Gene-diet Interactions Research Articles

Interactions of dietary insulin index and dietary insulin load with brain-derived neurotrophic factor (BDNF) Val66Met polymorphism in relation to cardiometabolic markers in Iranian diabetic patients: a cross-sectional study.

The progression of cardiometabolic diseases is determined by both genetic and environmental factors. Gene-diet interactions may therefore be important in modulating the risks of developing metabolic diseases. The objectives were to investigate the effect of the interaction between brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms and dietary insulin index (DII) and dietary insulin load (DIL) on cardiometabolic markers among diabetic patients. In this cross-sectional study, blood samples were collected from 667 patients. DIL and DII were defined using a validated FFQ. Genotyping the BDNF Val66Met polymorphism was conducted by the PCR-Restriction fragment length polymorphism(RFLP) method. Interactions between dietary indices and gene variants were evaluated using a generalised linear model. PGF2a concentrations were significantly higher among Val homozygotes than Met-allele carrier. This study revealed that, compared with individuals with the Val/Val genotype, those with the Met/Val or Met/Met genotype had lower BMI (Pinteraction = 0·04), TAG (Pinteraction = 0·04), leptin (Pinteraction = 0·01), LDL (Pinteraction = 0·04) and total cholesterol (Pinteraction = 0·01) when they consumed diets higher on the DIL index. Moreover, the highest quartile of the DIL, compared with the lowest, showed increase in waist circumference (Pinteraction = 0·02) and LDL/HDL (Pinteraction = 0·04) for Val/Val homozygotes compared with Met-allele carriers. BDNF Val66Met variants may interact with DIL and DII, thus be involved in the development of cardiometabolic risk factors. If diabetic patients with Met alleles regulate dietary intakes, they have a protective opportunity to regulate their cardiometabolic markers.

The iMPROVE Study; Design, Dietary Patterns, and Development of a Lifestyle Index in Overweight and Obese Greek Adults.

Background: Dietary and lifestyle habits constitute a significant contributing factor in the formation of anthropometric and biochemical characteristics of overweight and obese populations. The iMPROVE study recruited overweight and obese Greek adults and investigated the effect of gene–diet interactions on weight management when adhering to a six-month, randomized nutritional trial including two hypocaloric diets of different macronutrient content. The present paper displays the design of the intervention and the baseline findings of the participants’ dietary habits and their baseline anthropometric and biochemical characteristics. Methods: Baseline available data for 202 participants were analyzed and patterns were extracted via principal component analysis (PCA) on 69-item Food-Frequency Questionnaires (FFQ). Relationships with indices at baseline were investigated by multivariate linear regressions. A Lifestyle Index of five variables was further constructed. Results: PCA provided 5 dietary patterns. The “Mixed” pattern displayed positive associations with logBMI and logVisceral fat, whereas the “Traditional, vegetarian-alike” pattern was nominally, negatively associated with body and visceral fat, but positively associated with HDL levels. The Lifestyle Index displayed protective effects in the formation of logBMI and logGlucose levels. Conclusions: Dietary patterns and a Lifestyle Index in overweight and obese, Greek adults highlighted associations between diet, lifestyle, and anthropometric and biochemical indices.

Interaction between dietary total antioxidant capacity and BDNF Val66Met polymorphism on lipid profiles and atherogenic indices among diabetic patients

