Dominique Cottel

β2-adrenoceptor gene polymorphism, body weight, and physical activity

Lipolysis activation and inhibition modulate body weight, body fat, and obesity. These metabolic pathways are influenced by environmental factors, such as physical activity, and by genetic determinants associated with sequence polymorphisms of proteins involved in lipolysis. Among these proteins, adrenergic receptors, activated by catecholamines, play a major part: b-adrenoreceptors stimulate while a2adrenoreceptors inhibit lipolysis in fat. Polymorphisms in the coding sequence of the b2-adrenoreceptor ( B A R 2 ) gene have been associated with obesity, increased body mass index (BMI) and body fat. In a large representative sample of the northern French p o p u l a t i o n , we explored the influences of the B A R 2 Gln27Glu polymorphism and of physical activity on anthropometric variables and obesity (BMI >30 kg/m) . Individuals were randomly sampled from the electoral rolls between 1995 and 1997 (n=1195), equally distributed in tenyear age groups (35 to 64 y) and by gender. For each individual, weight, height, waist and hip circumferences, and physical activity were collected. Physical activity was defined as at least 15 min walk a day, and/or lifting or carrying heavy objects at work daily, and/or doing sport or physical exercise more than 2 h a week. Genotypes for the Gln27Glu polymorphism were obtained for 1152 men and women. Individuals who were taking no medical treatments likely to interfere with body weight were selected (n=836, age=49·5 [SD 8·1] years, BMI=25·7 [4·4] kg/m). Data were analysed by multivariate covariance and logistic regression. Statistical analyses were stratified on gender and were adjusted on age and consumption of cigarettes and of alcohol. Genotype and allele frequencies were in Hardy-Weinberg equilibrium (Gln27Gln 33·1%, Gln27Glu 51·0%, and Glu27Glu 15·9%, Gln allele frequency 0·59) and were similar in men and women. A statistically significant interaction was detected between the Gln27Glu polymorphism and physical activity for body weight (p=0·009), BMI (p=0·007), waist (p=0·03) and hip (p=0·01) circumference in men, but not in women. We analysed the effect of the Gln27Glu polymorphism in men, stratified on physical activity (figure). In men who did not take physical activity (n=255), Gln27Gln men (n=91), compared with Glu27 carriers (n=164), had higher body weight (adjusted mean 83·2 [SEM 1·3] v s 7 6 · 3 [1·0] kg, p=0·0001), BMI (27·2 [0·4] v s 25·2 [0·3] kg/m, p=0·0001), waist circumference (98·7 [1·0] v s 93·2 [0·7] cm, p=0·0001), hip circumference (103·0 [0·7] v s 100·0 [0·5] cm, p=0·0007) and waist to hip ratio (0·96 [0·01] v s 0·93 [0·01], p=0·002) (figure). Conversely, no effect of the Gln27Glu polymorphism was found in men who took regular physical activity (n=165). In men taking no physical activity, the risk of obesity associated with the Gln27Gln genotype was 3·45 (95% CI 1·56–7·80, p=0·002), while this risk was not significantly increased in men who took regular physical activity (OR 1·61, 95% CI 0·67–3·87, p=0·30). We have shown that physical activity may counterbalance the effect of a genetic predisposition to increase body weight, body fat, and obesity. Obese individuals with the B A R 2 Gln27Gln genotype may benefit from physical activity to reduce their weight. Genotyping may be a useful tool to target prevention such as physical activity, to individuals that have highest benefit from it. 1 Mauriege P, Prud’homme D, Marcotte M, Yoshioka M, Tremblay A, Despres JP. Regional differences in adipose tissue metabolism between Effects of the Gln27Glu polymorphism in men according to physical activity. Statistical tests were adjusted on age, and alcohol and tobacco consumptions. Data are mean and SEM. Black bars represent Gln27Gln individuals and white bars Gln27Glu+Glu27Glu individuals.

