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.

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.

Association between CNTF Polymorphisms and Adiposity Markers in European Adolescents.

OBJECTIVE: To examine the association between polymorphisms of the ciliary neurotrophic factor gene (CNTF) and total and central adiposity markers in adolescents. STUDY DESIGN: This cross-sectional study involved 1057 European adolescents aged 12-18 years enrolled in the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study. Five polymorphisms of CNTF were genotyped, and the weight, height, waist and hip circumference, and triceps and subscapular skinfold thickness of the subjects were measured and recorded. RESULTS: The T allele of rs2509914, the C allele of rs2515363, and the G allele of rs2515362 were significantly associated (after Bonferroni correction) with higher values for several adiposity markers under different inheritance models. The CNTF CCGGA haplotype (rs2509914, rs17489568, rs2515363 rs1800169, and rs2515362) was also significantly associated with lower body mass index, waist circumference, waist/height ratio, and waist/hip ratio values compared with the TCCGG haplotype under several inheritance models. CONCLUSIONS: Three polymorphisms-rs2509914, rs2515363, and rs2515362-and the CCGGA haplotype of CNTF were significantly associated with adiposity in European adolescents. These results suggest the potential role of CTNF in the development of obesity-related phenotypes.

Association of UCP1, UCP2 and UCP3 gene polymorphisms with cardiovascular disease risk factors in European adolescents: the HELENA study.

BACKGROUND: Cardiovascular diseases (CVDs) are responsible for 31% of all deaths worldwide. Genetic predisposition to CVDs in adolescents remains largely unknown. The aim of this study was to examine the association of UCP1, UCP2 and UCP3 gene polymorphisms with CVD risk factors in European adolescents. METHOD: A cross-sectional study that involves 1.057 European adolescents (12-18 years old) from the HELENA study. A total of 18 polymorphisms of UCP1, UCP2 and UCP3 genes were genotyped. We measured serum total cholesterol, high-density lipoprotein,low-density lipoprotein, ApoA1, ApoB, leptin, triglycerides, glucose, insulin and blood pressure, and calculated HOMA (homeostatic model assessment), Quantitative Insulin Sensitivity Check Index (QUICKI) and a CVD risk score. RESULTS: The G allele of UCP2 rs2735572 and T allele of UCP2 rs17132534 were associated with higher diastolic blood pressure (P = 0.001; false discovery rate [FDR] = 0.009 and P = 8e-04; FDR = 0.009, respectively). We observed that the AATAG haplotype of UCP1 was associated with higher serum ApoB/ApoA1 (P = 0.008; FDR = 0.031) and ApoB levels (P = 0.008; FDR = 0.031). Moreover, the ACC haplotype of UCP3 was associated with a higher CVD risk score (P = 0.0036; FDR = 0.01). CONCLUSIONS: Two UCP2 polymorphisms and haplotypes of UCP1 and UCP3 were associated with CVD risk factors. These findings suggest that UCPs may have a role in the development of CVD already in adolescents.

Association between lipoprotein lipase gene polymorphisms and cardiovascular disease risk factors in European adolescents: The Healthy Lifestyle in Europe by Nutrition in Adolescence study.

OBJECTIVES: To examine the association of lipoprotein lipase (LPL) polymorphisms with cardiovascular disease (CVD) risk factors in European adolescents, along with the influence of physical activity on these associations. METHODS: A total of 13 LPL polymorphisms were genotyped in 1.057 European adolescents (12-18 years old) from the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study. Serum lipids, glucose, insulin, and leptin (LEP) levels were measured and a CVD risk score was computed. We also measured body weight and height, waist and hip circumferences, and triceps and subscapular skinfold thickness. Physical activity was objectively measured by accelerometry for 7 days. RESULTS: The rs1534649, rs258, rs320, and rs328 polymorphisms were associated with several CVD risk factors (ie, body mass index, triglycerides [TG], LEP, and cholesterol/high-density lipoprotein [HDL], low-density lipoprotein [LDL]/HDL, TG/HDL ratios). TG and TG/HDL were associated with haplotype blocks 3 (rs282, rs285 polymorphisms) and 4 (rs3126, rs320, rs328, rs10099160 polymorphisms), being the latter also associated with the CVD risk score. Physical activity modulated the association of adiposity with rs1534649 and rs258 polymorphisms. CONCLUSIONS: Polymorphisms rs1534649, rs258, rs320 and rs328, and two haplotypes of LPL were significantly associated with CVD risk factors in European adolescents. Higher levels of moderate to vigorous physical activity may attenuate the effects of rs1534649 and rs258 polymorphisms on adiposity.