Brain-derived neurotrophic factor (BDNF) belongs to the “neurotrophin” family of growth factors, and it has recently been associated to cardiovascular disease (CVD). We anticipated that BDNF Val66Met polymorphisms may alter CVD risk markers such as serum lipid profile differences, and interaction with total antioxidant capacity of diet (DTAC) could alter these clinical parameters. This cross-sectional study consisted of 667 diabetic patients (39.7% male and 60.3% female). DTAC was calculated by international databases. Biochemical markers including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), superoxide dismutase (SOD), C-reactive protein (CRP), total antioxidant capacity (TAC), pentraxin-3 (PTX3), isoprostaneF2α (PGF2α). interleukin 18 (IL18), leptin and ghrelin were measured by standard protocol. Atherogenic indices (AIP, AC, CR-I, CR-II) were calculated. Genotyping of the BDNF Val66Met polymorphisms was conducted by the real-time PCR–RFLP method. The gene-diet interactions were evaluated using a generalized linear mode (GLMs). Carriers of the Val/Met genotype who were in the higher median intake of FRAP had lower HDL (P:0.04) and higher TG (P:0.005), AIP (P:0.02) and AC (P:0.02) index compared to Val/Val genotypes with lower median intake. Moreover, diabetic patients with Val/Met genotype who consumed higher ORAC intake had increased odds for anthropometric indices (BMI (P:0.01) and WC (P:0.03)), lipid profiles (TG) (P:0.01), and atherogenic index (AIP) (P:0.02), also decreased odds for HDL (P:0.03) concentration compared to reference group whit lower ORAC intake. Individuals with Val/Met genotype who consumed higher TRAP intake had increased odds for WC (P:0.04), TC (P:0.001), TG (P < 0.001), AIP (P < 0.001) and AC (P < 0.001). Finally, Val/Met patients with a higher median intake of TEAC had higher TG (P:0.02), AIP (P:0.009) and AC (P:0.03) compared to the reference group whit lower TEAC intake. Our study showed that Val/Met genotype had also the highest lipid profile and atherogenic indices even in the highest adherence to DTAC. While it seems that the presence of the Val/Val wild-type and BDNF Met/Met homozygotes in diabetic patients with a high DTAC is a protective factor.

GeNuIne (gene-nutrient interactions) Collaboration: towards implementing multi-ethnic population-based nutrigenetic studies of vitamin B12 and D deficiencies and metabolic diseases.

Gene-nutrient interactions (GeNuIne) collaboration, a large-scale collaborative project, has been initiated to investigate the impact of gene-nutrient interactions on cardiometabolic diseases using population-based studies from ethnically diverse populations. In this project, the relationship between deficiencies of vitamins B12 and D, and metabolic diseases was explored using a nutrigenetic approach. A genetic risk score (GRS) analysis was used to examine the combined effect of several genetic variations that have been shown to be associated with metabolic diseases and vitamin B12 and D deficiencies, respectively. In Sri Lankan, Indonesian and Brazilian populations, those carrying a high B12-GRS had an increased risk of metabolic diseases under the influence of dietary protein, fibre and carbohydrate intakes, respectively; however, in Asian Indians, genetically instrumented metabolic disease risk showed a significant association with low vitamin B12 status. With regards to nutrigenetic studies on vitamin D status, although high metabolic-GRS showed an interaction with dietary carbohydrate intake on vitamin D status, the study in Indonesian women demonstrated a vitamin D GRS-carbohydrate interaction on body fat percentage. In summary, these nutrigenetic studies from multiple ethnic groups have provided evidence for the influence of the dietary factors on the relationship between vitamin B12/D deficiency and metabolic outcomes. Furthermore, these studies highlight the existence of genetic heterogeneity in gene-diet interactions across ethnically diverse populations, which further implicates the significance of personalised dietary approaches for the prevention of these micronutrient deficiencies and metabolic diseases.

Dietary Patterns Influence Target Gene Expression through Emerging Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) refers to the pathologic buildup of extra fat in the form of triglycerides in liver cells without excessive alcohol intake. NAFLD became the most common cause of chronic liver disease that is tightly associated with key aspects of metabolic disorders, including insulin resistance, obesity, diabetes, and metabolic syndrome. It is generally accepted that multiple mechanisms and pathways are involved in the pathogenesis of NAFLD. Heredity, sedentary lifestyle, westernized high sugar saturated fat diet, metabolic derangements, and gut microbiota, all may interact on a on genetically susceptible individual to cause the disease initiation and progression. While there is an unquestionable role for gene-diet interaction in the etiopathogenesis of NAFLD, it is increasingly apparent that epigenetic processes can orchestrate many aspects of this interaction and provide additional mechanistic insight. Exciting research demonstrated that epigenetic alterations in chromatin can influence gene expression chiefly at the transcriptional level in response to unbalanced diet, and therefore predispose an individual to NAFLD. Thus, further discoveries into molecular epigenetic mechanisms underlying the link between nutrition and aberrant hepatic gene expression can yield new insights into the pathogenesis of NAFLD, and allow innovative epigenetic-based strategies for its early prevention and targeted therapies. Herein, we outline the current knowledge of the interactive role of a high-fat high-calories diet and gene expression through DNA methylation and histone modifications on the pathogenesis of NAFLD. We also provide perspectives on the advancement of the epigenomics in the field and possible shortcomings and limitations ahead.

