMI and age, adolescents who reported a dieting history had higher levels of rigid control and disinhibition (P < 0·05-0·0001) than those reporting no dieting history. A greater proportion of adolescents characterised by high rigid control and high disinhibition were past dieters, compared to those characterised by low levels of both behaviour traits (53 v. 4 %). The study arrived at the following conclusions: as observed in adults, adolescents with a history of dieting present unfavourable eating behaviour traits. These behavioural traits may represent an additional challenge to the long-term regulation of body weight.

The objective of this cross-sectional study was to examine the association between sleep duration and alcohol consumption in adults (301 men and 402 women aged 18-64years) from the greater Quebec City area. Sleep duration (self-reported), alcohol consumption (3-day food record and questions on drinking habits), and disinhibition eating behavior trait (score ≥ 6 on the Three-Factor Eating Questionnaire) were assessed. Participants were categorized as short- ( ≤ 6h), average- (7-8h) or long- ( ≥ 9h) duration sleepers. Overall, short-duration sleepers consumed significantly more alcohol than the two other sleep-duration groups. After adjusting for relevant covariates, short sleep duration was associated with an increase in the odds of exceeding the recommendations for sensible weekly alcohol intake of 14 drinks for men and 7 drinks for women compared to those sleeping between 7 and 8h (OR 1.87, 95%CI 1.03-3.54, both sexes combined). In both men and women, daily alcohol intake was significantly higher in short-duration sleepers having a high disinhibition eating behavior trait. However, the prevalence of a binge drinking occasion (i.e. ≥5 drinks on one occasion) was more common in men than women. Men sleeping less than 6h per night with a disinhibited eating behavior were more likely to report binge drinking (41% of them). In summary, the combination of short sleep duration with disinhibited eating behavior is associated with greater alcohol intake in adults., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Obesity is a major health problem that can be influenced by eating behaviors. Evidence suggests that the sensory properties of food influence eating behaviors and lead to overeating and overweight. A previous genome-wide linkage scan for eating behavior traits assessed with the Three-Factor Eating Questionnaire (cognitive dietary restraint, disinhibition and hunger) performed in the Quebec Family Study (QFS) revealed a quantitative trait locus for disinhibition on chromosome 19p13. This region encodes a cluster of seven olfactory receptor (OR) genes, including OR7D4, previously associated with odor perceptions. Direct sequencing of the OR7D4 gene revealed 16 sequence variants. Nine OR7D4 sequence variants with minor allele frequency (MAF)>1% as well as 100 SNPs spanning the cluster of OR genes on 19p13 were tested for association with age- and sex-adjusted eating behaviors as well as adiposity traits in 890 subjects. One OR7D4 sequence variant (rs2878329 G>A) showed evidence of association with reduced levels of adiposity (p=0.03), cognitive dietary restraint (p=0.05) and susceptibility to hunger (p=0.008). None of the OR7D4 SNPs was associated with disinhibition, but a SNP (rs2240927) in another OR gene (OR7E24) showed evidence of association (p=0.03). Another SNP in the OR7G3 gene (rs10414255) was also found to be associated with adiposity and eating behaviors. These results are the first to suggest that variations in human olfactory receptor genes can influence eating behaviors and adiposity. The associations reported in the present study should be interpreted with caution considering the number of tests performed and considered as potential new hypotheses about the effects OR polymorphisms on eating behaviors and obesity that need to be further explored in other populations., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The aim of this study was to determine the independent contribution of previously reported risk factors for adult overweight and obesity. A cross-sectional (n=537) and a longitudinal (n=283; 6-year follow-up period) analysis was performed for nine risk factors for overweight and obesity assessed in adult participants (aged 18-64 years) of the Quebec Family Study (QFS). The main outcome measure was overweight/obesity, defined as a BMI>or=25 kg/m2. Using logistic regression analysis adjusted for age, sex, and socioeconomic status, short sleep duration, high disinhibition eating behavior, low dietary calcium intake, high susceptibility to hunger behavior, nonparticipation in high-intensity physical exercise, high dietary restraint behavior, nonconsumption of multivitamin and dietary supplements, high dietary lipid intake, and high alcohol intake were all significantly associated with overweight and obesity in the cross-sectional sample. The analysis of covariance adjusted for age, socioeconomic status, and all other risk factors revealed that only individuals characterized by short sleep duration, high disinhibition eating behavior, and low dietary calcium intake had significantly higher BMI compared to the reference category in both sexes. Over the 6-year follow-up period, short-duration sleepers, low calcium consumers, and those with a high disinhibition and restraint eating behavior score were significantly more likely to gain weight and develop obesity. These results show that excess body weight or weight gain results from a number of obesogenic behaviors that have received considerable attention over the past decade. They also indicate that the four factors, which have the best predictive potential of variations in BMI, be it in a cross-sectional or a longitudinal analytical design, do not have a "caloric value" per se.

