Vanessa Legry

Attenuation of the effect of the FTO rs9939609 polymorphism on total and central body fat by physical activity in adolescents: the HELENA study.

OBJECTIVE To examine whether physical activity attenuates the effect of the FTO rs9939609 polymorphism on body fat estimates in adolescents. DESIGN Cross-sectional study. SETTING Athens, Greece; Dortmund, Germany; Ghent, Belgium; Heraklion, Greece; Lille, France; Pécs, Hungary; Rome, Italy; Stockholm, Sweden; Vienna, Austria; and Zaragoza, Spain, from October 2006 to December 2007. PARTICIPANTS Adolescents from the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study (n = 752). MAIN EXPOSURE Physical activity. MAIN OUTCOME MEASURES The FTO rs9939609 polymorphism was genotyped. Physical activity was assessed by accelerometry. We measured weight, height, waist circumference, and triceps and subscapular skinfolds; body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]) and body fat percentage were calculated. RESULTS The A allele of the FTO polymorphism was significantly associated with higher BMI (+0.42 per risk allele), higher body fat percentage (+1.03% per risk allele), and higher waist circumference (+0.85 cm per risk allele). We detected significant or borderline gene x physical activity interactions for the studied body fat estimates (for interaction, P = .02, .06, and .10 for BMI, body fat percentage, and waist circumference, respectively). Indeed, the effect of the FTO rs9939609 polymorphism on these body fat parameters was much lower in adolescents who met the daily physical activity recommendations (ie, >/=60 min/d of moderate to vigorous physical activity) compared with those who did not: +0.17 vs +0.65 per risk allele in BMI, respectively; +0.40% vs +1.70% per risk allele in body fat percentage, respectively; and +0.60 vs +1.15 cm per risk allele in waist circumference, respectively. CONCLUSION Adolescents meeting the daily physical activity recommendations may overcome the effect of the FTO rs9939609 polymorphism on obesity-related traits.

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.

Single-nucleotide polymorphism of CD36 locus and obesity in european adolescents.

CD36 is a membrane receptor with a wide variety of functions, including the regulation of energy metabolism, fat storage, and adipocyte differentiation. To assess the relationship between CD36 gene single‐nucleotide polymorphisms (SNPs) and obesity in adolescents, we evaluated the relationship between CD36 SNPs and the risk of obesity in a case–control study composed of 307 obese (age = 15.0 ± 1.1 years) and 339 normal‐weight adolescents (age = 14.6 ± 1.1 years). To validate the results, we assessed the relation between the same SNPs and percentage of body fat (BF%) and BMI in 1,151 European adolescents (age = 14.8 ± 1.4 years). SNPs with a minor allele frequency >0.10 were selected to tag CD36. Genotyping was performed on an Illumina system. Four SNPs (rs3211867, rs3211883, rs3211908, and rs1527483) were associated with increased risk of obesity in the case–control study (odds ratio (OR) (95% confidence interval)): 1.96 (1.26–3.04], P = 0.003; 1.73 (1.16–2.59), P = 0.007; 2.42 (1.47–4.01), P = 0.0005 and 1.95 (1.25–3.05), P = 0.003, respectively). The same four SNPs were associated with higher BMI (P < 0.05) and BF% (P < 0.04) in the validation study. Further analyses identified a haplotype (frequency: 0.05) carrying the minor allele of these SNPs as being associated with obesity (OR: 2.28; P = 0.0008) in the case–control study and with excess adiposity (i.e., higher BF% (P = 0.03) and BMI (P = 0.04)) in the validation study. Our data suggest that genetic variability at the CD36 gene locus could be associated with body weight variability in European adolescents but these findings require replication.

Association between liver X receptor alpha gene polymorphisms and risk of metabolic syndrome in French populations

Context:The metabolic syndrome is a complex and multifactorial disorder often associated with type 2 diabetes mellitus and cardiovascular diseases. The liver X receptor α (NR1H3) plays numerous roles in metabolic pathways involved in metabolic syndrome.Objective:In the search for susceptibility genes to metabolic syndrome, we hypothesized that common genetic variation in NR1H3 gene influences metabolic syndrome susceptibility.Design:Two large French population-based studies (n=1130 and 1160) including overall 664 individuals with and 1626 individuals without metabolic syndrome were genotyped for three polymorphisms (rs12221497, rs11039155 and rs2279239) of NR1H3.Results:We found that the −6A allele of rs11039155 was consistently associated with a 30% reduction in risk of metabolic syndrome in the two independent population samples (adjusted OR (95% CI)=0.68 (0.53–0.86), P=0.001 for the combined sample). Moreover, it was associated with an increase in plasma HDL-cholesterol concentrations (P=0.02 for the combined sample). Neither rs12221497 nor rs11039155, both polymorphisms located in the 5′ region of NR1H3, had significant influence on NR1H3 and ATP-binding cassette transporter A1 (ABCA1) gene expression in primary human macrophages.Conclusions:These results suggest that NR1H3 plays an important role in the HDL-cholesterol metabolism and in the genetic susceptibility to metabolic syndrome.

