A new 165-SNP low-density lipoprotein cholesterol polygenic risk score based on next generation sequencing outperforms previously published scores in routine diagnostics of familial hypercholesterolemia.

Genetic diagnosis of familial hypercholesterolemia (FH) remains unexplained in 30 to 70% of patients after exclusion of monogenic disease. There is now a growing evidence that a polygenic burden significantly modulates LDL-cholesterol (LDL-c) concentrations. Several LDL-c polygenic risk scores (PRS) have been set up. However, the balance between their diagnosis performance and their practical use in routine practice is not clearly established. Consequently, we set up new PRS based on our routine panel for sequencing and compared their diagnostic performance with previously-published PRS. After a meta-analysis, four new PRS including 165 to 1633 SNP were setup using different softwares. They were established using two French control cohorts (MONA LISA n=1082 and FranceGenRef n=856). Then the explained LDL-c variance and the ability of each PRS to discriminate monogenic negative FH patients (M-) versus healthy controls were compared with 4 previously-described PRS in 785 unrelated FH patients. Between all PRS, the 165-SNP PRS developed with PLINK showed the best LDL-c explained variance (adjusted R²=0.19) and the best diagnosis abilities (AUROC=0.77, 95%CI=0.74-0.79): it significantly outperformed all the previously-published PRS (p<1 × 10-4). By using a cut-off at the 75th percentile, 61% of M- patients exhibited a polygenic hypercholesterolemia with the 165-SNP PRS versus 48% with the previously published 12-SNP PRS (p =3.3 × 10-6). These results were replicated using the UK biobank. This new 165-SNP PRS, usable in routine diagnosis, exhibits better diagnosis abilities for a polygenic hypercholesterolemia diagnosis. It would be a valuable tool to optimize referral for whole genome sequencing.

Interplay of physical activity and genetic variants of the endothelial lipase on cardiovascular disease risk factors.

BACKGROUND: The aim of this study was to investigate the association of endothelial lipase gene (LIPG) polymorphisms with cardiovascular disease (CVD) risk factors in adolescents and their interaction with physical activity. METHODS: Six polymorphisms of LIPG were genotyped in 1057 European adolescents (12-18 years old) enrolled in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) Study. CVD risk factors related to lipid profile, blood pressure, adiposity and glucose regulation were recorded. Physical activity was objectively measured by accelerometry. RESULTS: The major C allele of rs2000813, the minor T allele of rs2276269 and the minor G allele of rs9951026 were associated with lower levels of several CVD risk factors related to lipid profile. We also found a significant association of the TTACA LIPG haplotype (rs2000812, rs2000813, rs8093249, rs2276269 and rs9951026) with higher concentrations of low-density cholesterol and apolipoprotein B. Finally, the interaction between physical activity and the polymorphisms rs2000813, rs2276269 and rs9951026 had a significant influence on several CVD risk factors. CONCLUSIONS: LIPG polymorphisms were significantly associated with CVD risk factors in European adolescents. Interestingly, alleles of these polymorphisms were associated with a better cardiovascular profile in physically active adolescents only. High physical activity may reduce the development of CVD, modulating its genetic risk. IMPACT: Using gene-phenotype and gene × environment analyses, we detected associations between the endothelial lipase gene and cardiovascular risk factors, along with interactions with physical activity. This study shows that physical activity may modulate the influence of LIPG gene on cardiovascular risk in adolescents. These results bring insights into the mechanisms by which physical activity positively influences CVD in adolescents.

The association between blood cadmium and glycated haemoglobin among never-, former, and current smokers: A cross-sectional study in France.

INTRODUCTION: The association between cadmium levels in the body and diabetes has been extensively studied, with sometimes contrasting results. Smoking is the primary non-occupational source of cadmium, and constitutes a risk factor for diabetes. One can therefore hypothesize that the putative association with cadmium is actually explained by tobacco. To fully control for this confounding factor, we studied the relationship between blood cadmium and glycated haemoglobin (HbA1c) levels separately in never-, former and current smokers. METHODS: We studied a sample of 2749 middle-aged adults from the cross-sectional ELISABET survey in and around the cities of Lille and Dunkirk; none had chronic kidney disease or a history of haematological disorders, and none were taking antidiabetic medication. The blood cadmium level-HbA1c associations in never-, former and current smokers were studied in separate multivariate models. The covariables included age, sex, city, educational level, tobacco consumption (or passive smoking, for the never-smokers), body mass index, estimated glomerular filtration rate, and (to take account of the within-batch effect) the cadmium batch number. RESULTS: In the multivariate analysis, a significant association between cadmium and HbA1c levels was found in all three smoking status subgroups. A 0.1 µg/L increment in blood cadmium was associated with an HbA1c increase [95% confidence interval] of 0.016% [0.003; 0.029] among never-smokers, 0.024% [0.010; 0.037] among former smokers, and 0.020% [0.012; 0.029] among current smokers. CONCLUSIONS: The observation of a significant association between the blood cadmium concentration and HbA1c levels in a group of never-smokers strengthens the hypothesis whereby diabetes is associated with cadmium per se and not solely with tobacco use. The small effect size observed in our population of never smokers with low levels of exposure to cadmium suggested that the risk attributable to this metal is not high. However, the impact of exposure to high cadmium levels (such as occupational exposure) on the risk of diabetes might be of concern.

