Maria Dimitriou

Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake

Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants. Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake. Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10−6 were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data. Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10−8) and lower fat (β ± SE: −0.21 ± 0.04%; P = 1.57 × 10−9) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)–increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10−10), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10−7). Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

Meta-Analysis Investigating Associations Between Healthy Diet and Fasting Glucose and Insulin Levels and Modification by Loci Associated With Glucose Homeostasis in Data From 15 Cohorts

Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 U.S. and European cohort studies comprising 51,289 persons without diabetes to test whether genotype and diet interact to influence FG or FI concentration. We constructed a diet score using study-specific quartile rankings for intakes of whole grains, fish, fruits, vegetables, and nuts/seeds (favorable) and red/processed meats, sweets, sugared beverages, and fried potatoes (unfavorable). We used linear regression within studies, followed by inverse-variance-weighted meta-analysis, to quantify 1) associations of diet score with FG and FI levels and 2) interactions of diet score with 16 FG-associated loci and 2 FI-associated loci. Diet score (per unit increase) was inversely associated with FG (β = -0.004 mmol/L, 95% confidence interval: -0.005, -0.003) and FI (β = -0.008 ln-pmol/L, 95% confidence interval: -0.009, -0.007) levels after adjustment for demographic factors, lifestyle, and body mass index. Genotype variation at the studied loci did not modify these associations. Healthier diets were associated with lower FG and FI concentrations regardless of genotype at previously replicated FG- and FI-associated loci. Studies focusing on genomic regions that do not yield highly statistically significant associations from main-effect genome-wide association studies may be more fruitful in identifying diet-gene interactions.

Prevalence of iron deficiency among schoolchildren of different socio-economic status in urban Turkey

Objective: To investigate the prevalence of iron deficiency among schoolchildren of different socio-economic status (SES), living in the three largest cities of Turkey.Design: Cross-sectional study.Settings: Primary schools of Istanbul, Ankara and Izmir.Subjects: Schoolchildren aged 12 and 13 y (males: 504; females: 510) from nine primary schools. Inclusion of subjects in the study was on a voluntary basis.Methods: Data were obtained on children SES, anthropometry, haematological and biochemical indices of iron status and consumption of food items related to dietary iron bioavailability. One-way analysis of variance was mainly applied, for the evaluation of the tested hypotheses, using Bonferroni correction in order to take into account the inflation of Type I error.Results: Iron deficiency (serum ferritin <15 μg/l) prevalence was 17.5% among boys and 20.8% among girls. Furthermore, iron deficiency was significantly more prevalent among boys of lower SES, who were also found to have significantly lower levels of serum iron, serum ferritin, transferrin saturation, mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration compared to those of higher SES. In terms of dietary factors affecting iron bioavailability, low SES boys exhibited significantly higher frequency of tea consumption and lower frequency of citrus fruit, red meat and fish consumption, compared to their higher SES counterparts.Conclusion: The prevalence of iron deficiency was relatively high, particularly among lower SES schoolboys. Higher tea and lower citrus fruits, red meat and fish consumption by boys of lower SES may provide an indication about the possible role of certain dietary patterns in the different manifestation of this medical condition among the socio-economic groups. However, further research is needed.Sponsorship: This study was supported by a research grant from Kellogg Europe and Bogazici University.