Effect of Diet Quality and Genetic Predisposition on Hemoglobin A1c and Type 2 Diabetes Risk: Gene-Diet Interaction Analysis of 357,419 Individuals.

To assess the interactions between diet quality and genetic predisposition to incident type 2 diabetes (T2D). Between 2006 and 2010, 357,419 participants with genetic and complete dietary data from the UK Biobank were enrolled and prospectively followed up to 2017. The genetic risk score (GRS) was calculated on the basis of 424 variants associated with T2D risk, and a higher GRS indicates a higher genetic predisposition to T2D. The adherence to a healthy diet was assessed by a diet quality score comprising 10 important dietary components, with a higher score representing a higher overall diet quality. There were 5,663 incident T2D cases documented during an average of 8.1 years of follow-up. A significant negative interaction was observed between the GRS and the diet quality score. After adjusting for major risk factors, per SD increment in the GRS and the diet quality score was associated with a 54% higher and a 9% lower risk of T2D, respectively. A simultaneous increment of 1 SD in both the diet quality score and GRS was additionally associated with a 3% lower T2D risk due to the antagonistic interaction. In categorical analyses, a sharp reduction of 23% in T2D risk associated with a 1-SD increment in the diet quality score was detected among participants in the extremely high GRS group (GRS >95%). We also observed a strong negative interaction between the GRS and the diet quality score on the blood HbA1c level at baseline (P < 0.001). The adherence to a healthy diet was associated with more reductions in blood HbA1c levels and subsequent T2D risk among individuals with a higher genetic risk. Our findings support tailoring dietary recommendations to an individual's genetic makeup for T2D prevention.

The Effects of Nutrients on Gene Expression in the Pathogenesis of Type 2 Diabetes Mellitus

To review current research identifying relationships between individual genetic loads, diet, and Type II diabetes mellitus. Type II diabetes mellitus is considered a global pandemic, with increasing rates worldwide (Berna, G. et al., 2014). The pathophysiology of diabetes mellitus is not completely understood, but as recent research shows, gene variants and nutrient interactions play an important role in dietary interventions to prevent the onset of type II diabetes mellitus. A literature search of trials was conducted using five databases: Academic Search Complete, PubMed, CINAHL Plus with Full Text, Cochrance, and Scopus. Key terms included in the search were “nutrigenomics,” “diabetes mellitus” and “gene expression”. In addition, key terms “precision nutrition” and “diet-gene interaction” were used in Scopus and PubMed to further narrow the results. A total of 122 articles were found. Eligibility criteria for reports included the year of publication from 2010-current, peer-reviewed studies, published in English, use of objective measures, and focused on obesity and type II diabetes mellitus. A total of ten studies were included in this review. Findings suggest nearly 90 different genes associated with the pathogenesis of type 2 diabetes mellitus. Healthier diets were found to be associated with genes involved in metabolic function. Studies also suggest that the Mediterranean dietary pattern seems to have a beneficial effect in modulating gene expression associated with obesity and type 2 diabetes mellitus. Seven out of ten studies analyzed used animal subjects to determine gene expression. Further research should be conducted to determine the gene expressions in the pathogenesis of type 2 diabetes mellitus using longitudinal studies amongst human subjects.