Assessing the Presence of Recent Adaptation in the Human Genome With Mixture Density Regression.

How much genome differences between species reflect neutral or adaptive evolution is a central question in evolutionary genomics. In humans and other mammals, the presence of adaptive versus neutral genomic evolution has proven particularly difficult to quantify. The difficulty notably stems from the highly heterogeneous organization of mammalian genomes at multiple levels (functional sequence density, recombination, etc.) which complicates the interpretation and distinction of adaptive versus neutral evolution signals. In this study, we introduce mixture density regressions (MDRs) for the study of the determinants of recent adaptation in the human genome. MDRs provide a flexible regression model based on multiple Gaussian distributions. We use MDRs to model the association between recent selection signals and multiple genomic factors likely to affect the occurrence/detection of positive selection, if the latter was present in the first place to generate these associations. We find that an MDR model with two Gaussian distributions provides an excellent fit to the genome-wide distribution of a common sweep summary statistic (integrated haplotype score), with one of the two distributions likely enriched in positive selection. We further find several factors associated with signals of recent adaptation, including the recombination rate, the density of regulatory elements in immune cells, GC content, gene expression in immune cells, the density of mammal-wide conserved elements, and the distance to the nearest virus-interacting gene. These results support the presence of strong positive selection in recent human evolution and highlight MDRs as a powerful tool to make sense of signals of recent genomic adaptation.

Development of a genetic risk score to predict the risk of hypertension in European adolescents from the HELENA study.

Introduction: From genome wide association study (GWAS) a large number of single nucleotide polymorphisms (SNPs) have previously been associated with blood pressure (BP) levels. A combination of SNPs, forming a genetic risk score (GRS) could be considered as a useful genetic tool to identify individuals at risk of developing hypertension from early stages in life. Therefore, the aim of our study was to build a GRS being able to predict the genetic predisposition to hypertension (HTN) in European adolescents. Methods: Data were extracted from the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) cross-sectional study. A total of 869 adolescents (53% female), aged 12.5-17.5, with complete genetic and BP information were included. The sample was divided into altered (≥130 mmHg for systolic and/or ≥80 mmHg for diastolic) or normal BP. Based on the literature, a total of 1.534 SNPs from 57 candidate genes related with BP were selected from the HELENA GWAS database. Results: From 1,534 SNPs available, An initial screening of SNPs univariately associated with HTN (p < 0.10) was established, to finally obtain a number of 16 SNPs significantly associated with HTN (p < 0.05) in the multivariate model. The unweighted GRS (uGRS) and weighted GRS (wGRS) were estimated. To validate the GRSs, the area under the curve (AUC) was explored using ten-fold internal cross-validation for uGRS (0.802) and wGRS (0.777). Further covariates of interest were added to the analyses, obtaining a higher predictive ability (AUC values of uGRS: 0.879; wGRS: 0.881 for BMI z-score). Furthermore, the differences between AUCs obtained with and without the addition of covariates were statistically significant (p < 0.05). Conclusions: Both GRSs, the uGRS and wGRS, could be useful to evaluate the predisposition to hypertension in European adolescents.

Novel brown adipose tissue candidate genes predicted by the human gene connectome.

Brown adipose tissue (BAT) is a promising therapeutic target against obesity. Therefore, research on the genetic architecture of BAT could be key for the development of successful therapies against this complex phenotype. Hypothesis-driven candidate gene association studies are useful for studying genetic determinants of complex traits, but they are dependent upon the previous knowledge to select candidate genes. Here, we predicted 107 novel-BAT candidate genes in silico using the uncoupling protein one (UCP1) as the hallmark of BAT activity. We first identified the top 1% of human genes predicted by the human gene connectome to be biologically closest to the UCP1, estimating 167 additional pathway genes (BAT connectome). We validated this prediction by showing that 60 genes already associated with BAT were included in the connectome and they were biologically closer to each other than expected by chance (p < 2.2 × 10-16). The rest of genes (107) are potential candidates for BAT, being also closer to known BAT genes and more expressed in BAT biopsies than expected by chance (p < 2.2 × 10-16; p = 4.39 × 10-02). The resulting new list of predicted human BAT genes should be useful for the discovery of novel BAT genes and metabolic pathways.