Age- and Sex-Specific Causal Effects of Adiposity on Cardiovascular Risk Factors

Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10−107) and stratified analyses (all P < 3.3 × 10−30). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.

Associations between common genetic polymorphisms in angiopoietin-like proteins 3 and 4 and lipid metabolism and adiposity in European adolescents and adults

CONTEXT Plasma-borne angiopoietin-like proteins (ANGPTL) act as endocrine factors on their target tissues. Because ANGPTL3 and ANGPTL4 play important roles in lipid metabolism and the regulation of adiposity in mice, we hypothesized that genetic variability at the ANGPTL3 and ANGPTL4 genes loci might influence lipid metabolism and fat deposition in humans. OBJECTIVE The aim of the study was to examine the association between ANGPTL3 and ANGPTL4 genetic polymorphisms and metabolic phenotypes in adolescent and adult samples. DESIGN AND PARTICIPANTS Two independent population-based studies, one composed of 1144 adolescents (mean age, 14.8 +/- 1.4 yr) from nine European countries (the HELENA study) and the other composed of 1155 adults (age range, 35-65 yr) from Northern France (the MONICA Lille study), were genotyped for one ANGPTL3 polymorphism and four ANGPTL4 polymorphisms. RESULTS The ANGPTL3 rs11207997 polymorphism (minor allele frequency, 0.32) was associated with lower plasma HDL-cholesterol and apolipoprotein A-I levels in both adolescents (P = 0.0004, P = 0.00006, respectively) and adults (P = 0.03, P = 0.02, respectively). The ANGPTL4 rs4076317 polymorphism (minor allele frequency, 0.29) was associated with a higher percentage of body fat (P = 0.02) in adolescents and a higher waist-to-hip ratio (in interaction with the peroxisome proliferator-activated receptor gamma Pro12Ala polymorphism) in adults (P = 0.0004). CONCLUSION The present study underlines the role of ANGPTL3 in HDL-cholesterol metabolism as early as in adolescence. Our data also suggest possible associations between ANGPTL4 polymorphisms and body fat, but these findings require replication.

Suggestive evidence of associations between liver X receptor β polymorphisms with type 2 diabetes mellitus and obesity in three cohort studies: HUNT2 (Norway), MONICA (France) and HELENA (Europe)

BackgroundThe liver X receptors (LXR) α and β regulate lipid and carbohydrate homeostasis and inflammation. Lxrβ-/-mice are glucose intolerant and at the same time lean. We aimed to assess the associations between single nucleotide polymorphisms (SNPs) in LXRβ and risk of type 2 diabetes mellitus (T2DM), obesity and related traits in 3 separate cohort studies.MethodsTwenty LXRβ SNPs were identified by sequencing and genotyped in the HUNT2 adult nested case-control study for T2DM (n = 835 cases/1986 controls). Five tag-SNPs (rs17373080, rs2695121, rs56151148, rs2303044 and rs3219281), covering 99.3% of the entire common genetic variability of the LXRβ gene were identified and genotyped in the French MONICA adult study (n = 2318) and the European adolescent HELENA cross-sectional study (n = 1144). In silico and in vitro functionality studies were performed.ResultsWe identified suggestive or significant associations between rs17373080 and the risk of (i) T2DM in HUNT2 (OR = 0.82, p = 0.03), (ii) obesity in MONICA (OR = 1.26, p = 0.05) and (iii) overweight/obesity in HELENA (OR = 1.59, p = 0.002). An intron 4 SNP (rs28514894, a perfect proxy for rs17373080) could potentially create binding sites for hepatic nuclear factor 4 alpha (HNF4α) and nuclear factor 1 (NF1). The C allele of rs28514894 was associated with ~1.25-fold higher human LXRβ basal promoter activity in vitro. However, no differences between alleles in terms of DNA binding and reporter gene transactivation by HNF4α or NF1 were observed.ConclusionsOur results suggest that rs17373080 in LXRβ is associated with T2DM and obesity, maybe via altered LXRβ expression.

