Association between PTPN1 polymorphisms and obesity-related phenotypes in European adolescents: influence of physical activity

Background: To study the associations of Protein Tyrosine Phosphatase-N1 (PTPN1) polymorphisms with obesity-related phenotypes in European adolescents, and the influence of physical activity on these relationships. Methods: Five polymorphisms of PTPN1 were genotyped in 1057 European adolescents (12–18 years old). We measured several phenotypes related to obesity, such as adiposity markers, and biochemical and clinical parameters. Physical activity was objectively measured by accelerometry. Results: The T, A, T, T and G alleles of the rs6067472, rs10485614, rs2143511, rs6020608 and rs968701 polymorphisms, respectively, were associated with lower levels of obesity-related phenotypes (i.e., body mass index, body fat percentage, hip circumference, fat mass index, systolic blood pressure and leptin) in European adolescents. In addition, the TATTG haplotype was associated with lower body fat percentage and fat mass index compared to the AACCA haplotype. Finally, when physical activity levels were considered, alleles of the rs6067472, rs2143511, rs6020608 and rs968701 polymorphisms were only associated with lower adiposity in active adolescents. Conclusions: PTPN1 polymorphisms were associated with adiposity in European adolescents. Specifically, alleles of these polymorphisms were associated with lower adiposity only in physically active adolescents. Therefore, meeting the recommendations of daily physical activity may reduce obesity risk by modulating the genetic predisposition to obesity. Impact: - Using gene-phenotype and gene*environment analyses, we detected associations between polymorphisms of the Protein Tyrosine Phosphatase-N1 (PTPN1) gene and obesity-related phenotypes, suggesting a mechanism that can be modulated by physical activity. - This study shows that genetic variability of PTPN1 is associated with adiposity, while physical activity seems to modulate the genetic predisposition. - This brings insights about the mechanisms by which physical activity positively influences obesity

Peroxisome Proliferator-Activated Receptor Gamma Polymorphisms and Coronary Heart Disease

Single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor γ (PPARG) gene have been associated with cardiovascular risk factors, particularly obesity and diabetes. We assessed the relationship between 4 PPARG SNPs (C-681G, C-689T, Pro12Ala, and C1431T) and coronary heart disease (CHD) in the PRIME (249 cases/494 controls, only men) and ADVANCE (1,076 cases/805 controls, men or women) studies. In PRIME, homozygote individuals for the minor allele of the PPARG C-689T, Pro12Ala, and C1431T SNPs tended to have a higher risk of CHD than homozygote individuals for the frequent allele (adjusted OR [95% CI] = 3.43 [0.96–12.27], P = .058, 3.41 [0.95–12.22], P = .060 and 5.10 [0.99–26.37], P = .050, resp.). No such association could be detected in ADVANCE. Haplotype distributions were similar in cases and control in both studies. A meta-analysis on the Pro12Ala SNP, based on our data and 11 other published association studies (6,898 CHD cases/11,287 controls), revealed that there was no evidence for a significant association under the dominant model (OR = 0.99 [0.92–1.07], P = .82). However, there was a borderline association under the recessive model (OR = 1.29 [0.99–1.67], P = .06) that became significant when considering men only (OR = 1.73 [1.20–2.48], P = .003). In conclusion, the PPARG Ala12Ala genotype might be associated with a higher CHD risk in men but further confirmation studies are needed

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

<p>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.</p> <p>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.</p> <p>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.</p&gt

A study of the relationships between KLF2 polymorphisms and body weight control in a French population

BACKGROUND: Factors governing adipose tissue differentiation play a major role in obesity development in humans. The Krüppel-like zinc finger transcription factor KLF2/Lung KLF (LKLF) is a negative regulator of adipocyte differentiation. In this study, we sequenced the human KLF2 gene and several common polymorphisms were found, among them the Pro104Leu and 3'UTR 1239C>A polymorphisms. METHODS: To evaluate the impact of these polymorphisms on anthropometric variables in humans, we genotyped a general population composed of 1155 French individuals (including 232 obese subjects) for these polymorphisms and looked for potential statistical associations with obesity-related variables. RESULTS: The frequency of the Leu104 and 1239A alleles were 0.22 and 0.18 respectively. Genotype and allele frequencies of the two polymorphisms were comparable in obese, overweight and normal weight subjects. No association between the rare alleles of the polymorphisms and anthropometric variables (BMI, weight, waist and hip circumferences, waist-to-hip ratio and plasma leptin levels) could be detected. Haplotype analyses did not reveal further significant associations. CONCLUSION: These data indicate that the Pro104Leu and 3'UTR 1239C>A polymorphisms in KLF2 are not associated with obesity and obesity-related traits in humans