Impact of dietary and obesity genetic risk scores on weight gain

Whether genetic background and/or dietary behaviors influence weight gain in middle-aged subjects is debated. To assess whether genetic background and/or dietary behaviors are associated with changes in obesity markers (BMI, weight, and waist and hip circumferences) in a Swiss population-based cohort. Cross-sectional and prospective (follow-up of 5.3 y) study. Two obesity genetic risk scores (GRS) based on 31 or 68 single nucleotide polymorphisms were used. Dietary intake was assessed using a semiquantitative FFQ. Three dietary patterns "Meat & fries" (unhealthy), "Fruits & vegetables" (healthy), and "Fatty & sugary" (unhealthy), and 3 dietary scores (2 Mediterranean and the Alternative Healthy Eating Index [AHEI]) were computed. On cross-sectional analysis (N=3033, 53.2% females, 58.4±10.6 y), obesity markers were positively associated with unhealthy dietary patterns and GRS, and negatively associated with healthy dietary scores and patterns. On prospective analysis (N=2542, 54.7% females, age at baseline 58.0±10.4 y), the AHEI and the "Fruits & vegetables" pattern were negatively associated with waist circumference gain: multivariate-adjusted average±SE 0.96±0.25 compared with 0.11±0.26 cm (P for trend 0.044), and 1.14±0.26 compared with -0.05±0.26 cm (P for trend 0.042) for the first and fourth quartiles of the AHEI and the "Fruits & vegetables" pattern, respectively. Similar inverse associations were obtained for changes in waist>5 cm: multivariate-adjusted OR (95% CI): 0.65 (0.50, 0.85) and 0.67 (0.51, 0.89) for the fourth versus the first quartile of the AHEI and the "Fruits & vegetables" dietary pattern, respectively. No associations were found between GRS and changes in obesity markers, and no significant gene-diet interactions were found. Dietary intake, not GRS, are associated with waist circumference in middle-aged subjects living in Lausanne, Switzerland.

Association of maternal dietary habits and ADIPOQ gene polymorphisms with the risk of congenital heart defects in offspring: a hospital-based case-control study.

To estimate the association of maternal ADIPOQ gene, dietary habits in early pregnancy, and their interactions with the risk of congenital heart defects (CHDs) in offspring. A case-control study of 464 mothers of CHDs children and 504 mothers of healthy children was included. Maternal dietary habits and genetic polymorphisms of ADIPOQ were the main exposure of interest. Their independent effects and interactions in the development of CHDs were analyzed in our study. The excessive consumption of pickled vegetables (aOR = 1.58, 95%CI: 1.17-2.12), smoked foods (aOR = 1.84, 95%CI:1.34-2.52), barbecued foods (aOR = 1.62, 95%CI: 1.09-2.39), fish and shrimp (aOR = 0.37, 95%CI: 0.27-50), and milk products (aOR = 0.64, 95%CI: 0.51-80) had a significant association with total CHDs risk. The polymorphisms of ADIPOQ gene at rs1501299 (T/T vs G/G: aOR = 0.27, 95%CI: 0.14-50; G/T vs G/G: aOR = 0.67, 95%CI: 0.46-98) and rs2241766 (G/G vs T/T: aOR = 4.35, 95%CI: 2.23-8.51; T/G vs T/T: aOR = 2.23, 95%CI: 1.51-3.28) showed a significant association with total CHDs risk. Likewise, our results found that maternal dietary habits and ADIPOQ genetic variants also were significantly related to the risk of specific CHDs phenotypes. In addition, gene-diet interaction revealed significant associations between the ADIPOQ gene and maternal dietary habits with total CHDs. Maternal dietary habits, ADIPOQ gene, and their interactions show a significant association with the risk of CHDs. However, our study has some limitations, thus our findings need to be taken with caution, which highlights that more studies are required to further corroborate our findings.

Interactions between Caveolin-1 (rs3807992) polymorphism and major dietary patterns on cardio-metabolic risk factors among obese and overweight women