Decreased recent adaptation at human mendelian disease genes as a possible consequence of interference between advantageous and deleterious variants.

Advances in genome sequencing have improved our understanding of the genetic basis of human diseases, and thousands of human genes have been associated with different diseases. Recent genomic adaptation at disease genes has not been well characterized. Here, we compare the rate of strong recent adaptation in the form of selective sweeps between mendelian, non-infectious disease genes and non-disease genes across distinct human populations from the 1000 Genomes Project. We find that mendelian disease genes have experienced far less selective sweeps compared to non-disease genes especially in Africa. Investigating further the possible causes of the sweep deficit at disease genes, we find that this deficit is very strong at disease genes with both low recombination rates and with high numbers of associated disease variants, but is almost non-existent at disease genes with higher recombination rates or lower numbers of associated disease variants. Because segregating recessive deleterious variants have the ability to interfere with adaptive ones, these observations strongly suggest that adaptation has been slowed down by the presence of interfering recessive deleterious variants at disease genes. These results suggest that disease genes suffer from a transient inability to adapt as fast as the rest of the genome.

Fatigue in Women with Fibromyalgia: A Gene-Physical Activity Interaction Study.

Fatigue is a cardinal symptom in fibromyalgia. Fatigue is assumed to be the result of genetic susceptibility and environmental factors. We aimed at examining the role of genetic susceptibility for fatigue in southern Spanish women with fibromyalgia, by looking at single nucleotide polymorphisms in 34 fibromyalgia candidate-genes, at the interactions between genes, and at the gene-physical activity interactions. We extracted DNA from saliva of 276 fibromyalgia women to analyze gene-polymorphisms. Accelerometers registered physical activity and sedentary behavior. Fatigue was assessed with the Multidimensional Fatigue Inventory. Based on the Bonferroni's and False Discovery Rate values, we found that the genotype of the rs4453709 polymorphism (sodium channel protein type 9 subunit alpha, SCN9A, gene) was related to reduced motivation (AT carriers showed the highest reduced motivation) and reduced activity (AA carriers showed the lowest reduced activity). Carriers of the heterozygous genotype of the rs1801133 (methylene tetrahydrofolate reductase, MTHFR, gene) or rs4597545 (SCN9A gene) polymorphisms who were physically active reported lower scores on fatigue compared to their inactive counterparts. Highly sedentary carriers of the homozygous genotype of the rs7607967 polymorphism (AA/GG genotype; SCN9A gene) presented more reduced activity (a dimension of fatigue) than those with lower levels of sedentary behavior. Collectively, findings from the present study suggest that the contribution of genetics and gene-physical activity interaction to fatigue in fibromyalgia is modest.

Single nucleotide polymorphisms of ADIPOQ gene associated with cardiovascular disease risk factors in European adolescents: the Healthy Lifestyle in Europe by Nutrition in Adolescence study.

OBJECTIVES: Cardiovascular diseases (CVDs) are responsible of 31% of all deaths worldwide. Genetic predisposition to CVDs in adolescents remains largely unknown. Aims of present research are to examine the association of ADIPOQ gene polymorphisms with cardiovascular disease risk factors in European adolescents. METHODS: A total of 14 polymorphisms in the ADIPOQ gene were genotyped in 1057 European adolescents (12-18 years old) from the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study. We measured serum lipids and a CVD risk score, along with weight, height, triceps, and subscapular skinfold thickness, leptin, insulin and other markers of glucose regulation. RESULTS: The rs822393, rs822395 and rs7649121 polymorphisms of ADIPOQ gene were significantly associated with several CVD risk factors [i.e. high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo) A1, SBP and CVD risk score] in European adolescents. We also found an association of the TGAAGT ADIPOQ haplotype (rs822393, rs16861210, rs822395, rs822396, rs12495941 and rs7649121) with HDL-C and ApoA1 levels. CONCLUSION: Several individual polymorphisms (rs822393, rs822395 and rs7649121) and a haplotype of ADIPOQ gene were significantly associated with cardiovascular disease risk factors in European adolescents.