Gene × dietary pattern interactions in obesity: Analysis of up to 68 317 adults of European ancestry

Obesity is highly heritable. Genetic variants showing robust associations with obesity traits have been identified through genome-wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphisms were genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GR

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Μη αλκοολική λιπώδης νόσος του ήπατος (NAFLD): o ρόλος γενετικών και περιβαλλοντικών παραγόντων

Aims and Objectives: Non-alcoholic fatty liver disease (NAFLD) is a complex disease, resulting from a variety of genetic and environmental factors. The aim of this Doctoral dissertation was to figure out the role of these factors in NAFLD odds and in common NAFLD-related biomarkers in a Greek sample. The study sample consisted of 351 non-related individuals, 134 NAFLD patients and 217 controls. Disease was diagnosed by liver ultrasound and by exclusion of other factors of liver disease. Subjects were clinically assessed and interviewed for their dietary and lifestyle factors. Food groups were extracted from a 172 food-item food-frequency questionnaire (FFQ) and four dietary patterns were derived by factor analysis. Regarding the genetic background of the disease, four well-replicated loci were selected. Genotypes for PNPLA3 rs738409, TM6SF2 rs58542926, GCKR rs780094 and MBOAT7 rs641738 were extracted from a genome-wide single nucleotide polymorphism (SNP) database. Main Results: We replicated the effect of previously reported contributors to NAFLD likelihood in this Greek sample, including PNPLA3 genotype. Carrying one copy of the rs738409 was associated with 2.28U/L higher alanine transaminase (ALT), 0.08% higher glycated haemoglobin (HbA1c) levels and 0.08U/L lower aspartate transaminase (AST) to ALT ratio compared to non-carriers, independent of age, gender, BMI & NAFLD status. Carrying one copy of rs780094 was associated with 1.45U/L higher AST levels and one copy of rs58542926 with increased gamma-glutamyltransferase (gamma-GT) levels by 7.89U/L compared to non-carriers, after adjusting for the same confounding factors. Fish, fatty fish and nuts intakes were associated with decreased odds of developing NAFLD, whereas refined starchy foods, fast food, sweet spreads and sugar, sauces and fried food increased the odds of NAFLD, independent of confounding factors. Individuals in the highest quartile of a “Fast-food type” pattern compared to the lowest had 3.9 times higher odds for NAFLD, after adjusting for confounding factors (p=0.003). Furthermore, individuals in the 2nd quartile of a “Unsaturated fatty acids” pattern had 55.7% reduced risk of developing the disease compared to those in the 1st quartile, after adjusting for confounding factors (p=0.039). Greater adherence to the “Fast-food type” pattern was associated with higher levels of CRP and uric acid, whereas greater adherence to a “Prudent” dietary pattern was negatively associated with TG and uric acid levels, after adjusting for confounding factors. A 1-unit increase of the “Unsaturated FA” pattern score was significantly associated with lower levels of