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

Objective: To examine the long-term relationship between sleep duration and type 2 diabetes or impaired glucose tolerance (IGT)., Methods: Body composition measurements and self-reported sleep duration were determined in a longitudinal sample of 276 individuals aged 21 to 64 years followed for a mean of 6 years. Risk factors of type 2 diabetes/IGT over the follow-up were determined and relative risks (RRs) calculated for the development of type 2 diabetes/IGT by sleep duration group., Results: Independent risk factors of type 2 diabetes/IGT over the follow-up included age, obesity, sleep duration, and glucose/insulin homeostasis indicators. Using adults with 7-8h of sleep as a reference, the adjusted RR for the development of type 2 diabetes/IGT was 2.78 (1.61-4.12) for those with 6h of sleep and 2.54 (1.42-3.53) for those with 9h of sleep. These elevated RRs remained significant after adjustment for body mass index, waist circumference or percent body fat., Conclusion: Short and long sleeping times are associated with a higher risk of developing type 2 diabetes/IGT, independent of several covariates. These results suggest that sleep duration may represent a novel risk factor for type 2 diabetes/IGT.

Aims: To test for associations between type 2 diabetes mellitus (T2DM)-related traits and polymorphisms (SNPs) in the hepatocyte nuclear factor 4-alpha 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 75g 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 (p2h/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.

A large body of evidence suggests that the environment plays an important role in the development of obesity. The hormone-sensitive lipase (encoded by the LIPE gene) is an intracellular enzyme that mobilises fat stores in a hormone-stimulated manner. The aim of the present study was to determine the effects of the LIPE C-60G polymorphism on body fat and plasma lipid and lipoprotein concentrations, and to test for its interaction with physical activity. The LIPE C-60G polymorphism was genotyped in 862 subjects from the Quebec Family Study. Body mass index (BMI), fat mass, percentage body fat, abdominal fat areas assessed by computed tomography, and detailed fasting plasma lipid and lipoprotein profiles were measured. Levels of physical activity were estimated using a three-day diary, and a moderate to strenuous physical activity score was retained for this study. The main effects of the LIPE C-60G polymorphism, physical activity and their interaction were determined by regression analyses separately in men and women using the MIXED model procedure. In men, we observed significant gene-physical activity interactions for BMI (p = 0.006), fat mass (p = 0.04), abdominal visceral fat area (p = 0.005) and plasma cholesterol (C) high-density lipoprotein cholesterol (HDL-C) ratio (p = 0.003). A high level of physical activity was associated with reduced adiposity and a lower plasma-C/HDL-C ratio, but only in non-carriers of the genetic variant (G-60 allele). In women, no evidence of a gene by physical activity interaction was observed, except for subcutaneous abdominal fat (p = 0.05). These results suggest that the associations between physical activity and body fat and plasma lipoprotein/lipid concentrations in men are dependent on the LIPE C-60G polymorphism, and highlight the importance of taking into account the role of gene-physical activity interactions in candidate gene studies of obesity and obesity-related traits.

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 < or = 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 < or = 0.008) and glucose tolerance (SNP effect p < or= 0.009 and interaction effect, p < or = 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., (Copyright 2010 S. Karger AG, Basel.)

Background: Little is known about the genes influencing dietary energy and nutrient intakes, despite evidence that these intakes are influenced by genetic factors., Objective: We aimed to identify, by using a genome-wide linkage analysis, chromosomal regions harboring genes that affect energy and macronutrient intakes., Design: Energy, carbohydrate, lipid, and protein intakes were assessed in 836 subjects from 217 families by using a 3-d dietary record. A total of 443 markers were genotyped and tested for linkage; age- and sex-adjusted energy and macronutrient intakes were expressed in grams and as percentages of total energy intake. Regression-based (Haseman-Elston) and variance-component (MERLIN) methods were applied to test for linkage with dietary data. A maximum of 454 sibpairs from 217 nuclear families were available for analysis., Results: The genome scan provided suggestive evidence (P < or = 0.0023) for the presence of 6 quantitative trait linkages influencing total caloric and macronutrient intakes in the Québec Family Study. Of these, multiple linkages were found on chromosome 3q27.3, in a region harboring the adiponectin gene, at marker D3S1262 for energy [logarithm of odds (LOD): 2.24], carbohydrate (LOD: 2.00), and lipid (LOD: 1.65) intakes. The peak linkages for carbohydrate, lipid, and protein intakes were found on chromosomes 1p32.2 (LOD: 2.39), 1p35.2 (LOD: 2.41), and 10p15.3 (LOD: 2.72), respectively. The linkage results remained significant after adjustment for body mass index, which suggested that the genes underlying these quantitative trait linkages influence dietary intake independent of body size., Conclusion: The linkage on chromosome 3q27.3 with energy, lipid, and carbohydrate intakes suggests that this region of the genome may harbor genes that influence energy and macronutrient intakes in humans.

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.

Background: Clinical trials of low-fat diets characteristically produce small mean long-term weight loss but a large interindividual variation in response. This variation has been attributed to psychological and behavioral factors, although biological differences may also play a role., Objective: The objective was to determine whether physiologic differences in insulin secretion explain differences in weight gain among individuals consuming low- and high-fat diets., Design: Of 276 individuals followed in the Quebec Family Study for a mean of 6 y, we compared those in the lowest with those in the highest dietary fat tertiles. We performed oral-glucose-tolerance tests at baseline and examined the insulin concentration at 30 min (insulin-30) as a proxy measure of insulin secretion. Six-year changes in body weight and waist circumference were the primary endpoints. We determined the associations between insulin-30 and the primary endpoints by linear regression analysis, with adjustment for potentially confounding factors., Results: Mean changes in body weight and waist circumference did not differ significantly between the lowest- and highest-fat diet groups. However, these endpoints were strongly associated with insulin-30, especially among individuals consuming the lowest-fat diet. Insulin-30 at baseline was significantly associated with 6-y weight gain (r = 0.51, P < 0.0001) and change in waist circumference (r = 0.55, P < 0.0001) in the lowest diet fat, group [corrected], but not in the highest diet fat group (r = 0.18, P = 0.086 and r = 0.20, P = 0.058, respectively) [corrected] Individuals in the highest insulin-30 and lowest dietary fat group gained 1.8 kg more than did those in the highest insulin-30 and highest dietary fat group (51%; P = 0.034); they gained 4.5 kg more than did those in the lowest insulin-30 and lowest dietary fat group (6.5-fold; P = 0.0026)., Conclusion: A proxy measure of insulin secretion strongly predicts changes in body weight and waist circumference over 6 y in adults, especially among those consuming lower-fat diets, which demonstrates the existence of a novel diet-phenotype interaction.

Objective: To clarify the relationship between the amount of mid-thigh subcutaneous adipose tissue (SCAT) and glucose tolerance in men and women., Methods: Midthigh and abdominal computed tomography (CT) scans were obtained from 63 men and 110 women from the Quebec Family Study. Areas and attenuations of adipose tissue compartments and skeletal muscle measured from CT scans were related to glycemia and insulinemia values from an oral glucose tolerance test (OGTT)., Results: Adjusted for age and fat mass or age and percent fat, negative relationships (all p < 0.05) between the surface area of mid-thigh SCAT and OGTT data (glucose and insulin area under the curve, glycemia and insulin at 120 min) were seen in men (r range -0.22 to -0.37) and women (r range -0.20 to -0.30). Similar but weaker tendencies were observed when correcting for visceral adiposity. Correlations of OGTT variables with ratios of midthigh SCAT to abdominal visceral adipose tissue and to fat mass revealed significant negative relationships in both genders. Tertile analyses showed better glucose handling in subjects with a higher content of mid-thigh SCAT., Conclusion: These data suggest that the preferential deposition of adipose tissue as mid-thigh SCAT is a strategy to prevent glucose intolerance.

Adipose tissue synthesizes and secretes a wide range of biologically active molecules considered as inflammatory markers whose dysregulation in obesity plays a role in the development of insulin resistance and vascular disorders. Thus, finding genes that influence circulating levels of inflammatory biomarkers may provide insights into the genetic determinants of obesity-related metabolic diseases. We performed linkage analyses for fasting plasma levels of adiponectin, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor-necrosis factor-alpha (TNF-alpha) in 764 subjects enrolled in the Quebec family study (QFS). A maximum of 393 pairs of siblings from 211 nuclear families were available for analyses. A total of 443 markers spanning the 22 autosomal chromosomes with an average inter-marker distance of 6.24 Mb were genotyped. Linkage was tested using both allele-sharing (SIBPAL) and variance component linkage methods (MERLIN). We showed suggestive evidence of linkage for plasma adiponectin levels on chromosome 15q21.1 [D15S659; logarithm of the odds (LOD) score = 2.23], 3q13.33 (D3S3023; LOD = 2.09), 20q13.2 (D20S197; LOD = 1.96) and 14q32.2 (D14S1426; LOD = 1.79). Evidence of linkage (SIBPAL) was also found for CRP on 12p11.23 (P = 0.001) and 12q15 (P = 0.0005) and for IL-6 on 14q12 (P = 0.002). None of these linkages remained significant after adjustment for body mass index. No evidence of linkage was found for TNF-alpha plasma levels. These results suggest that several QTLs can influence plasma levels of adiponectin and CRP, partly via their effects on adiposity.