The Molecular Genetic Architecture of Self-Employment

Economic variables such as income, education, and occupation are known to affect mortality and morbidity, such as cardiovascular disease, and have also been shown to be partly heritable. However, very little is known about which genes influence economic variables, although these genes may have both a direct and an indirect effect on health. We report results from the first large-scale collaboration that studies the molecular genetic architecture of an economic variable–entrepreneurship–that was operationalized using self-employment, a widely-available proxy. Our results suggest that common SNPs when considered jointly explain about half of the narrow-sense heritability of self-employment estimated in twin data (σg 2/σP 2 = 25%, h 2 = 55%). However, a meta-analysis of genome-wide association studies across sixteen studies comprising 50,627 participants did not identify genome-wide significant SNPs. 58 SNPs with p<10−5 were tested in a replication sample (n = 3,271), but none replicated. Furthermore, a gene-based test shows that none of the genes that were previously suggested in the literature to influence entrepreneurship reveal significant associations. Finally, SNP-based genetic scores that use results from the meta-analysis capture less than 0.2% of the variance in self-employment in an independent sample (p≥0.039). Our results are consistent with a highly polygenic molecular genetic architecture of self-employment, with many genetic variants of small effect. Although self-employment is a multi-faceted, heavily environmentally influenced, and biologically distal trait, our results are similar to those for other genetically complex and biologically more proximate outcomes, such as height, intelligence, personality, and several diseases.

Cardiovascular disease risk factors among children of different socioeconomic status in Istanbul, Turkey: directions for public health and nutrition policy.

ObjectivesThe aim of the current study was to examine the influence of socioeconomic status (SES) on physiological (lipid profile, obesity indices) and behavioral (dietary habits, physical activity) cardiovascular disease (CVD) risk factors among primary schoolchildren in Istanbul.DesignCross sectional study.SettingOne private school and two public schools from different SES districts in Istanbul.Participants510 randomly selected children aged 12 and 13 years old (257 boys, 253 girls).ResultsThe prevalence of overweight (15.2%) and the energy intake (p < 0.001 and p < 0.05 for boys and girls respectively) were found to be higher for the middle/ high SES group for both genders. Regarding biochemical indices, middle/ high SES children had higher values of High Density Lipoprotein-cholesterol (HDL-C) (p < 0.001 and p < 0.05 for boys and girls respectively) and lower values of TC/HDL-C ratio and LDL-C/HDL-C ratio (p < 0.05 and p < 0.001 for boys and girls respectively). This could be attributed to the higher physical activity levels observed for middle/ high SES children (p < 0.001).ConclusionThe findings of the current study revealed a coexistence of both overweight and higher energy intake in middle/ high SES children, as well as a coexistence of underweight and lower physical activity levels in low SES children. These observations should guide the public health policy in developing appropriate intervention strategies to efficiently tackle these health and social issues early in life.

Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians

BACKGROUND Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. OBJECTIVE We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus. DESIGN Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations. RESULTS Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance. CONCLUSION The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

Parental educational level and cardiovascular disease risk factors in schoolchildren in large urban areas of Turkey: Directions for public health policy

BackgroundIt is widely accepted that the development of atherosclerosis starts at an early age. However, there are very few studies evaluating the prevalence of the common clinical and behavioral cardiovascular disease (CVD) risk factors among children, especially in developing countries. The aim of the present cross-sectional survey was to evaluate the distribution of blood lipid profile and various behavioral (i.e. dietary habits, physical activity status) factors related to CVD risk and its relationships to paternal (PEL) and maternal educational level (MEL) among primary schoolchildren in Turkey.MethodsIn three major metropolises in Turkey (Istanbul, Ankara and Izmir), a random sample of 1044 children aged 12 and 13 years old was examined. ANOVA was applied to evaluate the tested hypothesis, after correcting for multiple comparisons (Tukey correction).ResultsAfter controlling for energy and fat intake, physical activity status and Body Mass Index (BMI), it was found that mostly PEL had a significant positive effect for most of the subgroups examined (Lower vs. Higher and Medium vs. Higher) on TC and HDL-cholesterol and a negative effect on TC/HDL ratio for both genders. Furthermore, both boys and girls with higher PEL and MEL were found to have higher energy intake derived from fat and protein than their counterparts with Medium and Lower PEL and MEL, while the opposite was observed for the percentage of energy derived from carbohydrates.ConclusionsOur study provides indications for a possible association between an adverse lipid profile, certain dietary patterns and Higher PEL and MEL among schoolchildren in Turkey. These findings underline the possible role of social status, indicated by the degree of education of both parents, in developing certain health behaviors and health indices among Turkish children and provide some guidance for Public Health Policy.