insulin and HOMAIR, independent of confounding factors. Starting smoking one year later significantly decreased NAFLD odds by 9.5%, whereas daily television (TV) viewing duration was positively associated with AST, FBG and CRP levels, independent of age, gender, BMI and NAFLD status. Sleep duration was not associated with the disease or any disease parameter. Remarkably, it was found that fish and fatty fish intake confers susceptibility to carriers of the TM6SF2 polymorphism and significantly increases NAFLD odds by 50.3% and 69.3% compared to non-carriers, respectively, after adjusting for age, gender, energy intake, pack-years, PAL, rs58542926 and fish/fatty fish consumption. Moreover, a significant interaction between rs58542926 and the “Prudent” dietary pattern was observed regarding serum triglycerides levels (betainteraction =20.53, p=7.1E-4), independent of age, gender, energy intake, NAFLD status, rs58542926 and the “Prudent” dietary pattern. An additive effect of GCKR rs780094 and TV viewing on AST levels was identified (betainteraction= 1.079, p=6.3E-4), independent of confounding factors.Conclusions: Widely replicated regarding NAFLD genetic polymorphisms alter the effect of environmental factors, such as diet, smoking and physical activity on liver health. The novel findings of this Doctoral dissertation provide further rationale on the need for personalized nutritional advice, based on the genetic makeup of NAFLD patients.Σκοπός της μελέτης: Η μη-αλκοολική νόσος του λιπώδους ήπατος (ΝAFLD) είναι μία νόσος με σύνθετη αιτιολογία, η οποία αποδίδεται σε ποικιλία γενετικών και περιβαλλοντικών παραγόντων. Σκοπός της παρούσας Διδακτορικής διατριβής ήταν η διερεύνηση του ρόλου των παραγόντων αυτών στην πιθανότητα εμφάνισης ΝAFLD καθώς και σε κοινούς βιοδείκτες που σχετίζονται με την παθογένεια της νόσου. Το δείγμα της μελέτης αποτελείτο από 351 μη-σχετιζόμενα άτομα, 134 ασθενείς με ΝAFLD και 217 μάρτυρες. Η διάγνωση της νόσου έγινε με υπερηχογράφημα ήπατος και έπειτα από αποκλεισμό άλλων αιτιών παρουσίας της νόσου. Πραγματοποιήθηκε κλινική αξιολόγηση των συμμετεχόντων, καθώς και λήφθηκαν δεδομένα σχετικά με τις διατροφικές τους συνήθειες και τον τρόπο ζωής τους μέσω συνέντευξης. Από ένα ερωτηματολόγιο συχνότητας κατανάλωσης 172 τροφίμων, έγινε εξαγωγή των ομάδων τροφίμων καθώς και 4 διατροφικών προτύπων μέσω ανάλυσης παραγόντων. Όσον αφορά στα γενετικά δεδομένα, οι 4 ευρέως επαληθευμένoι ως προς τη ΝAFLD πολυμορφισμοί γονιδίων επιλέχτηκαν από μία βάση 300,000 πολυμορφισμών: PNPLA3 rs738409, TM6SF2 rs58542926, GCKR rs780094 και MBOAT7 rs641738. Κύρια αποτελέσματα: Σε αυτό το δείγμα Ελληνικού πληθυσμού, επαληθεύσαμε την επίδραση γνωστών παραγόντων από τη διεθνή βιβλιογραφία στην πιθανότητα εμφάνισης της νόσου, συμπεριλαμβανομένου του PNPLA3 γονοτύπου. Η παρουσία ενός αντιγράφου του rs738409 συσχετίστηκε με 2,28U/L υψηλότερα επίπεδα ALT, 0,08% υψηλότερα επίπεδα HbA1c και 0,08U/L χαμηλότερo λόγο AST/ALT, συγκριτικά με τους μη-φορείς, ανεξάρτητα από την ηλικία, το φύλο, τον δείκτη μάζας σώματος (ΔΜΣ) και την παρουσία νόσου. Η παρουσία ενός αντιγράφου του rs780094 συσχετίστηκε με 1,45U/L υψηλότερα επίπεδα AST, ενώ η παρουσία ενός αντιγράφου του rs58542926 με αυξημένα επίπεδα γ-γλουταμυλτρανσφεράσης κατά 7,89U/L, συγκριτικά με τους μη-φορείς, ανεξάρτητα από τους ίδιους συγχυτικούς παράγοντες. Η κατανάλωση ψαριών, λιπαρών ψαριών και ξηρών καρπών συσχετίστηκε με μειωμένες πιθανότητες εμφάνισης της νόσου, ενώ η κατανάλωση επεξεργασμένων δημητριακών, γρήγορου φαγητού, γλυκών αλοιφών και ζάχαρης, σαλτσών και τηγανιτών τροφίμων αύξησαν τις πιθανότητες παρουσίας ΝAFLD, ανεξάρτητα από συγχυτικούς παράγοντες. Συμμετέχοντες που ανήκαν στο ανώτερο τεταρτημόριο κατανάλωσης ενός «Τύπου γρήγορου φαγητού» προτύπου είχαν 3,9 φορές υψηλότερη πιθανότητα εμφάνισης της νόσου συγκριτικά με εκείνους του κατώτερου τεταρτημορίου, ανεξάρτητα από συγχυτικούς παράγοντες (p=0.003). Επιπλέον, άτομα του 2ου τεταρτημορίου ενός «πλούσιου σε ακόρεστα λιπαρά οξέα» προτύπου είχαν μειωμένο κίνδυνο εμφάνισης της νόσου συγκριτικά με εκείνα του 1ου, μετά από διόρθωση για συγχυτικούς παράγοντες (p=0.039). Υψηλότερη προσκόλληση στο «Τύπου γρήγορου φαγητού» πρότυπο συσχετίστηκε με υψηλότερα επίπεδα CRP και ουρικού οξέος, ενώ υψηλότερη προσκόλληση σε ένα «Συνετό» διατροφικό πρότυπο συσχετίστηκε αρνητικά με τα επίπεδα τριγλυκεριδίων και ουρικού οξέος, ανεξάρτητα από συγχυτικούς παράγοντες. Αύξηση του σκορ για το «πλούσιο σε ακόρεστα λιπαρά οξέα» πρότυπο κατά μία μονάδα συσχετίστηκε με χαμηλότερα επίπεδα ινσουλίνης και HOMAIR, μετά από διόρθωση για συγχυτικούς παράγοντες. Η καθυστέρηση της έναρξης καπνίσματος κατά ένα χρόνο μείωσε στατιστικά σημαντικά της πιθανότητες εμφάνισης της νόσου κατά 9,5%, ενώ ο χρόνος που δαπανάται καθημερινά στην τηλεόραση συσχετίστηκε θετικά με τα επίπεδα AST, CRP και γλυκόζης νηστείας, έπειτα από διόρθωση για ηλικία, φύλο, ΔΜΣ και παρουσία ΝAFLD. Δε βρέθηκε κάποια συσχέτιση της διάρκειας του ύπνου με τη νόσο ή παραμέτρους αυτής. Παρατηρήθηκε ότι η κατανάλωση ψαριών και λιπαρών ψαριών αυξάνει σημαντικά τις πιθανότητες εμφάνισης της νόσου κατά 50,3% και 69,3%, αντίστοιχα, στους φορείς του TM6SF2 πολυμορφισμού συγκριτικά με τους μη φορείς, ανεξάρτητα από την ηλικία, το φύλο, την ενεργειακή πρόσληψη, τα πακετο-έτη, το επίπεδο φυσικής δραστηριότητας, του rs58542926 και της κατανάλωσης ψαριών/λιπαρών ψαριών. Επιπλέον, παρατηρήθηκε μία σημαντική αλληλεπίδραση μεταξύ του TM6SF2 rs58542926 και του διατροφικού προτύπου «Συνετό» σε σχέση με τα επίπεδα τριγλυκεριδίων ορού (betainteraction=20,53, p=7,1E-4), ανεξάρτητα από την ηλικία, το φύλο, την ενεργειακή πρόσληψη, την παρουσία ΝAFLD, του TM6SF2 πολυμορφισμού και της κατανάλωσης του προτύπου. Τέλος, παρατηρήθηκε μία αθροιστική επίδραση του GCKR rs780094 και του χρόνου παρακολούθησης τηλεόρασης στα επίπεδα AST (betainteraction= 1.079, p=6.3E-4), ανεξάρτητα από συγχυτικούς παράγοντες.Συμπεράσματα: Ευρέως επαληθευμένοι πολυμορφισμοί γονιδίων σχετικά με το ρόλο τους στη ΝAFLD τροποποιούν την επίδραση περιβαλλοντικών παραγόντων, όπως η δίαιτα, το κάπνισμα και η φυσική δραστηριότητα στην υγεία του ήπατος. Tα πρωτοπόρα ευρήματα της Διδακτορικής αυτής διατριβής προσφέρουν περαιτέρω στοιχεία σχετικά με την ανάγκη παροχής εξατομικευμένων διατροφικών συμβουλών, με βάση τη γενετική σύσταση των ασθενών με ΝAFLD