Objective: The aim of this study was to assess gene-diet interaction effects on cardiovascular disease (CVD) risk factors (waist circumference, plasma triacylglycerol, high-density lipoprotein-cholesterol and fasting glucose concentrations, and diastolic and systolic blood pressure) in the Quebec Family Study cohort., Design: Sixty-four polymorphisms from 45 candidate genes were studied in 645 subjects. Dietary fat intake was obtained from a 3-day weighted food record., Results: We observed 18 significant interactions at a p value

Objective: In the present study, we undertook a two-step fine mapping of a 20-megabase region around a quantitative trait locus previously reported on chromosome 15q26 for abdominal subcutaneous fat (ASF) in an extended sample of 707 subjects from 202 families from the Quebec Family Study., Research Methods and Procedure: First, 19 microsatellites (in addition to the 7 markers initially available on 15q24-q26; total = 26) were genotyped and tested for linkage with abdominal total fat, abdominal visceral fat, and ASF assessed by computed tomography and with fat mass (FM) using variance component-based approach on age- and sex-adjusted phenotypes. Second, 16 single nucleotide polymorphisms (SNPs) were genotyped and tested for association using family-based association tests., Results: After the fine mapping, the peak logarithm of odds ratio (LOD) score (marker D15S1004) increased from 2.79 to 3.26 for ASF and from 3.52 to 4.48 for FM, whereas for abdominal total fat, the peak linkage (marker D15S996) decreased from 2.22 to 1.53. No evidence of linkage was found for abdominal visceral fat. Overall, for genotyped SNPs, three variants located in the putative MCTP2 gene were significantly associated with FM and the three abdominal fat phenotypes (p

Objective: To explore cross-sectional associations between short sleep duration and variations in body fat indices and leptin levels during adulthood in a sample of men and women involved in the Québec Family Study., Research Methods and Procedures: Anthropometric measurements, plasma lipid-lipoprotein profile, plasma leptin concentrations, and total sleep duration were determined in a sample of 323 men and 417 women ages 21 to 64 years., Results: When compared with adults reporting 7 to 8 hours of sleep per day, the adjusted odds ratio for overweight/obesity was 1.38 (95% confidence interval, 0.89 to 2.10) for those with 9 to 10 hours of sleep and 1.69 (95% confidence interval, 1.15 to 2.39) for those with 5 to 6 hours of sleep, after adjustment for age, sex, and physical activity level. In each sex, we observed lower adiposity indices in the 7- to 8-hour sleeping group than in the 5- to 6-hour sleeping group. However, all of these significant differences disappeared after statistical adjustment for plasma leptin levels. Finally, the well-documented regression of plasma leptin levels over body fat mass was used to predict leptin levels of short-duration sleepers (5 and 6 hours of sleep), which were then compared with their measured values. As expected, the measured leptin values were significantly lower than predicted values., Discussion: There may be optimal sleeping hours at which body weight regulation is facilitated. Indeed, short sleep duration predicts an increased risk of being overweight/obese in adults and is related to a reduced circulating leptin level relative to what is predicted by fat mass. Because sleep duration is a potentially modifiable risk factor, these findings might have important clinical implications for the prevention and treatment of obesity.