Associations between common genetic polymorphisms in the liver X receptor alpha and its target genes with the serum HDL-cholesterol concentration in adolescents of the HELENA Study

OBJECTIVE Genetic variability in the NR1H3 gene (encoding LXRα) and in several of its target genes is associated with serum HDL-cholesterol (HDL-C) concentrations. We sought to assess if these associations could be detected in adolescents. METHODS Thirty-nine polymorphisms in NR1H3, ABCA1, APOE, CETP, PLTP and LPL were analysed in the HELENA study (n = 1144 European adolescents). RESULTS The minor alleles of rs11039155 in NR1H3, rs2575879 in ABCA1, rs708272, rs17231506 and rs5882 in CETP and rs328 in LPL were associated with higher serum HDL-C concentrations (p ≤ 0.0012). The minor alleles of rs12221497 in NR1H3, rs1800978 in ABCA1 and the APOE ɛ4 allele were associated with lower HDL-C concentrations (p ≤ 0.01). The combined set of associated polymorphisms accounted for ∼6.6% of the variance in HDL-C. CONCLUSION We report for the first time that polymorphisms in NR1H3 and its target genes ABCA1, APOE, CETP and LPL contribute to the genetic variance for HDL-C concentrations in adolescence.

Association Between a Thyroid Hormone Receptor-α Gene Polymorphism and Blood Pressure but Not With Coronary Heart Disease Risk

BACKGROUND Thyroid hormones (THs) exert multiple biological roles including effects on the cardiovascular system (lipid profile, blood pressure (BP) and cardiac output). The lipid-lowering actions of TH are mediated by the TH receptor-β whereas the mechanisms explaining the BP variations concomitant with the thyroid disorders are less understood. As the TH receptor-α (TR-α) has been associated with many of TH actions on the cardiovascular system in mice models, we hypothesized that it could be involved in the latter. We thus tested whether polymorphisms in TR-α (THRA gene) could be associated with BP level variation. Secondarily, we tested for association with coronary heart disease (CHD) risk. METHODS We analyzed the associations between five THRA polymorphisms and (i) BP level in two population-based studies (MONICA Lille n = 1,155; MONICA Toulouse n = 1,170) and (ii) the risk of CHD in two case-control studies (Lille CHD n = 558 cases/568 controls; PRIME n = 527 cases/584 controls). RESULTS Individuals carrying the rs939348 T allele had higher systolic BP (~+1.3 mm Hg) than CC individuals in both the MONICA Lille (P = 0.02) and Toulouse (P = 0.03) studies. The odds ratio (OR) for hypertension was 1.25 (P = 0.02) in the combined sample. Concerning the CHD risk, no significant association could be detected. CONCLUSIONS For the first time, our study showed associations between the THRA rs939348 polymorphism and systolic BP and the risk of hypertension but not with CHD, although we admit that the statistical power available to study any relationship with CHD was very limited. Further larger association studies are needed to confirm our findings.

Association between angiopoietin-like 6 (ANGPTL6) gene polymorphisms and metabolic syndrome-related phenotypes in the French MONICA Study

AIM Although the ANGPTL6 (angiopoietin-like 6) gene product is now known to be involved in the regulation of fat mass and insulin sensitivity in mice, its physiological functions in humans have yet to be determined. METHODS Subjects from the population-based French MONICA Study (n=3402) were genotyped for single nucleotide polymorphisms (SNPs) in ANGPTL6, and associations with anthropometric or biochemical phenotypes were looked for. RESULTS On evaluating the frequency of 17 ANGPTL6 SNPs in 100 randomly selected subjects on the basis of linkage disequilibrium mapping, four SNPs (rs6511435, rs8112063, rs11671983 and rs15723) were found to cover more than 95% of the known ANGPTL6 genetic variability. Subjects from the entire MONICA Study were then genotyped for these four SNPs. No significant association was detected for rs11671983 and rs15723. In contrast, the G allele of rs8112063 was associated with lower plasma glucose levels (P=0.009). Also, obese subjects carrying the G allele of rs6511435 had higher plasma insulin levels than AA subjects (P=0.0055). Moreover, the G allele of rs6511435 tended to be associated with a 20% higher risk of the metabolic syndrome (P=0.034). However, when false discovery rate testing (40 tests) was applied, these associations were no longer statistically significant. CONCLUSION These findings constitute the first study in humans of ANGPTL6 genetic variability. Although there was no evidence that polymorphisms in ANGPTL6 might be significantly associated with the metabolic syndrome-related phenotypes, a weak association of these polymorphisms with these parameters cannot be excluded. Further association studies are needed to arrive at any definite conclusions.