Identification of a functional FADS1 3'UTR variant associated with erythrocyte n-6 polyunsaturated fatty acids levels.

BACKGROUND: Blood polyunsaturated fatty acid (PUFA) levels are determined by diet and by endogenous synthesis via Δ5- and Δ6-desaturases (encoded by the FADS1 and FADS2 genes, respectively). Genome-wide association studies have reported associations between FADS1-FADS2 polymorphisms and the plasma concentrations of PUFAs, HDL- and LDL-cholesterol, and triglycerides. However, much remains unknown regarding the molecular mechanisms explaining how variants affect the function of FADS1-FADS2 genes. OBJECTIVE: Here, we sought to identify the functional variant(s) within the FADS gene cluster. METHODS: To address this question, we (1) genotyped individuals (n = 540) for the rs174547 polymorphism to confirm associations with PUFA levels used as surrogate estimates of desaturase activities and (2) examined the functionality of variants in linkage disequilibrium with rs174547 using bioinformatics and luciferase reporter assays. RESULTS: The rs174547 minor allele was associated with higher erythrocyte levels of dihomo-γ-linolenic acid and lower levels of arachidonic acid, suggesting a lower Δ5-desaturase activity. In silico analyses suggested that rs174545 and rs174546, in perfect linkage disequilibrium with rs174547, might alter miRNA binding sites in the FADS1 3'UTR. In HuH7 and HepG2 cells transfected with FADS1 3'UTR luciferase vectors, the haplotype constructs bearing the rs174546T minor allele showed 30% less luciferase activity. This relative decrease reached 60% in the presence of miR-149-5p and was partly abolished by cotransfection with an miR-149-5p inhibitor. CONCLUSION: This study identifies FADS1 rs174546 as a functional variant that may explain the associations between FADS1-FADS2 polymorphisms and lipid-related phenotypes.

Sex Differences in Stroke Attack, Incidence, and Mortality Rates in Northern France.

BACKGROUND: Age and sex have a major impact on stroke onset. AIMS: We aimed to compare the attack, incidence, and 28-day mortality rate for stroke as well as risk factors in men and women aged 35 and over. METHODS: Data were obtained between 2008 and 2015 from the stroke population-based registry covering the city of Lille (northern France). RESULTS: A total of 2426 strokes (1917 incident strokes) were recorded. The number of strokes was lower in women than in men when considering individuals under the age of 75 but was twice as high when considering individuals aged 75 or over. Overall, there were 25% more strokes in women than in men. The age-adjusted attack (P = .017) and incident (P = .027) rates of stroke were ~30% lower in women than in men (a ~30% lower risk of ischemic stroke (P = .02) and a ~40% lower risk of intracerebral hemorrhage (ICH) (P = .004)). The age-adjusted mortality rate after ICH was ~35% lower in women than in men (P = .014). With regard to cardiovascular risk factors, women with stroke were older, smoked less, and were more likely to have a history of migraine or atrial fibrillation than the men. CONCLUSION: The risk of stroke is lower in women than in men under the age of 75 but is similar when comparing women and men after that age. Nevertheless, the age structure of the population (with more elderly women than elderly men) translates into a higher absolute number of strokes in women than in men.

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.

Cardiorespiratory fitness and ideal cardiovascular health in European adolescents.