Background: Despite adiponectin's presumed role in fatty acid oxidation and energy homeostasis, little is known about the effect of gene variants on substrate oxidation, energy expenditure, and adiposity-related phenotypes., Objective: We examined the effects of genetic variation in adiponectin (ADIPOQ) and adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2) on resting metabolic rate, respiratory quotient (RQ), and adiposity-related phenotypes., Design: We studied the associations of ADIPOQ, ADIPOR1, and ADIPOR2 polymorphisms with resting metabolic rate, RQ, and body mass index, percentage body fat, sum of 6 skinfold thicknesses, waist circumference, and total, subcutaneous, and visceral fat in 759 participants in the Québec Family Study., Results: The ADIPOQ 45T-->G single-nucleotide polymorphism (SNP) was significantly (P = 0.0002 to 0.04) associated with overall adiposity and abdominal adiposity; the rare homozygotes (G/G) had a leaner phenotype than did the carriers of the common allele. One SNP each in the putative promoter of ADIPOR1 (ie, -3882T-->C) and ADIPOR2 (ie, IVS1 -1352G-->A) was associated with RQ (P = 0.03 and 0.04, respectively), and the association was even stronger in nonobese persons (P = 0.02 and 0.003). Carriers of the common alleles (ADIPOR1 T and ADIPOR2 G alleles) had a lower RQ than did the rare homozygotes. A significant genotype-by-genotype interaction (P = 0.0002 to 0.02) was found between SNPs in the promoters of ADIPOQ (-3971A-->G) and ADIPOR1 (-3882T-->C). Subjects carrying the minor ADIPOQ allele (G allele) who were rare homozygotes (C/C) for the ADIPOR1 SNP had a higher RQ (P = 0.003) and greater overall (P < 0.03) and abdominal (P < 0.05) adiposity than did persons with other genotype combinations., Conclusions: Previous findings that the ADIPOQ 45T-->G variant contributes to overall fatness and abdominal obesity are confirmed. Moreover, variants in the promoter region of both ADIPOR genes contribute to substrate oxidation.

The adipokine visfatin (PBEF1) exhibits insulin-mimetic effects and correlates strongly with visceral adiposity. We sequenced visfatin gene exons and 1,480 bp of the promoter in 23 individuals, including 18 individuals from the Quebec Family Study (QFS) with varying degrees of abdominal visceral fat, assessed by computed tomography, and 5 individuals from the Saguenay-Lac-Saint-Jean region of Québec. We identified a synonymous polymorphism in exon 7 (SER301SER) but no nonsynonymous mutations. We observed an additional 10 polymorphisms, including 5 intronic, 4 within the promoter, and 1 within the 3' untranslated region. Further promoter sequencing (816 bp) identified five additional single nucleotide polymorphisms (SNPs) in the QFS population. To investigate the role of visfatin gene variants in obesity-related phenotypes, we genotyped a total of 13 SNPs in the promoter region of the gene. From these, we analyzed the seven common SNPs in the QFS sample (918 participants from 208 families). A significant association was found between two SNPs (rs9770242 and rs1319501), in perfect linkage disequilibrium, and fasting insulin levels (P = 0.002). These SNPs were also associated with fasting glucose (P

Objective: To explore a quantitative trait locus (QTL) on human chromosome 1q affecting BMI, adiposity, and fat-free mass phenotypes in the Quebec Family Study cohort., Research Methods and Procedures: Non-parametric sibpair and variance component linkage analyses and family-based association studies were performed with a dense set of chromosome 1q43 microsatellites and single-nucleotide polymorphism markers in 885 adult individuals., Results: Linkage was observed between marker D1S184 and BMI (p = 0.0004) and with body fat mass or percentage body fat (p < or = 0.0003), but no linkage was detected with fat-free mass. Furthermore, significant linkages (p < 0.0001) were achieved with subsamples of sibpairs at both ends of phenotype distributions. Association studies with quantitative transmission disequilibrium tests refined the linkage to a region overlapping the regulator of G-protein signaling 7 (RGS7) gene and extending to immediate upstream gene loci., Discussion: The present study indicates that the QTL on chromosome 1q43 specifically affects total adiposity and provides a genetic mapping framework for the dissection of this adiposity locus.

Objectives: People of African descent may be at greater risk of metabolic syndrome (MS) compared with whites. We examined the associations among MS markers, body composition, and resting metabolic rate (RMR) in black Haitians and in white subjects living in Quebec, Canada., Research Methods and Procedures: Forty randomly selected Haitians were matched with 40 white subjects for age, sex, and BMI. Glycemic status and insulin resistance were assessed based on a 3-hour glucose tolerance test. Blood lipids, blood pressure, abdominal fat (computed tomography), and waist circumference (WC) were measured. RMR was estimated by indirect calorimetry., Results: Triglycerides were significantly correlated with blood pressure only in Haitians and with the area under the curve for insulin only in whites. Haitians had significantly (p < 0.05) lower triglycerides and higher high-density lipoprotein-cholesterol concentrations but higher blood pressure than whites at any given WC value. General linear models showed that Haitians had less visceral adipose tissue than whites for the same WC. RMR was lower among Haitians for any given value of BMI or WC than in whites. Also, WC was more strongly associated with glucose area under the curve and to log-homeostasis model assessment in white than in Haitian subjects., Discussion: The MS may be ethnospecific in its features and etiology. The standard anthropometric indices of obesity may not be as effective in populations of African descent compared with whites, unless appropriate cut-off values are defined.

