[show abstract][hide abstract] ABSTRACT: 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.
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).
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.
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.
American Journal of Hypertension 06/2011; 24(9):1027-34. · 3.67 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
American Journal of Hypertension 06/2011; 24(9):1027-1034. · 3.67 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Thirty-nine polymorphisms in NR1H3, ABCA1, APOE, CETP, PLTP and LPL were analysed in the HELENA study (n = 1144 European adolescents).
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.
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.
[show abstract][hide abstract] ABSTRACT: The 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.
Twenty 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.
We 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.
Our results suggest that rs17373080 in LXRβ is associated with T2DM and obesity, maybe via altered LXRβ expression.
BMC Medical Genetics 10/2010; 11:144. · 2.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: To examine whether physical activity attenuates the effect of the FTO rs9939609 polymorphism on body fat estimates in adolescents.
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.
Adolescents from the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study (n = 752).
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.
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.
Adolescents meeting the daily physical activity recommendations may overcome the effect of the FTO rs9939609 polymorphism on obesity-related traits.
Archives of pediatrics & adolescent medicine 04/2010; 164(4):328-33. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: We selected twenty genes from the "Top Results" list on the AlzGene database website and assessed their association with risk of developing Alzheimer's disease (AD) in a large, genome-wide association study (using 526 SNPs from 2,032 AD cases and 5,328 controls) performed in France. The APOE, CLU, PICALM, and CR1 loci were excluded, since they had already been extensively analyzed. Ten genes/loci (TFAM, SORL1, CHRNB2, SORCS1, DAPK1, MTHFR, GWA 14q32.13, BDNF, NEDD9, and CH25H) showed weak nominal association with AD risk, in line with previous studies. In the remaining ten genes/loci (TNK1, ACE, CST3, IL1B, hCG2039140, PRNP, GAB2, LOC651924, IL1A, and TF), no single nucleotide polymorphisms were associated in our dataset. Of the genes showing nominal association in our cohorts, TFAM and CHRNB2 appear particularly interesting and warrant further genetic and functional follow-up analyses.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: 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.
The aim of the study was to examine the association between ANGPTL3 and ANGPTL4 genetic polymorphisms and metabolic phenotypes in adolescent and adult samples.
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.
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).
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.
The Journal of clinical endocrinology and metabolism 11/2009; 94(12):5070-7. · 6.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
[show abstract][hide abstract] ABSTRACT: 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.
Metabolism: clinical and experimental 04/2009; 58(7):971-5. · 2.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: ZAC1 (zinc finger protein regulating apoptosis and cell cycle arrest) is a member of the new subfamily of zinc-finger transcription factors, designated as PLAG (pleomorphic adenoma gene) family. The ZAC1 gene is maternally imprinted and is linked to developmental disorders such as growth retardation and transient neonatal diabetes mellitus. We wanted to assess whether the genetic variability of the ZAC1 gene was associated with anthropometric (weight, BMI, waist-to-hip ratio) or biochemical (plasma lipid, insulin, glucose levels, blood pressure level) phenotypes.
We selected 37 independent SNPs (single nucleotide polymorphisms) or tagSNPs in the ZAC1 locus from the literature and several databases and, based on the linkage disequilibrium map, identified 27 independent SNPs. Those 27 SNPs were genotyped in a French population-based sample (n = 1155). Associations with a P value lower than 0.0019 (Bonferroni correction) were considered significant.
We found that women carrying the T allele of rs9403542 had lower waist-to-hip ratio (P = 0.0006) than women with the CC genotype. Also, men bearing the T allele of rs13218225 had lower systolic (P = 3.6 x 10(-5)) and diastolic (P = 4.1 x 10(-4)) blood pressure than GG men. As a consequence, the adjusted (for age, smoking habit, alcohol consumption, physical activity level and BMI) odds ratio (95% confidence interval) of hypertension for T allele carrier men was 0.55 [0.35-0.86], P = 0.009. We genotyped two other independent samples (MONICA Toulouse, n = 1130 and MONICA Strasbourg, n = 1048) for rs9403542 and rs13218225 but we could not confirm these associations.
We found no evidence that polymorphisms in ZAC1 might influence anthropometric, biochemical or clinical parameters in French individuals.
Journal of Hypertension 03/2009; 27(2):314-21. · 3.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: The metabolic syndrome is a complex and multifactorial disorder often associated with type 2 diabetes mellitus and cardiovascular diseases. The liver X receptor alpha (NR1H3) plays numerous roles in metabolic pathways involved in metabolic syndrome.
In the search for susceptibility genes to metabolic syndrome, we hypothesized that common genetic variation in NR1H3 gene influences metabolic syndrome susceptibility.
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.
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.
These results suggest that NR1H3 plays an important role in the HDL-cholesterol metabolism and in the genetic susceptibility to metabolic syndrome.
International journal of obesity (2005) 04/2008; 32(3):421-8. · 4.34 Impact Factor