A Functional Polymorphism in a STAT5B Site of the Human PPARγ3 Gene Promoter Affects Height and Lipid Metabolism in a French Population

Objective—The peroxisome proliferator-activated receptor-&ggr; (PPAR&ggr;) plays a role in adipocyte differentiation and insulin sensitization. It has been shown that genetic variation in the PPAR&ggr; gene alters body weight control, lipid and insulin homeostasis, and the susceptibility to type 2 diabetes. Four PPAR&ggr; isoforms are generated by alternative splicing and promoter usage. PPAR&ggr;3 is only expressed in adipose tissue, colon, and macrophages and therefore seems to be a good candidate gene for metabolic and cardiovascular-associated diseases. In the present study, we looked for genetic variation in the PPAR&ggr;3 promoter. Methods and Results—The proximal PPAR&ggr;3 promoter was sequenced in 20 individuals. We detected a C/G polymorphism at position −681 from exon A2. Interestingly, it was located in a signal transducer and activator of transcription 5B (STAT5B) binding consensus site. In a French population (n=836), the −681G allele was associated with increased height and plasma low-density lipoprotein cholesterol concentrations. In vitro, we showed that the −681G allele completely abolished the binding of STAT5B to the cognate promoter element as well as the transactivation of the PPAR&ggr;3 promoter by the growth hormone/STAT5B pathway. Conclusions—Our results suggest that PPAR&ggr;3 may regulate the control of height and lipid homeostasis via the STAT5B pathway.

Association between nutrition knowledge and nutritional intake in middle-aged men from Northern France

OBJECTIVE The way in which nutrition knowledge transforms into dietary behaviour and nutrient intake may vary among populations. Therefore, the goal of the study was to examine whether nutrition knowledge is associated with nutritional intake in middle-aged men who are at major risk of cardiovascular disease. DESIGN Cross-sectional population study aimed at comparing the response to a nutrition quiz with food habits and nutrient intake determined by a 3-day food record. SETTING Men of the Urban Community of Lille (France) examined at home. SUBJECTS 361 men aged 45-64 y, randomly selected from the electoral rolls. RESULTS Subjects were separated in a high-score and a low-score group according to their responses to the nutrition quiz. Subjects in the high-score group had better educational and higher income levels than those from the low-score group. Multivariate analysis, adjusting on educational and socio-economic levels and other confounding variables - such as age, body mass index, cigarette smoking, physical activity and energy intake underreporting - showed that subjects in the high-score group were more often consumers of olive oil (36 vs. 12%; ), cheese (85 vs. 76%; or cereals (27 vs. 15%; and less often consumers of sunflower oil (51 vs. 68%; or dry vegetables (12 vs. 22%; than those in the low-score group. Subjects in the high-score group had lower intakes of fat vs. and especially of monounsaturated fat of animal origin vs. than individuals in the low-score group. CONCLUSION Nutrition quiz score is associated with specific patterns of food choices and nutrient intake suggesting that nutrition knowledge influences dietary behaviour in middle-aged men from Northern France.

The deletion allele of the angiotensin I converting enzyme gene as a genetic susceptibility factor for cognitive impairment

Experimental evidences suggest an implication of the renin angiotensin system (RAS) as a potential determinant of cognitive functions. To explore this hypothesis, we compared the distribution of an insertion (I)/deletion (D) polymorphism of the gene coding for the angiotensin I converting enzyme (ACE), a key enzyme of the RAS, in 228 elderly with cognitive impairment to that of 255 controls. The ACE D allele frequency was higher in the group with cognitive impairment (0.594) than in controls (0.514) (P < 0.02). The ACE DD genotype carriers had an increased risk of cognitive impairment (OR = 1.60, 95% CI (1.04-2.36), P < 0.03), independent of other risk factors of cognitive impairment: age, gender and presence of the apolipoprotein E epsilon 4 allele. This association was stronger in men (OR = 3.25, 95% CI (1.40-7.58), P < 0.006). This result suggests a possible implication of the RAS in human brain and cognitive functions.