Low-density lipoprotein (LDL) size, a coronary heart disease risk factor, is influenced by both genetic and environmental factors. Results from the Quebec Family Study (QFS) revealed that the LDL peak particle diameter (LDL-PPD) aggregates in families with a heritability coefficient above 50% and is affected by a major quantitative trait locus on chromosome 17q (LOD=6.8). Complex segregation analyses have consistently demonstrated a major gene effect influencing LDL size. In the present study, we report a similar analysis in the QFS cohort, which suggests that a major gene explains 23% of the variance in age-body mass index and triglyceride-adjusted LDL-PPD. The most intuitive positional candidate gene on chromosome 17q is the apolipoprotein H gene. Direct sequencing of the promoter, coding regions, and exon-intron splicing boundaries of this gene revealed the presence of three missense mutations and two polymorphisms in the untranslated regions. Using family-based association tests, none of these variants was individually associated with LDL-PPD. However, analysis of the haplotypes constructed from the three missense mutations, suggested that one particular haplotype (frequency=20.9%) was associated with a significant increase in LDL-PPD trait values (p=0.046). Taken together, these results suggest the presence of a major gene effect influencing LDL-PPD and a positive association with a positional candidate gene located on chromosome 17q. Replication of the association between apolipoprotein H gene haplotype and LDL-PPD is required before reaching firm conclusion.

Objective: It is commonly recognized that genetic, environmental, behavioral, and social factors are involved in the development of obesity. The family environment may play a key role in shaping children's eating behaviors. The purpose of this study was to estimate the degree of familial resemblance in eating behavioral traits (cognitive dietary restraint, disinhibition, and susceptibility to hunger)., Research Methods and Procedures: Eating behavioral traits were assessed with the Three-Factor Eating Questionnaire in 282 men and 402 women (202 families) from the Quebec Family Study. Familial resemblance for each trait (adjusted for age, sex, and BMI) was investigated using a familial correlation model., Results: The pattern of familial correlation showed significant spouse correlation for the three eating behavior phenotypes, as well as significant parent-offspring and sibling correlations for disinhibition and susceptibility to hunger. According to the most parsimonious model, generalized heritability estimates (including genetic and shared familial environmental effects) reached 6%, 18%, and 28% for cognitive dietary restraint, disinhibition, and susceptibility to hunger, respectively., Discussion: These results suggest that there is a significant familial component to eating behavioral traits but that the additive genetic component appears to be small, with generalized heritability estimates ranging from 6% to 28%. Thus, non-familial environmental factors and gene-gene and gene-environmental interactions seem to be the major determinants of the eating/behavioral traits.

We investigated the associations between a polymorphism in the melanocortin 4 receptor (MC4R) gene and changes in body size and composition from childhood to adulthood in the Québec Family Study. Ninety-one subjects (43 males) less than 18 years of age (mean age 13.5 +/- 2.4 years; range 8.4-17.8 years) at baseline were re-measured 11.2 years later on average. The anthropometric variables analyzed were height, weight, body mass index, percent body fat, sum of skinfolds, fat mass index, and fat free mass index (FFMI). All variables were adjusted for age and sex. The subjects were genotyped for the MC4R C-2745T polymorphism. Forty-five subjects were homozygotes for the common allele (C/C), 36 were heterozygotes (C/T) and 10 were homozygotes for the rare allele (T/T). The rare allele was associated with increased height at baseline as well as at the follow-up visit. Although FFMI tended to increase more in subjects carrying the rare allele, no significant differences were found for the changes over time for the other phenotypes. These results suggest that DNA sequence variation in the MC4R locus may contribute to the gain in body height from childhood to adulthood.

Objective: Obesity is associated with increased plasma levels of plasminogen-activator inhibitor-1 (PAI1), the major fibrinolysis inhibitor. PAI1 levels are also increased at menopause, a condition that is associated with fat mass gain, especially in the abdominal area., Design: We hypothesized that genetic variations within PAI1 gene are related to the amount of body fat and its regional distribution. We genotyped 666 subjects of the Quebec Family Study for five PAI1 gene polymorphisms. Stratified analyses were performed with analysis of covariance in men (n = 280) and women (n = 386) separately., Results: PAI1-675 4G/5G polymorphism was strongly associated with body mass index (P < or = 0.01) and fat mass (P < or = 0.05) in women. The PAI1-675 4G/5G promoter polymorphism and the c.43G

