Showing papers by "Claude Bouchard published in 2006"

The human obesity gene map: the 2005 update.

Abstract: This paper presents the 12th update of the human obesity gene map, which incorporates published results up to the end of October 2005. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTL) from animal cross-breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2005, 176 human obesity cases due to single-gene mutations in 11 different genes have been reported, 50 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 244 genes that, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 408. The number of human obesity QTLs derived from genome scans continues to grow, and we now have 253 QTLs for obesity-related phenotypes from 61 genome-wide scans. A total of 52 genomic regions harbor QTLs supported by two or more studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably, with 426 findings of positive associations with 127 candidate genes. A promising observation is that 22 genes are each supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. The electronic version of the map with links to useful publications and relevant sites can be found at http://obesitygene.pbrc.edu.

Physical Activity and Health

Abstract: Chapter 1 Why Study Physical Activity and Health? Chapter 4 Sedentary Behaviour and Inactivity Physiology Chapter 8 Skeletal Muscle Adaptation to Regular Physical Activity Chapter 17 Physical Activity, Fitness, and Children Chapter 23 From Science to Physical Activity Guidelines Chapter 25 An Integrated View of Physical Activity, Fitness and Health Index.

Genetics of Food Intake and Eating Behavior Phenotypes in Humans

Abstract: This review summarizes the research advances of the past decade regarding the role of human genetic differences in energy and nutrient intake as well as in eating behavior phenotypes and selected eating disorders. The evidence for familial aggregation and heritability based on twin and nuclear family study designs is summarized. Genome-wide linkage scans and quantitative trait loci identified to date are discussed. DNA sequence variants in candidate genes are reviewed. Single genes associated with classical eating disorders are also incorporated. Epigenetic events will need to be incorporated in future studies designed to investigate the effects of DNA variants on dietary phenotypes. Understanding the relative contribution of global genetic variation and of DNA sequence variants in specific genes is important in the effort to influence dietary habits in a healthier direction.

Common Polymorphisms in the Promoter of the Visfatin Gene (PBEF1) Influence Plasma Insulin Levels in a French-Canadian Population

Abstract: 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 Quebec. 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 ≤ 0.02). In addition, a more distal SNP (rs7789066) was significantly associated with the apolipoprotein B component of VLDL ( P = 0.012).

Heart rate recovery after maximal exercise is associated with acetylcholine receptor M2 (CHRM2) gene polymorphism

Abstract: The determinants of heart rate (HR) recovery after exercise are not well known, although attenuated HR recovery is associated with an increased risk of cardiovascular mortality. Because acetylcholi...

Spouse Resemblance in Body Mass Index: Effects on Adult Obesity Prevalence in the Offspring Generation

Abstract: Accruing evidence indicates that mate selection is promoted by similarity in body fatness. Assortative mating for obesity may contribute genetically to the obesity epidemic by increasing the risk in subsequent generations. To test this hypothesis, the authors analyzed measured and validated questionnaire data on family members, obtained between 1987 and 2000 from 7,834 obese probands and from 829 subjects randomly ascertained from the general Swedish population. Spouse correlations in body mass index were strongest among couples with the shortest duration of cohabitation. Obesity concordance in parents was associated with an obesity prevalence of 20.1% in adult offspring compared with 1.4% if parents were concordantly nonobese (odds ratio ¼ 18.3, 95% confidence interval: 9.0, 37.4). The prevalence was 8.2% if parents were obesity discordant (odds ratio ¼ 6.5, 95% confidence interval: 3.2, 13.2). No association was found between rearing parents’ and nonbiologic offspring’s body mass index. These results agree with the hypothesis that assortative mating for obesity confers a higher risk of obesity in the offspring generation and thus contributes to the obesity epidemic. Parental obesity concordance is a strong, easily identifiable genetic risk factor that should be considered in the complex network of risk factors for obesity in designing primary prevention programs. body mass index; genetic screening; genetics, population; marriage; obesity; spouses

Effect of regular exercise on homocysteine concentrations: the HERITAGE Family Study.