The APOA5 Trp19 allele is associated with metabolic syndrome via its association with plasma triglycerides

<p>Abstract</p> <p>Background</p> <p>The goal of the present study was to assess the effect of genetic variability at the APOA5/A4/C3/A1 cluster locus on the risk of metabolic syndrome.</p> <p>Methods</p> <p>The <it>APOA5 </it>Ser19Trp, <it>APOA5 </it>-12,238T>C, <it>APOA4 </it>Thr347Ser, <it>APOC3 </it>-482C>T and <it>APOC3 </it>3238C>G (<it>Sst</it>I) polymorphisms were analyzed in a representative population sample of 3138 men and women from France, including 932 individuals with metabolic syndrome and 2206 without metabolic syndrome, as defined by the NCEP criteria.</p> <p>Results</p> <p>Compared with homozygotes for the common allele, the odds ratio (OR) [95% CI] for metabolic syndrome was 1.30 [1.03–1.66] (<it>p </it>= 0.03) for <it>APOA5 </it>Trp19 carriers, 0.81 [0.69–0.95] (<it>p </it>= 0.01) for <it>APOA5 </it>-12,238C carriers and 0.84 [0.70–0.99] (<it>p </it>= 0.04) for <it>APOA4 </it>Ser347 carriers. Adjustment for plasma triglycerides, (but not for waist girth, HDL, blood pressure or glycemia – the other components of metabolic syndrome) abolished these associations and suggests that triglyceride levels explain the association with metabolic syndrome. There was no association between the <it>APOC3 </it>-482C>T or <it>APOC3 </it>3238C>G polymorphisms and metabolic syndrome. The decreased risk of metabolic syndrome observed in <it>APOA5 </it>-12,238C and <it>APOA4 </it>Ser347 carriers merely reflected the fact that the <it>APOA5 </it>Trp19 allele was in negative linkage disequilibrium with the common alleles of <it>APOA5 </it>-12,238T>C and <it>APOA4 </it>Thr347Ser polymorphisms.</p> <p>Conclusion</p> <p>The <it>APOA5 </it>Trp19 allele increased susceptibility to metabolic syndrome via its impact on plasma triglyceride levels.</p

Cardiometabolic risk is positively associated with underreporting and inversely associated with overreporting of energy intake among european adolescents: The healthy lifestyle in Europe by nutrition in adolescence (HELENA) study

[Background]: Dietary misreporting is the main limitation of dietary assessments and has been associated with BMI during youth. However there are no prior studies assessing misreporting and cardiometabolic risks (CMRs) in adolescence.[Objectives]: To examine the associations between dietary misreporting and CMR factors in adolescents and to assess the potential bias in the association between CMR and energy intake (EI) driven by dietary misreporting.[Methods]: Two 24-hour dietary recalls were obtained from 1512 European adolescents (54.8% girls) aged 12.5–17.5 years. Physical activity was measured by accelerometry. Cut-offs suggested by Huang were applied to identify misreporters. Height, waist circumference (WC), the sum of 4 skinfold thicknesses, diastolic blood pressure (DBP), systolic blood pressure (SBP), and cardiorespiratory fitness (CRF) measurements were taken and serum triglycerides and total-/high-density lipoprotein cholesterol ratio were analyzed. A sex- and age-specific clustered CMR score (n = 364) was computed. Associations were investigated by multilevel regression analyses adjusting for age, sex, center, socioeconomic status, and physical activity.[Results]: Underreporting (24.8% adolescents) was significantly (P < 0.05) associated with a higher WC, waist-to-height ratio (WHeR), and sum of skinfold thickness, whereas overreporting (23.4% adolescents) was significantly associated with a lower WC, WHeR, sum of skinfold thickness, and SBP. Associations between CMR factors and EI were significantly affected by misreporting, considering various approaches. Significant, positive associations became inverse after adjusting for misreporting for WC and WHeR. The opposite was true for the sum of skinfold thickness, SBP, and CMR score. The associations between EI and DBP and CRF did not remain significant after adjusting for misreporting.[Conclusions]: CMR factors differed among misreporting groups, and both abdominal and total fat mass indicators were more strongly associated with all forms of misreporting than was BMI. Moreover, misreporting seems to bias EI and CMR associations in adolescents. Therefore, energy misreporting should be taken into account when examining diet-CMR associations.The Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study was carried out with the financial support of the European Community Sixth Framework Programme Research and Technological Development (RTD) Framework Programme (contract FOODCT-2005-007034).Peer reviewe