OBJECTIVE: We studied in European adolescents (i) the association between cardiorespiratory fitness and ideal cardiovascular health as defined by the American Heart Association and (ii) whether there is a cardiorespiratory fitness threshold associated with a more favourable cardiovascular health profile. METHODS: Participants included 510 (n=259 girls) adolescents from 9 European countries. The 20 m shuttle run test was used to estimate cardiorespiratory fitness. Ideal cardiovascular health was defined as meeting ideal levels of the following components: four behaviours (smoking, body mass index, physical activity and diet) and three factors (total cholesterol, blood pressure and glucose). RESULTS: Higher levels of cardiorespiratory fitness were associated with a higher number of ideal cardiovascular health components in both boys and girls (both p for trend ≤0.001). Levels of cardiorespiratory fitness were significantly higher in adolescents meeting at least four ideal components (13% higher in boys, p<0.001; 6% higher in girls, p=0.008). Receiver operating characteristic curve analyses showed a significant discriminating accuracy of cardiorespiratory fitness in identifying the presence of at least four ideal cardiovascular health components (43.8 mL/kg/min in boys and 34.6 mL/kg/min in girls, both p<0.001). CONCLUSIONS: The results suggest a hypothetical cardiorespiratory fitness level associated with a healthier cardiovascular profile in adolescents. The fitness standards could be used in schools as part of surveillance and/or screening systems to identify youth with poor health behaviours who might benefit from intervention programmes.

Genetic and molecular insights into the role of PROX1 in glucose metabolism.

Genome-wide association studies have shown that the rs340874 single nucleotide polymorphism (SNP) in PROX1 is a genetic susceptibility factor for type 2 diabetes. We conducted genetic and molecular studies to better understand the role of PROX1 in type 2 diabetes. We assessed the impact of the whole common genetic variability of PROX1 (80 SNPs) on type 2 diabetes-related biochemical traits in the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) study (n = 1,155). Three SNPs (rs340838, rs340837, and rs340836) were significantly associated with fasting plasma insulin levels (P ≤ 0.00295). We evaluated the impact of nine PROX1 SNPs (the three insulin-associated SNPs plus six SNPs in strong linkage disequilibrium) on luciferase reporter gene expression. The insulin-lowering alleles of rs340874, rs340873, and rs340835 were associated with lower luciferase activity in MIN6 and HepG2 cells (except for rs340874, which was in HepG2 cells only). Electrophoretic mobility shift assays indicated that specific nuclear protein bindings occur at the three SNPs in HepG2 cells, with allele-binding differences for rs340874. We also showed that the knockdown of Prox1 expression by small interfering RNAs in INS-1E cells resulted in a 1.7-fold reduction in glucose-stimulated insulin secretion. All together, we propose that reduced expression of PROX1 by cis-regulatory variants results in altered ß-cell insulin secretion and thereby confers susceptibility to type 2 diabetes.

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.

Mendelian randomization study of B-type natriuretic peptide and type 2 diabetes: evidence of causal association from population studies.

BACKGROUND: Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded. METHODS AND FINDINGS: We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies. We combined our results with existing data in a meta-analysis of 11 case-control studies. Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389. In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%-36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91-0.97) was similar to that expected (0.96, 0.93-0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74-0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15-0.29) per C allele of rs198389. No significant associations were observed between the rs198389 genotype and potential confounders. CONCLUSIONS: Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D. Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions. Please see later in the article for the Editors' Summary.

Physical activity attenuates the effect of low birth weight on insulin resistance in adolescents: findings from two observational studies.

OBJECTIVE: To examine whether physical activity influences the association between birth weight and insulin resistance in adolescents. RESEARCH DESIGN AND METHODS: The study comprised adolescents who participated in two cross-sectional studies: the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study (n = 520, mean age = 14.6 years) and the Swedish part of the European Youth Heart Study (EYHS) (n = 269, mean age = 15.6 years). Participants had valid data on birth weight (parental recall), BMI, sexual maturation, maternal education, breastfeeding, physical activity (accelerometry, counts/minute), fasting glucose, and insulin. Insulin resistance was assessed by homeostasis model assessment-insulin resistance (HOMA-IR). Maternal education level and breastfeeding duration were reported by the mothers. RESULTS: There was a significant interaction of physical activity in the association between birth weight and HOMA-IR (logarithmically transformed) in both the HELENA study and the EYHS (P = 0.05 and P = 0.03, respectively), after adjusting for sex, age, sexual maturation, BMI, maternal education level, and breastfeeding duration. Stratified analyses by physical activity levels (below/above median) showed a borderline inverse association between birth weight and HOMA-IR in the low-active group (standardized ß = -0.094, P = 0.09, and standardized ß = -0.156, P = 0.06, for HELENA and EYHS, respectively), whereas no evidence of association was found in the high-active group (standardized ß = -0.031, P = 0.62, and standardized ß = 0.053, P = 0.55, for HELENA and EYHS, respectively). CONCLUSIONS: Higher levels of physical activity may attenuate the adverse effects of low birth weight on insulin sensitivity in adolescents. More observational data, from larger and more powerful studies, are required to test these findings.