BackgroundCaveolin-1 (CAV-1) is a cholesterol-dependent essential component located in caveolae. Several studies have been CAV-1 related to cardio-metabolic parameters in animal models, however, there are few studies in humans. Importantly, there is no study has investigated the interaction between CAV-1 rs3807992 gene and dietary patterns (DPs) on cardio-metabolic risk factors.MethodsThe current cross-sectional study was conducted on 404 overweight and obese women. Dietary intake was obtained from FFQ with 147 items. The CAV-1 genotype was measured by the PCR-RFLP method. The anthropometric measurements, serum lipid profile, and inflammatory markers were measured by standard protocols.ResultsThere was a significant interaction between CAV-1 rs3807992 and healthy DP on high-density cholesterol (HDL) (P-interaction = 0.03), TC/HDL (P-interaction = 0.03) and high sensitivity C-reactive protein (hs-CRP) (P-interaction = 0.04); in A-allele carriers, higher following a healthy DP was related to a higher level of HDL and lower TC/HDL and hs-CRP. As well as, the significant interactions were observed between CAV-1 rs3807992 and unhealthy DP in relation to triglyceride (TG) (P-interaction = 0.001), aspartate aminotransferase (AST) (P-interaction = 0.01) and monocyte chemoattractant protein-1(MCP-1) (P-interaction = 0.01); A-allele carriers were more following the unhealthy DP had lower levels of TG, AST and MCP-1.ConclusionsOur study revealed a significant gene-diet interaction between rs3807992 SNPs and DPs in relation to cardio-metabolic risk factors; A-allele carriers might be more sensitive to dietary composition compared to GG homozygotes. Following a healthy DP in A-allele-carriers may be improved their genetic association with cardio-metabolic risk factors.

Assessing Interactions between PNPLA3 and Dietary Intake on Liver Steatosis in Mexican-Origin Adults.

Mexican-origin (MO) adults have among the highest rates of nonalcoholic fatty liver disease (NAFLD) placing them at increased risk of liver cancer. Evidence suggests that a single nucleotide polymorphism (SNP) in the PNPLA3 gene, rs738409, increases the risk and progression of NAFLD and may modify the relationship between certain dietary factors and liver steatosis. The purpose of this study was to identify whether interactions exist between specific dietary factors and rs738409 genotype status among MO adults in relation to levels of liver steatosis. We analyzed cross-sectional data from a sample of 288 MO adults. Participants completed at least two 24-h dietary recalls. Multiple linear regression was performed assuming an additive genetic model to test the main effects of several dietary variables on levels of hepatic steatosis, adjusting for covariates. To test for effect modification, the product of the genotype and the dietary variable was included as a covariate in the model. No significant association between dietary intake and level of hepatic steatosis was observed, nor any significant gene-diet interactions. Our findings suggest that dietary intake may have the same magnitude of protective or deleterious effect even among MO adults with high genetic risk for NAFLD and NAFLD progression.

Dietary Acid Load and Its Interaction with IGF1 (rs35767 and rs7136446) and IL6 (rs1800796) Polymorphisms on Metabolic Traits among Postmenopausal Women.

The objective of this study was to explore the effects of dietary acid load (DAL) and IGF1 and IL6 gene polymorphisms and their potential diet–gene interactions on metabolic traits. A total of 211 community-dwelling postmenopausal women were recruited. DAL was estimated using potential renal acid load (PRAL). Blood was drawn for biochemical parameters and DNA was extracted and Agena® MassARRAY was used for genotyping analysis to identify the signalling of IGF1 (rs35767 and rs7136446) and IL6 (rs1800796) polymorphisms. Interactions between diet and genetic polymorphisms were assessed using regression analysis. The result showed that DAL was positively associated with fasting blood glucose (FBG) (β = 0.147, p < 0.05) and there was significant interaction effect between DAL and IL6 with systolic blood pressure (SBP) (β = 0.19, p = 0.041). In conclusion, these findings did not support the interaction effects between DAL and IGF1 and IL6 single nucleotide polymorphisms (rs35767, rs7136446, and rs1800796) on metabolic traits, except for SBP. Besides, higher DAL was associated with higher FBG, allowing us to postulate that high DAL is a potential risk factor for diabetes.

Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies

ObjectiveTryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes...

The Interaction Between Fatty Acid Desaturase-2 (FADS2) rs174583 Genetic Variant and Dietary Quality Indices (DASH and MDS) Constructs Different Metabolic Phenotypes Among Obese Individuals.