Exclusive olive oil consumption has a protective effect on coronary artery disease; overview of the THISEAS study

OBJECTIVE The aims of the current report are to present the demographic characteristics, clinical characteristics/biochemical indices and lifestyle habits of the population and to explore the potential association of exclusive olive oil consumption, in relation to lifestyle factors, with coronary artery disease risk. DESIGN Demographic, lifestyle, dietary and biochemical variables were recorded. Logistic regression analysis was performed in order to estimate the relative risks of developing coronary artery disease. SETTING The Hellenic study of Interactions between Single nucleotide polymorphisms and Eating in Atherosclerosis Susceptibility (THISEAS), a medical centre-based case-control study conducted in Greek adults. SUBJECTS We consecutively enrolled 1221 adult patients with coronary artery disease and 1344 adult controls. RESULTS A higher prevalence of the conventional established risk factors was observed in cases than in controls. Physical activity level was higher in controls (1·4 (sd 0·2) than in cases (1·3 (sd 0·3); P<0·001). Regarding current and ex-smokers, the case group reported almost double the pack-years of the control group (54·6 (sd 42·8) v. 28·3 (sd 26·3), respectively; P<0·001). Exclusive olive oil consumption was associated with 37 % lower likelihood of developing coronary artery disease, even after taking into account adherence to the Mediterranean diet (OR=0·63; 95 % CI 0·42, 0·93; P=0·02). CONCLUSIONS Exclusive olive oil consumption was associated with lower risk of coronary artery disease, even after adjusting for adoption of an overall healthy dietary pattern such as the Mediterranean diet.

Gene–Diet Interactions in Cardiovascular Disease

Cardiovascular disease (CVD), the leading cause of mortality worldwide, results from a complex interplay between genetic and environmental factors. Genetic studies identified genetic variants providing insights into the pathogenesis and treatment of the disease. However, the mechanisms linking the genotypic and phenotypic expression remain to be elucidated. Gene–diet interaction studies attempt to elucidate how a modifiable factor interacts with the genetic background. The knowledge gained thus far confers to small increments of CVD risk and cannot explain the molecular mechanisms of the disease. Epigenetic studies attempt to elucidate the molecular pathways affected by an environmental stimulus, such as dietary exposure. The epigenomic changes and their link to gene–diet interactions remain a challenging area for research. Understanding the complex interplay among the epigenome, genome, and dietary exposure should lead to accurate prediction, prevention, or treatment of the disease.

Evaluating the glucose raising effect of established loci via a genetic risk score

Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with glucose levels. We tested the hypothesis here whether the cumulative effect of glucose raising SNPs, assessed via a score, is associated with glucose levels. A total of 1,434 participants of Greek descent from the THISEAS study and 1,160 participants form the GOMAP study were included in this analysis. We developed a genetic risk score (GRS), based on the known glucose-raising loci, in order to investigate the cumulative effect of known glucose loci on glucose levels. In the THISEAS study, the GRS score was significantly associated with increased glucose levels (mmol/L) (β ± SE: 0.024 ± 0.004, P = 8.27e-07). The effect of the genetic risk score was also significant in the GOMAP study (β ± SE: 0.011 ± 0.005, P = 0.031). In the meta-analysis of the two studies both scores were significantly associated with higher glucose levels GRS: β ± SE: 0.019 ± 0.003, P = 1.41e-09. Also, variants at the SLC30A8, PROX1, MTNR1B, ADRA2A, G6PC2, LPIN3 loci indicated nominal evidence for association with glucose levels (p < 0.05). We replicate associations of the established glucose raising variants in the Greek population and confirm directional consistency of effects (binomial sign test p = 6.96e-05). We also demonstrate that the cumulative effect of the established glucose loci yielded a significant association with increasing glucose levels.