Abstract: We investigated whether regular aerobic exercise could affect plasma total homocysteine (tHcy), and whether there were sex-related or racial differences in tHcy changes. Data were available for 816 black and white men and women, aged 17-65 years, 711 of whom completed a 20 week aerobic exercise training program. The tHcy concentration was measured in frozen plasma samples by an HPLC method. In Blacks, tHcy did not change with exercise training [men -0.5 (SD 3.7) micromol/l, women 0.0 (2.2) micromol/l) but increased significantly in Whites (men +0.3 (1.7) micromol/l, women +0.2 (1.6) micromol/l). No sex-related differences were found in either racial group. Changes in tHcy correlated negatively with baseline homocysteine (r = -0.40, P or=15 micromol/l) group (n = 30) decreased significantly with regular aerobic exercise from 23.1 (12.1) to 19.6 (7.6) micromol/l. Homocysteine levels of the "Normal" group increased slightly from 8.2 +/- 2.2 to 8.5 +/- 2.4 micromol/l. Men exhibit racial differences for tHcy responses to exercise training. Regular aerobic exercise has favorable effects on individuals with hyperhomocysteinemia, but tHcy slightly increased in individuals within the normal range.

Increased Abdominal Obesity in Subjects with a Mutation in the 5‐HT2A Receptor Gene Promoter

Abstract: In the present study, we examined the potential impact of the 5-HT(2A) -1438G/A promoter polymorphism on obesity and estimates of insulin, glucose, and lipid metabolism as well as circulating hormones, including salivary cortisol, in 284 unrelated Swedish men born in 1944. The subjects were genotyped by using PCR amplification of the promoter region of the gene for 5-HT(2A) followed by digestion with the restriction enzyme MspI. The frequencies were 0.39 for allele -1438A and 0.61 for allele -1438G. Homozygotes for the -1438G allele had, in comparison with -1438A/A subjects, higher body mass index (BMI), waist-to-hip ratio (WHR), and abdominal sagittal diameter. Moreover, cortisol escape from 0.25 mg dexamethasone suppression was found in subjects with the -1438A/G genotype. Serum leptin, fasting insulin and glucose, as well as serum lipids were not different across the -1438G/A genotype groups. From these results, we suggest the possibility that an abnormal production rate of the 5-HT(2A) gene product might lead to the development of abdominal obesity. The pathophysiology could involve stress factors that destabilize the serotonin-hypothalamic-pituitary-adrenal systems in those with genetic vulnerability in the serotonin receptor gene.

Polymorphisms in the leptin and leptin receptor genes in relation to resting metabolic rate and respiratory quotient in the Québec Family Study

Abstract: Leptin (LEP) is an endocrine hormone that participates in many metabolic pathways, including those associated with the central regulation of energy homeostasis. We examined the associations between polymorphisms in the LEP and leptin receptor (LEPR) genes and resting metabolic rate (RMR) and respiratory quotient (RQ) in the Quebec Family Study. Three polymorphisms in LEPR (K109R, Q223R and K656N) and one in LEP (19A>G) were genotyped in 678 subjects. RMR, RQ at rest and RQ while sitting, standing and walking at 4.5 km/h (RQ45) were adjusted for age, sex, fat mass and fat-free mass. RQ45 was associated with the LEPR-K109R (P=0.004) and Q223R (P=0.03) polymorphisms, and RMR showed association with the LEPR-K656N polymorphism (P=0.006). For the LEP-19A>G polymorphism, no significant associations were observed. However, LEP-A19A homozygotes who were carriers of the LEPR N656 allele had a significantly lower RQ45 compared to other genotype combinations (P for interaction=0.003). These findings suggest that DNA sequence variation in the LEPR gene contributes to human variation in RMR and in the relative rates of substrate oxidation during low-intensity exercise in steady state but not in a resting state.

Greater than predicted decrease in resting energy expenditure with age: cross-sectional and longitudinal evidence.

Abstract: Greater than predicted decrease in resting energy expenditure with age: cross-sectional and longitudinal evidence

Muscle adiposity and body fat distribution in type 1 and type 2 diabetes: varying relationships according to diabetes type.