Background and Aim: Genetic variation in fatty acid desaturases (FADS) has previously been linked to several diet-related diseases. We aimed to determine whether the FADS2 rs174583 variant interacts with the Dietary Approach to Stop Hypertension (DASH) score and Mediterranean dietary score (MDS) to influence cardio-metabolic risk factors among obese adults.Methods: This cross-sectional study was performed among 347 apparently healthy obese adults (aged 20–50 years). Dietary quality indicator scores (DASH and MDS) were generated using a validated 147-item Food Frequency Questionnaire (FFQ). The FADS2 rs174583 variant was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The gene–diet interaction was analyzed by the ANCOVA multivariate interaction model.Results: A significant interaction was observed between rs174583 and adherence to the DASH score in relation to serum triglyceride (TG) concentration among the female group (P Interaction = 0.046); CT-genotype carriers who were assigned to the second tertile of DASH compared with those in the first tertile had a lower TG level (P < 0.05). Another significant interaction was revealed between adherence to MDS score and rs174583 polymorphism on serum glucose levels (P Interaction = 0.044); the lowest mean of glucose level was observed in homozygous minor subjects (TT) in the third tertile of MDS, in comparison with other tertiles of this dietary index (P < 0.05). There was a similar significant interaction between DASH and rs174583 in relation to diastolic blood pressure (P Interaction = 0.038) among the male group. Additionally, a significant positive association was found between TT genotype and odds of having high TG both in the crude (OR, 3.21; 95% CI, 1.02–10.14) and adjusted (OR, 3.58; 95% CI, 1.07–11.97) models, taking into account different confounders.Conclusion: Adherence to the dietary quality indicators (DASH and MDS) modified the relationship between FADS2 rs174583 polymorphism and cardio-metabolic risk factors in obese subjects. Prospective cohort studies are needed to confirm the results of our study.

Identification of Gene-Diet Interactions Impacting Glycemic Biomarkers in the Multi-Ethnic TOPMed Cohorts

ObjectivesIdentification of robust gene-diet interactions impacting cardiometabolic traits has been limited due to low statistical power and poor replication across populations. Emerging statistical methods increase power by simultaneously testing genetic interactions with multiple exposures, an especially appealing strategy for complex and highly-correlated dietary traits. Furthermore, meta-analysis across ancestrally and behaviorally diverse populations may allow for more robust discoveries. Here, our objective was to leverage multi-exposure interaction tests in a diverse set of cohorts to identify interactions involving macronutrient ratios and impacting multiple biomarkers of glycemia. MethodsSeven cohorts from the TOPMed consortium (total N ∼ 20,000) contributed whole-genome sequencing data, self-reported dietary data, and glycemic trait measurements (fasting glucose and insulin (FG and FI) and hemoglobin A1c). Three macronutrient ratios were defined to model realistic dietary exchanges and minimize collinearity: carbohydrate: fat, polyunsaturated: saturated fat, and fiber: carbohydrate. For each glycemic trait outcome and common genetic variant, we fit a model including all three ratios and their genetic interactions, with joint significance testing in each cohort followed by cross-cohort meta-analysis. ResultsFour variants showed promising sub-threshold signals (p < 1 × 10–7), though none reached genome-wide significance. For example, diet ratios collectively interacted with rs2276620 in the oxysterol-binding OSBPL6 gene to influence FG (p = 6.5 × 10–8) and rs114448070 in the beta cell function-associated KAT2B gene (p = 5.4 × 10–8) to influence FI. These associations were contributed to by multiple cohorts and multiple dietary factors, emphasizing the value of this multi-cohort and multi-exposure approach to GDI variant detection. ConclusionsOur approach takes advantage of population diversity and multi-faceted dietary exposures to understand genetic effects on the diet-glycemia relationship and support the development of genome-based precision nutrition. Our results will be updated with additional cohorts and gene-based tests using rare genetic variants, which are less common but may have stronger effects. Funding SourcesKEW is supported by an NIDDK T32 award.

Genome-wide analysis in Drosophila reveals diet-by-gene interactions and uncovers diet-responsive genes.