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-ß 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.

Study of estrogen receptor-α and receptor-ß gene polymorphisms on Alzheimer's disease.

Estrogen treatment can modulate the risk for developing dementia in women. Therefore, single nucleotide polymorphisms (SNPs) in the estrogen receptor genes may constitute genetic susceptibility factors to Alzheimer's disease (AD). Thus, we investigated the impact of the genetic variability of the estrogen receptor α 1 (ESR1) and estrogen receptor α 2 (ESR2) genes on late onset AD risk. We analyzed 39 SNPs in ESR1 and 5 SNPs in ESR2 in a French case-control study of sporadic AD (1007 cases/647 controls). Individuals carrying the minor allele of rs7450824 had a lower risk of AD than homozygous subjects for the major allele (age, gender, and APOE ε4 allele adjusted odds ratio = 0.71 [0.57-0.89], p = 0.003). However, this association did not resist Bonferroni correction for multiple testing (p-threshold < 0.001). Consistently, no significant association could be detected when considering age of onset. We also tested for possible interactions between the ESR SNPs and APOE status (ε4 allele) or gender but no significant interaction could be observed. Even after stratifying the sample on APOE status or gender, no significant association with AD risk could be detected. Finally, we searched for potential gene-gene interactions between ESR1 and ESR2 SNPs but no significant interaction could be detected. Our results reinforce the notion that SNPs in the ESR1 or ESR2 genes do not seem to play a major role in the genetic susceptibility of AD.

Common polymorphisms in six genes of the methyl group metabolism pathway and obesity in European adolescents.

OBJECTIVE: The goal of the present study was to assess the relationship between the genetic variability in six genes of methyl group (CH(3)) metabolism and the risk of obesity. METHODS: Single nucleotide polymorphisms (SNP) were selected among the methylene-tetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystationine betha-syntase (CBS), transcobalamin-II (TCN2) and paraoxonase-1 (PON1) genes. The associations between SNPs and the risk of obesity were assessed in a case-control study of obese and normal-weight adolescents (age: 14.9±1.2 years), and the relationship between SNPs and body fat markers (i.e., body mass index [BMI], percentage body fat [BF%] and waist circumference [WC]) in a cross-sectional study of 1 155 European adolescents (age: 14.8±1.4 years). Genotyping was performed on an Illumina system and plasma folate level was determined by immunoassay. RESULTS: In the case-control study, there was no evidence for any association between SNPs of MTHFR, MTR, CBS, TCN2 and PON1 and obesity (all p values ≥0.08). In contrast, two SNPs of MTRR were associated with a higher (rs10520873, Odds Ratio: 1.68 [1.18-2.39]; p=0.004) or lower (rs1801394, 0.61 [0.42-0.87]; p=0.007) risk of obesity. In the cross-sectional sample, rs1801394 was associated with lower BMI (p=0.03) and lower waist circumference (p=0.02). However, after Bonferroni correction these associations were no longer significant. No other significant association or interaction between folate levels and SNPs were detected for anthropometric variables. CONCLUSION: Our findings do not support an association between MTHFR, MTR, CBS, TCN2 and PON1 SNPs and obesity in adolescence. Further investigations are necessary to confirm the possible association between the rs1801394 variant of MTRR and obesity.

Study of thyroid hormone receptor alpha gene polymorphisms on Alzheimer's disease.

Because the action of thyroid hormone (T3) is involved in adult cognitive functions, we wanted to assess the association between THRA gene polymorphisms, which encodes the T3 nuclear receptor TRα1, and Alzheimer's disease (AD) risk. We analysed 5 single nucleotide polymorphisms (SNPs) of THRA, covering the known common genetic variability of the gene, in the Lille AD case-control study (710 cases/597 controls). We observed that subjects bearing the rs939348 TT genotype had a tendency to have a higher risk of developing AD (adjusted OR [95%CI]=1.71 [0.99-2.95] p=0.06). We extended our finding to three other independent AD case-control studies and observed similar trends. When combining the 4 studies (1749 cases/1339 controls), we observed an overall significant higher risk of AD in TT subjects (adjusted OR [95%CI]=1.42 [1.03-1.96], p=0.03) compared with C allele bearers. However, when combining our data with the available data coming from 2 American genome wide association studies on AD, we observed a weak and not significant association (OR=1.19 [0.97-1.45], p=0.10). The relationship between the genetic variability of the THRA gene and AD risk remains uncertain but cannot be entirely excluded.