Associations of VEGF-A-Related Variants with Adolescent Cardiometabolic and Dietary Parameters

Previous research has allowed the identification of variants related to the vascular endothelial growth factor-A (VEGF-A) and their association with anthropometric, lipidemic and glycemic indices. The present study examined potential relations between key VEGF-A-related single-nucleotide polymorphisms (SNPs), cardiometabolic parameters and dietary habits in an adolescent cohort. Cross-sectional analyses were conducted using baseline data from 766 participants of the Greek TEENAGE study. Eleven VEGF-A-related SNPs were examined for associations with cardiometabolic indices through multivariate linear regressions after adjusting for confounding factors. A 9-SNP unweighted genetic risk score (uGRS) for increased VEGF-A levels was constructed to examine associations and the effect of its interactions with previously extracted dietary patterns for the cohort. Two variants (rs4416670, rs7043199) displayed significant associations (p-values p-values p-values < 0.01). The present analyses constitute the first-ever attempt to investigate the influence of VEGF-A-related variants on teenage cardiometabolic determinants, unveiling several associations and the modifying effect of diet

A Posteriori Dietary Patterns and Coronary Artery Disease in a Greek Case–Control Study

Introduction: Diet is one of the most important modifiable risk factors associated with cardiovascular health (CH). Research identifying dietary patterns (DPs) through data-driven analysis and reporting associations between DPs and coronary artery disease (CAD) outcomes is rather limited. Objective: The aim of the present report was to generate DPs through factor analysis (FA) and to examine their association with CAD risk. Methods: Participants (n = 1017) consisted of cases diagnosed with CAD (n = 356) and controls (n = 661) drawn from the THISEAS study. Demographic, anthropometric and lifestyle data were collected. Dietary components were generated through FA. Logistic regression analysis was performed to estimate CAD relative risks. Results: FA generated seven dietary components, explaining 53.5% of the total variation in intake. The Western-type DP showed a modest significant association with CAD risk, after controlling for confounders (OR = 1.20; 95% CI = 1.09–1.32, p p = 0.259). Discussion: The Western-type DP was positively associated with CAD risk and the odds were further increased after controlling for confounders. This finding is in concordance with previously reported positive associations between Western patterns and CAD risk. Limited data exist regarding a posteriori DPs and their effect on CAD risk

A modified response of NAFLD patients with non-significant fibrosis in nutritional counseling according to GCKR rs1260326

Aim To investigate the association between GCKR gene and nutritional treatment in NAFLD-related biomarkers. Methods This was an open-label and single-arm clinical trial in 44 overweight or obese adults with NAFLD receiving nutritional counseling for 6 months. Nutritional data, MedDietScore, clinical, biochemical, inflammatory and oxidative stress biomarkers were evaluated before and after intervention. Further, we genotyped GCKR rs1260326 and in T-allele carriers and non-.-carriers we assessed associations between the GCKR variant and nutritional counseling related to change in all biomarkers evaluated. Results Anthropometric measurements were significantly reduced after the end of the intervention in patients assigned to nutritional counseling. Liver imaging and fibrosis were significantly improved. GCKR rs1260326 T-allele frequency was 46.7%. T-carriers responded better to nutritional counseling regarding fasting blood glucose levels -(mean6-0 change = -4.94 mg/ dL (+/- 9.33), p = 0.005), whereas non-T-carriers did not benefit from the intervention regarding glucose. On the other hand, levels of oxLDL decreased in the non-T-carriers group after the intervention, but not in T-carriers. Conclusions Our results show that GCKR rs1260326 T-allele is associated with better response of NAFLD patients to nutritional treatment regarding fasting blood glucose, but not oxLDL levels. Despite this important finding in the field of nutrigenetics, it is tricky to generalize this effect unless larger studies are conducted

The Effectiveness of Mediterranean Diet in Nonalcoholic Fatty Liver Disease Clinical Course: An Intervention Study