Abstract: OBJECTIVE : To compare the relationships between markers of total and regional adiposity with muscle fat infiltration in type 1 diabetic and type 2 diabetic subjects and their respective nondiabetic controls, and to document these relationships in type 1 diabetic subjects. DESIGN : Cross-sectional study. SUBJECTS : In total, 86 healthy, with type 1 diabetes, type 2 diabetes or control subjects. Each diabetic group was matched for age, sex and body mass index with its respective nondiabetic (...)

A Quantitative Trait Locus for Body Fat on Chromosome 1q43 in French Canadians: Linkage and Association Studies

Abstract: 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 ≤ 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.

Ethnic Differences in Body Composition and Other Markers of Cardiovascular Disease Risk: Study in Matched Haitian and White Subjects from Quebec

Abstract: 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.

Pleiotropic QTL on Chromosome 12q23–q24 Influences Triglyceride and High-Density Lipoprotein Cholesterol Levels: The HERITAGE Family Study

Abstract: To determine whether a common quantitative trait locus (QTL) influences the variation of fasting triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels, we used a bivariate multipoint linkage analysis with 654 polymorphic markers in 99 white and 101 black families. The phenotypes were investigated under two conditions: at baseline and after a 20-week exercise training intervention. A maximum genome-wide bivariate LOD score of 3.0 (p = 0.00010) was found on chromosome 12q23-q24, located within the IGF1 gene (insulin-like growth factor 1, at 107 cM) for TG and HDL-C at baseline in whites. This bivariate linkage peak is considerably higher than the univariate linkage results at the same chromosome location for either trait (for TG, LOD = 2.07, p = 0.00108; for HDL-C, LOD = 2.04, p = 0.00101). The genetic correlations between baseline TG and HDL-C levels were -0.14 for the residual and -0.33 for the QTL components. Moreover, association analysis showed that TG, HDL-C, and IGF1 are significantly associated (p = 0.04). In conclusion, these results suggest that a QTL on chromosome 12q23-q24 influences the variation of plasma TG and HDL-C levels. Further investigation should confirm whether IGF1 or another nearby gene is responsible for the concomitant variation in TG and HDL-C levels.

Association between a Variant at the GABAAα6 Receptor Subunit Gene, Abdominal Obesity, and Cortisol Secretion

Abstract: In the present study, we examined the potential impact of a T-to-C substitution at nucleotide 1519 of the GABA(A)alpha6 receptor subunit gene (GABRA6) on obesity and obesity-related phenotypes as well as circulating hormones, including salivary cortisol, in 284 unrelated Swedish men born in 1944. The subjects were genotyped by using PCR amplification followed by digestion with the restriction enzyme AlwNI. The frequency of allele T was 0.54 and that of allele C was 0.46. Carriers for the T allele (n = 211) had higher waist-to-hip ratio (p = 0.094) and abdominal sagittal diameter (p = 0.084) compared to homozygotes for the C allele (n = 56). The homozygotes for the T allele had, in comparison to heterozygotes, significantly (p = 0.004-0.024) higher mean cortisol levels at 11:45 am; at 30, 45, and 60 min after a standardized lunch; and finally at 5:00 pm. In addition, T/T subjects had significantly (p = 0.031) higher diurnal cortisol secretion compared to T/C subjects. Leptin, insulin, and glucose were not different across the genotype groups. In conclusion, these findings suggest a role of the point substitution (T-to-C) at nucleotide 1519 of GABRA6 in the predisposition to hypercortisolism and perhaps abdominal obesity. The pathophysiology may involve various environmental factors, particularly stress, that destabilize the GABA-hypothalamic-pituitary-adrenal systems in those with genetic vulnerability.

Quantitative trait locus on chromosome 20q13 for plasma levels of C-reactive protein in healthy whites: the HERITAGE Family Study.

Abstract: C-reactive protein (CRP) is a sensitive marker of systemic low-grade inflammation. Increased plasma levels of CRP predict the risk of cardiovascular and metabolic diseases. Although genetic factors...