Genetic and environmental factors play a major role in metabolic health. However, they do not act in isolation, as a change in an environmental factor such as diet may exert different effects based on an individual’s genotype. Here, we sought to understand how such gene–diet interactions influenced nutrient storage and utilization, a major determinant of metabolic disease. We subjected 178 inbred strains from the Drosophila genetic reference panel (DGRP) to diets varying in sugar, fat, and protein. We assessed starvation resistance, a holistic phenotype of nutrient storage and utilization that can be robustly measured. Diet influenced the starvation resistance of most strains, but the effect varied markedly between strains such that some displayed better survival on a high carbohydrate diet (HCD) compared to a high-fat diet while others had opposing responses, illustrating a considerable gene × diet interaction. This demonstrates that genetics plays a major role in diet responses. Furthermore, heritability analysis revealed that the greatest genetic variability arose from diets either high in sugar or high in protein. To uncover the genetic variants that contribute to the heterogeneity in starvation resistance, we mapped 566 diet-responsive SNPs in 293 genes, 174 of which have human orthologs. Using whole-body knockdown, we identified two genes that were required for glucose tolerance, storage, and utilization. Strikingly, flies in which the expression of one of these genes, CG4607 a putative homolog of a mammalian glucose transporter, was reduced at the whole-body level, displayed lethality on a HCD. This study provides evidence that there is a strong interplay between diet and genetics in governing survival in response to starvation, a surrogate measure of nutrient storage efficiency and obesity. It is likely that a similar principle applies to higher organisms thus supporting the case for nutrigenomics as an important health strategy.

Recent advances in understanding the adaptive evolution of metabolic genes and traits.

This review summarizes the recent advances in understanding the adaptive evolution of metabolic genes and traits, providing insights into gene-diet interactions in human evolution and health. The rapid accumulation of ancient DNA across time and geography illuminates unprecedented details of some well-established examples of genetic adaptation to diet, such as the LCT and FADS genes. Novel cases of thrifty genes were identified, especially a microRNA at the LCT locus that controls energy expenditure and glucose homeostasis, connecting the historical adaptation to present-day metabolic disorders. A new example of gene-diet-microbiota interactions was established among the AMY1 copy number, starchy diets, and resistant-starch-digesting Ruminococcus. The explosion of genome-wide association studies in large cohorts unravels the present-day health implications of historically adaptive genetic variants. It also enables studies into the polygenic adaptation of metabolic traits, revealing intriguing adaptive signals for increased bone mineral density, blood pressure, and risk of type 2 diabetes, but decreased body mass index and HbA1c. The rapid accumulation of ancient and modern DNA has fueled the characterization of novel and existing cases of genetic adaptation. However, transferring these evolutionary insights into genome-informed precision nutrition requires extensive mechanistic studies and genotype-aware clinical trials.

Genome-wide gene-diet interaction analysis in the UK Biobank identifies novel effects on hemoglobin A1c.

Diet is a significant modifiable risk factor for type 2 diabetes (T2D), and its effect on disease risk is under partial genetic control. Identification of specific gene-diet interactions (GDIs) influencing risk biomarkers such as glycated hemoglobin (HbA1c) is a critical step towards precision nutrition for T2D prevention, but progress has been slow due to limitations in sample size and accuracy of dietary exposure measurement. We leveraged the large UK Biobank (UKB) cohort and a diverse group of dietary exposures, including 30 individual dietary traits and 8 empirical dietary patterns, to conduct genome-wide interaction studies in ~340 000 European-ancestry participants to identify novel GDIs influencing HbA1c. We identified five variant-dietary trait pairs reaching genome-wide significance (P < 5 × 10-8): two involved dietary patterns (meat pattern with rs147678157 and a fruit & vegetable-based pattern with rs3010439) and three involved individual dietary traits (bread consumption with rs62218803, dried fruit consumption with rs140270534 and milk type [dairy vs. other] with 4:131148078_TAGAA_T). These were affected minimally by adjustment for geographical and lifestyle-related confounders, and four of the five variants lacked genetic main effects that would have allowed their detection in a traditional genome-wide association study for HbA1c. Notably, multiple loci near transient receptor potential subfamily M genes (TRPM2 and TRPM3) interacted with carbohydrate-containing food groups. These interactions were further characterized using non-European UKB subsets and alternative measures of glycaemia (fasting glucose and follow-up HbA1c measurements). Our results highlight GDIs influencing HbA1c for future investigation, while reinforcing known challenges in detecting and replicating GDIs.