Effect of an FTO polymorphism on fat mass, obesity, and type 2 diabetes mellitus in the French MONICA Study

We investigated the association between the rs9939609 (T>A) polymorphism in the FTO (fat mass- and obesity-associated) gene and obesity- and type 2 diabetes mellitus-related phenotypes in the French Multinational MONItoring of Trends and Determinants in CArdiovascular Disease (MONICA) Study (n = 3367). In the study, TA or AA subjects had higher body mass index (BMI) (P = .017), waist circumference (P = .017), and hip (P = .01) circumference in an A allele dose-dependent manner. The A allele was also significantly associated with higher plasma insulin levels (P = .05), higher insulin resistance index (homeostasis model assessment) (P = .02), and higher systolic blood pressure (P = .003); but these associations disappeared after adjustment for BMI. In the study, 598 subjects were obese (BMI >or=30 kg/m(2)); and 2769 subjects were not obese (BMI <30 kg/m(2)). Subjects bearing the A allele of rs9939609 had a higher risk of obesity (adjusted odds ratio [95% confidence interval] = 1.29 [1.06-1.58], P = .01) compared with TT subjects. Moreover, the homozygous AA genotype of rs9939609 was associated with a higher risk of type 2 diabetes mellitus (odds ratio = 1.45 [1.05-1.99], P = .02, 283 subjects with and 2601 subjects without type 2 diabetes mellitus), independently of BMI. In conclusion, the role of the A allele of the FTO rs9939609 polymorphism on the risk of obesity and type 2 diabetes mellitus was confirmed in the French MONICA Study.

Association between coding variability in the LRP gene and the risk of late-onset Alzheimer's disease.

Abstract We have sequenced the entire (89 exons) open reading frame of the LRP gene in 12 cases of Alzheimer’s disease (AD) from Northern France. We have found no novel changes but confirm the occurrence of a polymorphism in exon 6 of the gene (A216V). This polymorphism is rare (2.8% of controls) and is in linkage equilibrium with previously reported polymorphisms. The V216 allele is negatively associated with the disease in a large case-controlled series. These data suggest that the LRP receptor may be involved in the pathobiology of AD, but the association that we report here cannot explain the previously reported genetic data implicating the LRP gene in AD. If the LRP gene is a major site of genetic variability leading to AD, there must be other biologically relevant variability in promoter or other regulatory elements of this large gene.

Trends in plasma lipids, lipoproteins and dyslipidaemias in French adults, 1996–2007

BACKGROUND In France, the reported decrease in cardiovascular death is due partly to improved cardiovascular prevention. The management of dyslipidaemias remains a priority of preventive cardiology. AIM To assess trends in lipids, lipoproteins and dyslipidaemias between 1996 and 2007 in France. METHODS Representative surveys of the general population were carried out in Lille, Strasbourg and Toulouse during two periods, 1996 to 1997 and 2006 to 2007. Men and women aged 35 to 64 years were included. Investigators recorded cardiovascular risk factors, and a blood sample was drawn to measure glycaemia and to provide a complete lipid profile. The data were corrected according to the respective original populations to study 10-year trends in the parameters measured. RESULTS From 1996 to 2007, a significant 5.7% decrease in low-density lipoprotein (LDL)-cholesterol levels was observed in adults aged 35 to 64 years (p<0.001). This decrease was greater in those aged 55 to 64 years (10.8% in men, 8.4% in women). A significant 7.8% increase in triglycerides was observed (p<0.001) over the same period. Variation in LDL-cholesterol was more striking in subjects treated with a lipid-lowering drug, with a 17.6% reduction (p<0.001). A decrease in most of dyslipidaemias was also observed over this 10-year interval. CONCLUSION This study shows a favourable downward trend in LDL-cholesterol concentration and dyslipidaemias in France. The significant decrease in LDL-cholesterol observed among all the subjects and more particularly among subjects treated with lipid-lowering drugs should provide an incentive for physicians to support the management of all French adults.