Are People Physically Inactive Because of Their Genes

Abstract: Research indicates that the inclination to be physically active or sedentary has a biological foundation. Twin and family studies confi rm that physical activityrelated traits are characterized by familial aggregation and infl uenced by genetic factors. Results from animal model studies indicate that single genes can markedly infl uence physical activity-related behavior. The fi rst molecular genetic studies on physical activity traits in humans have been published during the last few years. They support the notion that it is possible to detect relatively small, yet biologically important genetic effects impacting the tendency to be sedentary or habitual physical activity at the molecular level. We are beginning to appreciate that in utero environment and epigenetic events may play a role in postnatal physiology and behavior but their impact on physical inactivity or physical activity level remains to be determined. The complete article appears in the June 2006 issue of the President s Council on Physical Fitness and Sports Research Digest. The Research Digest is published four times a year and includes manuscripts related to physical activity and health. Articles are available free through the Presidentʼs Council on Physical Fitness and Sports at http://www.fi tness.gov/pcpfs_research_digs.htm

Scaling submaximal exercise cardiac output and stroke volume: the HERITAGE Family Study.

Abstract: This study investigated different methods of scaling submaximal cardiac output (Q) and stroke volume (SV) to best normalize for body size (body surface area [BSA], height [Ht], weight [Wt], and fat-free mass [FFM]). Q and SV were measured at both an absolute (50 W) and a relative power output (60 % of VO2max) in 337 men and 422 women, 17 to 65 years of age. Traditional ratio scaling was examined in addition to allometric scaling, where scaling exponents ( B) were determined for each body size variable (x) that best normalized the physiological outcome variables (y) for body size (y = ax(b)). With ratio scaling, regardless of the body size variable (x = BSA, Ht, Wt, FFM), there was no evidence of a linear relationship between x and y (y = Q or SV). A linear relationship is a necessary condition for appropriate normalization. Further, when ratio-scaled variables (e.g., Q/BSA) were correlated to the body size variable (e.g., BSA) by which they were scaled, significant (p

Genome-wide scan to identify quantitative trait loci for baseline resting heart rate and its response to endurance exercise training: the HERITAGE Family Study.

Abstract: Evidence of a genetic component for resting heart rate (RHR) has been found. Quantitative trait loci (QTLs) for baseline RHR have been reported, but not for RHR training response. It is of interest to identify QTLs that may harbor genes influencing RHR variation at baseline and in response to regular exercise training. Here, a multipoint variance components linkage scan using 654 markers was performed to search for QTLs that influence RHR adjusted for several covariates at baseline and in response to 20 weeks of endurance training (post-training minus baseline) in 99 White and 127 Black families in the HERITAGE Family Study. Potentially interesting linkages were revealed on 4q and 11 p for baseline RHR, and on 1 q and 21 q for RHR training response in Whites. The QTLs on 2q, 6q, 7q, 12 q,14q, and 15 q for baseline RHR, and on 3 p, 20 p and 21 q for RHR training response were found in Blacks. Promising linkages (lod scores >1.75, p≤0.0023) involved 11 p for baseline RHR in Whites and 3 p for RHR training response in Blacks, which did not replicate across races. Interestingly in this study, the linkage evidence on 11 p at the SUR locus was somewhat enhanced (lod score went up from 1.7 to 2.0) in a prehypertensive (BP ≥ 135/80 mm Hg) subset of 40 White families suggesting a pleiotropic gene for BP and RHR with interactions. In conclusion, among QTLs on 1 q, 2 p, 3 p, 4 q, and 11 p that replicated across subsamples and studies, 11 p is most promising for dense mapping and association studies in HERITAGE and other cohorts.

Exercise and inflammation: reply

Abstract: Our recent report from the HERITAGE Family Study showed that moderate to high-intensity exercise training reduced plasma levels of C-reactive protein, an important pro-inflammatory biomarker, in sedentary healthy adults with initial C-reactive protein levels >3.0 mg/L.1 This finding is potentially important from both a public health and a clinical point of view, because individuals with C-reactive protein >3.0 mg/L represent about one-fourth of all adults and are thought to have a markedly increased risk of cardiovascular disease and type-2 diabetes. A number of studies with different designs support the view that regular physical activity suppresses the inflammatory …