Background: Obesity is frequently associated with eating disorders, and evidence indicates that both conditions are influenced by genetic factors. However, little is known about the genes influencing eating behaviors., Objective: The objective was to identify genes associated with eating behaviors., Design: Three eating behaviors were assessed in 660 adults from the Quebec Family Study with the use of the Three-Factor Eating Questionnaire. A genome-wide scan was conducted with a total of 471 genetic markers spanning the 22 autosomes to identify quantitative trait loci for eating behaviors. Body composition and macronutrient and energy intakes were also measured., Results: Four quantitative trait loci were identified for disinhibition and susceptibility to hunger. Of these, the best evidence of linkage was found between a locus on chromosome 15q24-q25 and disinhibition (P <0.0058) and susceptibility to hunger (P <0.0001). After fine-mapping, the peak linkage was found between markers D15S206 and D15S201 surrounding the neuromedin beta (NMB) gene. A missense mutation (p.P73T) located within the NMB gene showed significant associations with eating behaviors and obesity phenotypes. The T73T homozygotes were 2 times as likely to exhibit high levels of disinhibition (odds ratio: 1.8; 95% CI: 1.07, 2.89; P=0.03) and susceptibility to hunger (odds ratio: 1.9; 95% CI: 1.15, 3.06; P=0.01) as were the P73 allele carriers. Six-year follow-up data showed that the amount of body fat gain over time in T73T subjects was >2 times that than in P73P homozygotes (3.6 compared with 1.5 kg; P <0.05)., Conclusion: The results suggest that NMB is a very strong candidate gene of eating behaviors and predisposition to obesity.

The purpose of the present cross-sectional study was to compare eating behaviours (cognitive dietary restraint, disinhibition and susceptibility to hunger), dietary profile and physiological variables according to the practice of dieting: current dieting; history of dieting in the 10-year period that preceded the study; no dieting during the same period. Dieting history, anthropometric markers of adiposity, RMR, dietary profile (3 d food record) and eating behaviours (three-factor eating questionnaire) were determined in a sample of 244 men and 352 women. A greater proportion of women (31.8 %) than men (16.8 %) reported that they had been on a diet over the past 10 years (P=0.0001). In both genders, current and past dieters had a higher BMI (P<0.05) than non-dieters and current dieters had lower reported energy intakes than past dieters and non-dieters (only in women) (P<0.05). Current and past dieters also had higher scores for all eating behaviours and their subscales (P<0.05; except for susceptibility to hunger in men) compared with non-dieters (adjusted for age, reported energy intake, percentage of dietary fat, BMI and RMR). Moreover, for each dieting-history category, women had significantly higher scores for cognitive dietary restraint than men (P<0.05). In conclusion, the present study showed that current and past dieters had higher scores for cognitive dietary restraint and disinhibition compared with non-dieters. As disinhibition has previously been associated with a greater risk of subsequent weight gain, interventions aimed at preventing an increase in disinhibition may be promising for long-term weight maintenance.

LDL size has been associated with the risk of coronary heart disease. The objective of the present study was to verify whether familial factors influence LDL peak particle diameter (LDL-PPD), a quantitative trait reflecting the size of the major LDL subclass. LDL-PPD was measured by 2-16% polyacrylamide gradient gel electrophoresis in 681 members of 236 nuclear families participating in the Quebec Family Study. LDL-PPD was adjusted for age (LDL-PPD1), age and body mass index (LDL-PPD2), or age, body mass index, and plasma triglyceride levels (LDL-PPD3) separately in men and women. The residual scores were used to test for familial aggregation, using an ANOVA and to compute maximum likelihood estimates of familial correlations. The ANOVA test revealed that family lines accounted for 47.4%, 46.7%, and 48.9% of the variance in the LDL-PPD1, LDL-PPD2, and LDL-PPD3 phenotypes, respectively. The pattern of familial correlations revealed no significant spouse correlations but significant parent-offspring and sibling correlations for the three LDL-PPD phenotypes, with maximal heritability estimates of 59%, 58%, and 52% for LDL-PPD1, LDL-PPD2, and LDL-PPD3, respectively. These results suggest that LDL-PPD strongly aggregates in families, and that the familial resemblance appears to be primarily attributable to genetic factors. Genes responsible for this genetic contribution remain to be identified., (Copyright 2003 Wiley-Liss, Inc.)

Considerable progress has been accomplished over the past 10 years in the understanding of the genetic basis of obesity and its related metabolic complications. It is now well established that obesity aggregates within families and that genes are partly responsible for this familial aggregation. The number of genes potentially involved in obesity continues to grow. This review summarizes the evidence accumulated so for regarding the contribution of genetic factors in obesity and the number of gene and loci linked to obesity in the Quebec Family Study.