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.

Study of the genetic variability of ZAC1 (PLAGL1) in French population-based samples.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: We found no evidence that polymorphisms in ZAC1 might influence anthropometric, biochemical or clinical parameters in French individuals.

Lack of association between certain candidate gene polymorphisms and the metabolic syndrome.

The goal of the present study was to assess the association between the metabolic syndrome (MS) and certain polymorphisms in genes involved in lipid transport, insulin resistance, intramitochondrial energy transport, appetite control, vasomotor tone, and adipocyte differentiation. The sample was composed of 601 men and 594 women aged 35-64 years recruited in the north of France that were genotyped for the following polymorphisms (SNPs): uncoupling protein, UCP3 -55 C/T; fatty acid transport protein, FATP1 intron 8 +48 G/A; tumor necrosis factor, TNF-alpha -308 G/A; leptin, LEP 5'UTR +19 G/A; and beta3 subunit of G proteins, GNB3 C825T. Waist girth, plasma triglycerides, HDL-cholesterol, glucose and systolic, and diastolic blood pressure were used to define the MS according to the National cholesterol education program (NCEP-III) guidelines. There were 155 (27.4%) men and 124 (21.8%) women who satisfied the NCEP-III criteria and 855 control subjects. By logistic regression using a dominant model (homozygous for the common allele versus carriers of the rare allele), the odds ratio [95% confidence interval] for the MS were: 0.91 [0.68-1.22] for FATP1, 0.93 [0.68-1.28] for TNF-alpha, 0.97 [0.73-1.29] for UCP3, 1.06 [0.80-1.40] for LEP, and 1.12 [0.84-1.48] for GNB3 SNPs. There was no evidence for a gender-specific effect. In conclusion, this study suggests that among a large sample of French men and women, the above named SNPs in UCP3, FATP1, TNF-alpha, LEP, and GNB3 genes are not major contributors to the MS risk.

The APOA4 Thr347->Ser347 polymorphism is not a major risk factor of obesity.

OBJECTIVE: The goal of this study was to assess the association between the APOA4 Thr(347)-->Ser(347) polymorphism and BMI and obesity. RESEARCH METHODS AND PROCEDURES: Men and women (n = 3320), randomly recruited in three independent population surveys from the north, east, and south of France, were genotyped for the APOA4 Thr(347)-->Ser(347) polymorphism. RESULTS: There were 1327 overweight (825 men, 502 women) and 611 obese (313 men, 298 women) subjects. The prevalences of subjects carrying at least one Ser(347) allele (*/Ser(347)) were 36.5%, 33.8%, and 34.3% in controls, overweight, and obese subjects, respectively (not significant), and those of the Ser(347)/Ser(347) genotype were 4.5%, 3.0%, and 2.2%, respectively (not significant). In both men and women, mean BMI and body weight were not significantly different among APOA4 genotypes. There was no evidence of heterogeneity among centers, smoking status, alcohol intake, physical activity, and educational level categories. In men, mean waist girth was lower in Ser(347)/Ser(347) (92.2 +/- 9.4 cm) than in Thr(347) carriers (95.9 +/- 10.9 cm; p = 0.01), and plasma triglycerides levels were lower in Ser(347) (1.41 +/- 1.04 mM) than in Thr(347)/Thr(347) carriers (1.55 +/- 1.23 mM; p = 0.01). DISCUSSION: These results suggest that the APOA4 347Ser allele is not a major risk factor for obesity or overweight.

Impact of genetic variation of PPARgamma in humans.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a transcription factor with a key role in adipocyte differentiation. Since 1997, studies of rare mutations and common polymorphisms of the PPARgamma gene have enabled us to expand our knowledge of the role of this transcription factor in humans. Rare monogenic mutations in PPARgamma have a limited impact on the health of the population due to their low frequency but are associated with severe phenotypes such as severe insulin resistance, partial lipodystrophy, type 2 diabetes and hypertension. Conversely, common polymorphisms of PPARgamma with a relatively high frequency can have a significant impact on the general population. Although they may modulate the risk of developing type 2 diabetes, obesity and cardiovascular diseases, the data remains controversial. This review details and discusses results obtained for PPARgamma variants, whose effects sometimes appear discordant.