The body mass index increases the genetic risk scores' ability to predict risk of hepatic damage in European adolescents: The HELENA study

Background Hepatic disorders are often complex and multifactorial, modulated by genetic and environmental determinants. During the last years, the hepatic disease has been progressively established from early stages in life. The use of genetic risk scores (GRS) to predict the genetic susceptibility to a particular phenotype among youth has gained interest in recent years. Moreover, the alanine aminotransferase (ALT) blood biomarker is often considered as hepatic screening tool, in combination with imaging techniques. The aim of the present study was to develop an ALT-specific GRS to help in the evaluation of hepatic damage risk in European adolescents. Methods A total of 972 adolescents (51.3% females), aged 12.5–17.5 years, from the Healthy Lifestyle in Europe by Nutrition in Adolescence study were included in the analyses. The sample incorporated adolescents in all body mass index (BMI) categories and was divided considering healthy/unhealthy ALT levels, using sex-specific cut-off points. From 1212 a priori ALT-related single nucleotide polymorphisms (SNPs) extracted from candidate gene selection, a first screening of 234 SNPs univariately associated was established, selecting seven significant SNPs (p < .05) in the multivariate model. An unweighted GRS (uGRS) was developed by summing the number of reference alleles, and a weighted GRS (wGRS), by multiplying each allele to its estimated coefficient. Results The uGRS and wGRS were significantly associated with ALT (p < .001). The area under curve was obtained integrating BMI as clinical factor, improving the predictive ability for uGRS (.7039) and wGRS (.7035), using 10-fold internal cross-validation. Conclusions Considering BMI status, both GRSs could contribute as complementary tools to help in the early diagnosis of hepatic damage risk in European adolescents

Development of a Genetic Risk Score to predict the risk of overweight and obesity in European adolescents from the HELENA study

Obesity is the result of interactions between genes and environmental factors. Since monogenic etiology is only known in some obesity-related genes, a genetic risk score (GRS) could be useful to determine the genetic predisposition to obesity. Therefore, the aim of our study was to build a GRS able to predict genetic predisposition to overweight and obesity in European adolescents. A total of 1069 adolescents (51.3% female), aged 11–19 years participating in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) cross-sectional study were genotyped. The sample was divided in non-overweight (non-OW) and overweight/obesity (OW/OB). From 611 single nucleotide polymorphisms (SNP) available, a first screening of 104 SNPs univariately associated with obesity (p < 0.20) was established selecting 21 significant SNPs (p < 0.05) in the multivariate model. Unweighted GRS (uGRS) was calculated by summing the number of risk alleles and weighted GRS (wGRS) by multiplying the risk alleles to each estimated coefficient. The area under curve (AUC) was calculated in uGRS (0.723) and wGRS (0.734) using tenfold internal cross-validation. Both uGRS and wGRS were significantly associated with body mass index (BMI) (p < .001). Both GRSs could potentially be considered as useful genetic tools to evaluate individual’s predisposition to overweight/obesity in European adolescents.European Commission FOOD-CT-2005-007034HELENA projectSpanish Ministry of Economy and Competitiveness RYC-2010-05957 RYC2011-09011Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn)Iberus Talent Pre-doctoral fellowships under the European Union 801586Instituto de Salud Carlos III CB15/0004