Purpose and Methods: It is commonly recognized that there is familial aggregation for physical activity level. However, the genes and sequence variants responsible for the familial clustering have not been investigated. We performed a genome-wide linkage scan based on 432 markers typed in 767 subjects from 207 families of the Quebec Family study with the aim of identifying loci affecting physical activity levels. Four physical activity level phenotypes were used., Results: Promising evidence of linkage (P < 0.0023) was found for physical inactivity on chromosome 2p22-p16. Suggestive linkages (0.0023

A role for dopamine neurotransmission in the regulation of motor activity and reinforcement of behavior is supported by considerable evidence. We studied the association between a marker in the dopamine D2 receptor gene (DRD2) and physical activity level in two cohorts. A first cohort consisted of 721 participants from 161 families of the Quebec Family Study (QFS). Physical activity phenotypes were obtained from a three-day diary and a questionnaire probing physical activity during the past year. The second cohort was the HERITAGE Family Study (HERITAGE), which included 275 Black and 497 White participants from 228 families, among whom past year leisure time and occupational physical activity were probed. A fragment length polymorphism in exon 6 of the DRD2 gene was detected by the polymerase chain reaction (PCR) and NcoI digestion. Frequencies for the T and C alleles were 28% and 72% in the QFS. In the QFS, TT homozygote women had 25% and 34% lower age and BMI-adjusted physical activity level during the past year, compared to CC homozygotes and CT heterozygotes (F=4.42, P=.016). The DRD2 genotype was not associated with the QFS phenotypes obtained from the three-day diary. In the HERITAGE, the frequency of the T allele was 30% among Whites and 63% among Blacks. Similarly, the TT homozygote White women had 29-38% lower sports index (F=4.09, P=.023) and 27-33% lower work index (F=6.23, P=.004) than the CC homozygotes and CT heterozygotes. The results suggest that DNA sequence variation in the DRD2 gene is associated with physical activity levels among White women.

Objective: Associations between preproghrelin DNA variants and obesity-related phenotypes were studied in 3004 subjects from the Québec Family Study (QFS), the HERITAGE Family Study (HERITAGE), and the Swedish Obese Subjects (SOS) Study., Research Methods and Procedures: Body mass index (BMI), fat mass (FM) from underwater weighing, and abdominal fat from computerized tomography were measured. The ghrelin polymorphisms were identified by polymerase chain reaction., Results: Arg51Gln QFS subjects (n = 6) had lower ghrelin concentrations (p = 0.007) than Arg51Arg subjects (n = 14). White preproghrelin Met72Met subjects in HERITAGE had the lowest BMI (p = 0.020), and those in the QFS cohort had the lowest FM (p < 0.001). Met72 carrier status (Met72+) was associated with lower FM (p = 0.026) and higher insulin-like growth factor-1 levels (p = 0.019) among blacks. Met72Met QFS subjects had less visceral fat (p = 0.002) and a lower fasting respiratory quotient (p = 0.037). HERITAGE Met72+ white subjects also showed lower exercise respiratory quotient (p = 0.030) and higher maximal oxygen uptake (p = 0.023). Furthermore, the prevalence of Met72+ was higher (19.2%; p < 0.05) in SOS subjects whose BMI was < or =25 kg/m(2) than in those with BMI >25 kg/m(2) (14.8%). SOS Met72+ obese women had a lower (11.4%; p = 0.032) prevalence of hypertension than noncarriers (23.9%)., Discussion: Arg51Gln mutation was associated with lower plasma ghrelin levels but not with obesity. The preproghrelin Met72 carrier status seems to be protective against fat accumulation and associated metabolic comorbidities.

Purpose: Familial aggregation of physical activity phenotypes was investigated in 696 subjects from 200 families of the Quebec Family Study. The mean age of offspring and parents was 27 and 53 yr, respectively., Methods: The levels of physical activity were estimated using a 3-d diary and a questionnaire dealing with physical activity during the past year., Results: An ANOVA performed on the age and sex adjusted physical activity phenotypes revealed that there were 1.40-1.52 times more variation in physical activity levels between families than within families (0.001 < P < 0.0001), suggesting that physical activity levels aggregate in families. Maximal heritabilities (SEGPATH), adjusted for the degree of spouse resemblance, reached 25%, 16%, 19%, and 17% for the degree of inactivity, time spent in moderate to strenuous physical activities, total level of daily activity, and weekly time spent in the main activity during the previous year, respectively., Conclusion: These results suggest that physical activity level is characterized by a significant degree of familial resemblance, and that inactivity has a slightly higher heritability level than moderate to strenuous physical activity or total physical activity phenotypes. The pattern of familial correlations suggests that shared familial environmental factors along with genetic factors are also important in accounting for the familial resemblance in physical activity level.