Diet is a modifiable key factor targeted in prevention and management of nonalcoholic fatty liver disease (NAFLD). The aim was to study the effect of Mediterranean Diet (MedDiet) on clinical, biochemical, and inflammatory profile in NAFLD patients with simple steatosis. Potential associations of signal transducer and activator of transcription 3 (STAT3) rs2293152 genotype to diet composition and patients&apos; profile were investigated. In this nonrandomized, open-label, 24-week prospective intervention study, 44 untreated NAFLD patients with nonsignificant fibrosis received nutritional counsel to increase adherence to MedDiet. Adherence to MedDiet was estimated with MedDietScore. Furthermore, we genotyped STAT3 rs2293152 single nucleotide polymorphism and performed clinical and inflammatory measurements. In all patients, MedDietScore increased and anthropometric indices improved, whereas liver imaging, liver fibrosis score, blood pressure, fasting glucose, glycated hemoglobin (HbA1c), C-reactive protein (CRP), visfatin, and oxidized low-density lipoprotein levels were also significantly ameliorated compared with baseline (P &lt; .05). No association of STAT3 polymorphism with diet composition was found. Comparisons of mean differences between G- and C-carriers at the end point of the trial showed that only visfatin was significantly associated with the STAT3 genotype (-0.0 +/- 4.6 vs. -4.2 +/- 3.9, P = .04, respectively). Carrying the G-allele was associated with an increase of the visfatin levels (3.4 +/- 1.5 ng/mL, P = .028). Our results show amelioration of clinical, biochemical, and inflammatory biomarkers in NAFLD patients in response to MedDiet. STAT3 rs2293152 G-carriers experienced more beneficial changes at the end of the intervention compared with baseline. An association between visfatin levels and STAT3 genotype has been shown for the first time

Dietary Patterns, Blood Pressure and the Glycemic and Lipidemic Profile of Two Teenage, European Populations

The present study sought to retrospectively investigate the dietary habits of two adolescent, European populations from the cross-sectional Greek TEENAGE Study and French STANISLAS Family Study. We aimed to explore the relation between the populations&rsquo; dietary patterns and blood pressure, glycemic and lipidemic profile. Dietary patterns were extracted via Principal Component Analysis (PCA), based on data collected from two 24 h dietary recalls for the TEENAGE study and a 3-day food consumption diary for the STANISLAS study. Multiple linear regressions and mixed models analyses, adjusting for confounding factors, were employed to investigate potential associations. A total of 766 Greek teenagers and 287 French teenagers, were included in analyses. Five dietary patterns were extracted for each population accounting for 49.35% and 46.69% of their respective total variance, with similarities regarding the consumption of specific food groups (i.e., western-type foods). In the TEENAGE Study, the &ldquo;chicken and sugars&rdquo; pattern was associated with lower CRP levels, after adjusting for confounding factors (p-value &lt; 0.01). The &ldquo;high protein and animal fat&rdquo; dietary pattern of the STANISLAS Family Study was related to higher BMI (p-value &lt; 0.01) and higher triglycerides levels (p-value &lt; 0.01). Our findings summarize the dietary habits of two teenage, European populations and their associations with cardiometabolic risk factors

Dietary Patterns, Blood Pressure and the Glycemic and Lipidemic Profile of Two Teenage, European Populations

The present study sought to retrospectively investigate the dietary habits of two adolescent, European populations from the cross-sectional Greek TEENAGE Study and French STANISLAS Family Study. We aimed to explore the relation between the populations’ dietary patterns and blood pressure, glycemic and lipidemic profile. Dietary patterns were extracted via Principal Component Analysis (PCA), based on data collected from two 24 h dietary recalls for the TEENAGE study and a 3-day food consumption diary for the STANISLAS study. Multiple linear regressions and mixed models analyses, adjusting for confounding factors, were employed to investigate potential associations. A total of 766 Greek teenagers and 287 French teenagers, were included in analyses. Five dietary patterns were extracted for each population accounting for 49.35% and 46.69% of their respective total variance, with similarities regarding the consumption of specific food groups (i.e., western-type foods). In the TEENAGE Study, the “chicken and sugars” pattern was associated with lower CRP levels, after adjusting for confounding factors (p-value p-value p-value < 0.01). Our findings summarize the dietary habits of two teenage, European populations and their associations with cardiometabolic risk factors