Association of plasma Aß peptides with blood pressure in the elderly

Background Aß peptides are often considered as catabolic by-products of the amyloid ß protein precursor (APP), with unknown physiological functions. However, several biological properties have been tentatively attributed to these peptides, including a role in vasomotion. We assess whether plasma Aß peptide levels might be associated with systolic and diastolic blood pressure values (SBP and DBP, respectively). Methodology/Principal Findings Plasma Aß1-40 and Aß1-42 levels were measured using an xMAP-based assay in 1,972 individuals (none of whom were taking antihypertensive drugs) from 3 independent studies: the French population-based 3C and MONA-LISA (Lille) studies (n = 627 and n = 769, respectively) and the Australian, longitudinal AIBL study (n = 576). In the combined sample, the Aß1-42/ Aß1-40 ratio was significantly and inversely associated with SBP (p = 0.03) and a similar trend was observed for DBP (p = 0.06). Using the median age (69) as a cut-off, the Aß1-42/Aß1-40 ratio was strongly associated with both SBP and DBP in elderly individuals (p = 0.002 and p = 0.03, respectively). Consistently, a high Aß1-42/ Aß1-40 ratio was associated with a lower risk of hypertension in both the combined whole sample (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.56-0.90) and (to an even greater extent) in the elderly subjects (OR, 0.53; 95% CI, 0.37–0.75). Lastly, all these associations appeared to be primarily driven by the level of plasma Aß1-40. Conclusion The plasma Aß1-42/Aß1-40 ratio is inversely associated with SBP, DBP and the risk of hypertension in elderly subjects, suggesting that Aß peptides affect blood pressure in vivo. These results may be particularly relevant in Alzheimers disease, in which a high Aß1-42/Aß1-40 plasma ratio is reportedly associated with a decreased risk of incident disease.

The Association of Metabolic Disorders with the Metabolic Syndrome Is Different in Men and Women

Aims: Metabolic disorders depend on genetic, hormonal and environmental factors, whose relations may differ between genders. Therefore, we compared the contribution of metabolic disorders to the metabolic syndrome in women and men. Methods: To this end, we used a hierarchical classification statistical method to classify subjects into similarity groups according to clinical and biological parameters. Data were collected from 3,508 men and women aged 35–64 years, from a cardiovascular disease survey. Results: In both women and men, hierarchical classification identified a cluster corresponding to the metabolic syndrome representing 14 and 15% of the women’s and men’s sample, respectively. In women, elevated body weight (women’s Z-score: 1.59 vs. men’s Z-score: 1.29; p < 0.005), waist girth (1.62 vs. 1.30; p < 0.001) and low HDL cholesterol (–0.95 vs. –0.75; p < 0.05) were significantly larger contributors to the metabolic syndrome than in men. In contrast, systolic (0.59 vs. 0.95; p < 0.0001) and diastolic (0.55 vs. 0.99; p < 0.0001) blood pressure and apolipoprotein B (0.51 vs. 0.71; p < 0.0001) contributed significantly less in women than in men. Finally, insulin (n.s.), glucose (n.s.), triglycerides (n.s.) and LDL-cholesterol (n.s.) contributions were not different between genders. Conclusion: These results are consistent with the concept that a clustering of metabolic disorders occurs frequently in both women and men. However, the contribution of several metabolic disorders to the metabolic syndrome is different in men and women. This finding supports the concept that different criteria are necessary to define the metabolic syndrome in women and men.

Types of alcoholic beverages and blood lipids in a French population

Study objective: Prospective studies have shown a consistent relation between alcohol consumption and decreasing incidence of coronary artery disease. The protective effect of alcohol could be mediated through increased levels of HDL cholesterol (HDL-c). The aim of this study was to examine the relation between blood lipid levels and the consumption of different types of alcoholic beverages among 1581 men and 1535 women. Design: Data from representative cross sectional surveys (1994–1997) in three different regions of France were used. The consumption of the different types of alcohol was quantified using a recall method according to a typical weekly consumption. Main results: The median daily alcohol intake was 24 g for men and 4 g for women. After adjustment for confounders, total alcohol showed a positive and significant association with HDL-c and triglycerides (TG) in both sexes. In multivariate analysis, wine was positively associated with HDL-c. Beer was positively associated with HDL-c in men and with triglycerides in men and women. When taking drinking patterns into account, wine drinkers had higher HDL-c levels than non-wine drinkers. Differences became non-significant after adjustment for confounders and particularly for socioeconomic parameters. Conclusions: In a French population sample, total alcohol was positively associated with HDL-c and triglycerides. The specific influence of any particular alcoholic beverage on blood lipids was not clearly demonstrated but wine preference found in a group with higher lifestyle standards was associated with a more favourable blood lipid profile.