Diet Modulates the Effects of Genetic Variants on the Vitamin D Metabolic Pathway and Bone Mineral Density in Mexican Postmenopausal Women.

Macro- and micronutrients, such as proteins, vitamin D, and calcium (Ca), are important dietary factors that can modify bone mineral density (BMD). Genetic factors can interact with diet, affecting an individual's predisposition to osteoporosis. This study aimed to evaluate the associations between macro- and micronutrient intakes and BMD in Mexican postmenopausal women, and their interactions with genetic polymorphisms involved in the vitamin D metabolic pathway. We analyzed data from 317 postmenopausal women from the Health Workers Cohort Study, a longitudinal cohort studied in Cuernavaca, Mexico. Postmenopausal women participated in 2 data collection waves (2004-2006 and 2010-2011), with a mean time of 6.4 years. Dietary intake was assessed with a semi-quantitative FFQ. BMD (femoral neck, hip, and lumbar spine) was measured by DXA. Hybrid mixed-effects regression models were used to assess the associations of dietary macro- and micronutrients on BMD, after adjusting for confounding factors and for diet and single nucleotide polymorphism interactions. At baseline, the median age was 57 years (IQR, 50-64). Mean femoral neck, hip, and lumbar spine BMDs decreased over time. We observed statistically significant longitudinal associations for diet (Ca, vitamin D, magnesium, phosphorus, and protein intake) and BMD. Increases of vitamin D, Ca, and protein intakes by 1 SD were associated with mean increases in the femoral neck BMD (0.083 SD, 0.064 SD, and 0.130 SD, respectively). Multiple significant interactions were identified between several loci (CYP2R1, CYP24A1, CYP27B1, VDR, and DHCR7/NADSYN1) and diet for BMDs (femoral neck, hip, and lumbar spine), mainly for protein intake. Our data support associations of vitamin D, Ca, protein, phosphorous, and magnesium consumption with BMD in Mexican postmenopausal women and suggest possible gene-diet interactions. These results could facilitate future personalized nutrition recommendations to help prevent low BMD.

Genome-wide association study of fish oil supplementation on lipid traits in 81,246 individuals reveals new gene-diet interaction loci.

Fish oil supplementation is widely used for reducing serum triglycerides (TAGs) but has mixed effects on other circulating cardiovascular biomarkers. Many genetic polymorphisms have been associated with blood lipids, including high- and low-density-lipoprotein cholesterol (HDL-C, LDL-C), total cholesterol, and TAGs. Here, the gene-diet interaction effects of fish oil supplementation on these lipids were analyzed in a discovery cohort of up to 73,962 UK Biobank participants, using a 1-degree-of-freedom (1df) test for interaction effects and a 2-degrees-of-freedom (2df) test to jointly analyze interaction and main effects. Associations with P < 1×10−6 in either test (26,157; 18,300 unique variants) were advanced to replication in up to 7,284 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Replicated associations reaching 1df P < 0.05 (2,175; 1,763 unique variants) were used in meta-analyses. We found 13 replicated and 159 non-replicated (UK Biobank only) loci with significant 2df joint tests that were predominantly driven by main effects and have been previously reported. Four novel interaction loci were identified with 1df P < 5×10−8 in meta-analysis. The lead variant in the GJB6-GJB2-GJA3 gene cluster, rs112803755 (A>G; minor allele frequency = 0.041), shows exclusively interaction effects. The minor allele is significantly associated with decreased TAGs in individuals with fish oil supplementation, but with increased TAGs in those without supplementation. This locus is significantly associated with higher GJB2 expression of connexin 26 in adipose tissue; connexin activity is known to change upon exposure to omega-3 fatty acids. Significant interaction effects were also found in three other loci in the genes SLC12A3 (HDL-C), ABCA6 (LDL-C), and MLXIPL (LDL-C), but highly significant main effects are also present. Our study identifies novel gene-diet interaction effects for four genetic loci, whose effects on blood lipids are modified by fish oil supplementation. These findings highlight the need and possibility for personalized nutrition.