Implementing personalized dietary interventions has become important as emerging evidence indicates that dietary and lifestyle-dependent epigenetic modifications affect insulin resistance. An epigenome-wide association study (EWAS) was conducted on 1,684 non-diabetic adults aged 57–75 from the Framingham Offspring Study (FOS). Associations between dietary and lifestyle factors (assessed via food frequency questionnaire) and DNA methylation sites (DNA-MS) were analyzed, with adjustments for confounders (age, sex, lifestyle) and multiple testing. Significant epigenetic mediators were evaluated using causal mediation models. Validation was executed using the Genetics of Lipid-Lowering Drugs and Diet Network Study (n = 945). The EWAS identified 35 DNA-MS linked to HOMA-IR, with 13 DNA-MS showing significant associations with dietary factors in the FOS. Key DNA-MS including cg17901584 (DHCR24), influenced by brown rice (natural indirect effect: β ± SE, -0.02 ± 0.01, p = 0.0003), cg22761431 (EFNB3) by wheat germ (-0.01 ± 0.003, p = 0.001), and cg00574958 (CPT1A) associated with lactose (-0.001 ± 0.0003, p = 0.0001) intakes, all correlated with decreased HOMA-IR. Other DNA-MS, cg06808571 (KCNH2), cg06690548 (SLC7A11), and intergenic cg07504977, mediated increases in HOMA-IR linked to intakes of low-calorie cola (0.003 ± 0.001, p = 0.001), alcohol (0.01 ± 0.001, p = 9.0E-11), and palmitoleic acid (0.03 ± 0.01, p = 9.0E-05), respectively. In the GOLDN study, alcohol intake mediated by cg06690548 methylation in SLC7A11 was positively associated with HOMA-IR. Notably, the DHCR24 gene, crucial for cholesterol biosynthesis, was highlighted as a potential dietary target for reducing metabolic risk. The identification of specific DNA methylation sites, such as those in DHCR24 and EFNB3, provides supportive evidence for the mechanistic basis of known dietary effects on metabolic health. These findings not only reinforce the importance of diet in managing insulin resistance but also open avenues for personalized dietary interventions tailored to an individual’s epigenetic profile.

Background:Diet quality is a key determinant of healthy aging, yet fully assessing dietary intake remains a challenge partly because of data limitations and difficulty in integrating information from methodologically distinct datasets. Different nationally representative datasets can offer complementary perspectives: the National Health and Nutrition Examination Survey (NHANES) captures self-reported dietary intake using 1 to 2 d of 24-h recall, whereas the Circana Consumer Network (CN) is a national retail dataset that records year-long grocery purchases from ∼60,000 United States households. Objectives:This study aimed to evaluate whether dietary intake reported in NHANES 2017-2018 aligns with food purchase trends in CN 2018 among United States adults aged ≥55 y. Methods:We examined self-reported dietary intake of grocery/store-bought foods from 24-h recalls in NHANES (n = 1950 individuals) and, separately, household grocery purchases from 1- and 2-person households in CN (n = 29,192 households), analyzed by sex and age group (55-64 y, 65-74 y, and 75+ y). For each dataset, healthfulness of food intakes or purchases was assessed using the 2015 Healthy Eating Index (HEI) and food group proportions were evaluated by percent mass (grams) and energy (kilocalorie). Results:Mean total HEI scores were modest and comparable across datasets (NHANES: 55.7 ± 0.9; CN: 51.3 ± 0.1; P = 0.004). Both sources demonstrated moderate agreement among the 13 HEI component scores, revealing consistent shortfalls in total/whole fruit, greens and beans, whole grains, and saturated fat moderation. Food group proportions had <10% difference across most categories by both mass and energy, although there were higher discrepancies for mixed dishes, condiments, and snacks/sweets. Conclusions:In United States adults aged ≥55 y, grocery/store-sourced intake from NHANES and household grocery purchases from CN showed broadly similar but not interchangeable patterns of diet quality, indicating that purchase data can complement, but not replace, recall-based dietary surveillance. Integrating purchase records with recalls could provide deeper insights into older adults' dietary behaviors and strengthen precision nutrition research.

BACKGROUND:Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with perception to sweet taste. The influence of genetic predisposition to sweet taste on diet quality remains poorly understood. OBJECTIVES:This study aimed to compare cross-sectional associations between a genetically driven sweet taste polygenic score (PGS) and alignment with diet quality indices in a cohort of Puerto Rican older adults residing in the Boston area. METHODS:We used baseline data from Boston Puerto Rican Health Study participants with complete genetic and dietary data (n = 583). A weighted sweet taste PGS was constructed using 38 SNPs from published GWAS with perceived intensity sweet taste outcomes (aspartame, fructose, glucose, neohespedirin dihydrochalcone, sucrose, and sweet substances). We derived 3 diet quality indices using data from a food frequency questionnaire validated for this population: Alternate Healthy Eating Index-2010 (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH), and Mediterranean diet (MeD). Multiple linear regression models between sweet taste PGS and diet quality indices were used to estimate associations and 95% confidence intervals (CIs). RESULTS:There were 428 females and 155 males, with mean age 52.2 ± 7.5 y. The PGS ranged from 30.0 to 50.1, mean (SD): 39.9 (3.4). There was an inverse association between PGS and DASH: β (95% CI) -0.03 [-0.05, -0.004, false discovery rate (FDR) = 0.06], but no association was observed with AHEI-2010: -0.02 (-0.04, 0.008), FDR = 0.19; or MeD: -0.02 (-0.04, 0.01), FDR = 0.19. Across all diet quality indices, higher sweet taste PGS was associated with lower alignment to recommendations for whole grain and vegetables. It also tended to be associated with lower intake of nuts/legumes in the AHEI-2010. CONCLUSIONS:In Puerto Rican adults, higher sweet taste PGS was associated with lower DASH diet quality, but not the AHEI-2010, or MeD, and with lower intake of whole grains, vegetables, and possibly, nuts/legumes. More research is needed on taste perception and dietary intake across populations to inform future intervention.

Trimethylamine N-oxide (TMAO) and its related metabolites have been linked to cardiovascular disease (CVD), but their impact on DNA methylation remains unclear. Investigating these relationships may clarify the role of epigenetic mechanisms in diseases. This study analyzed data from 1,356 adults from the Cardiovascular Health Study (CHS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Using stable-isotope dilution liquid chromatography with on-line electrospray ionization tandem mass spectrometry (LC–MS), we quantified TMAO and five related metabolites. DNA methylation levels were measured using Illumina BeadChip arrays. Epigenome-wide association analyses and meta-analyses were conducted across approximately 430,000 CpG sites. To explore the functional significance of the identified CpGs, we performed gene set enrichment analysis and Mendelian randomization (MR) analyses. We identified 143 metabolite-CpG pairs at FDR < 0.05, including four CpGs for TMAO (P ≤ 4.03e-7), 12 for betaine (P ≤ 1.19e-6), 53 for γ-butyrobetaine (P ≤ 6.11e-6), five for carnitine (P ≤ 5.42e-7), six for choline (P ≤ 2.81e-7), and 63 for crotonobetaine (P ≤ 7.25e-6). CpGs associated with γ-butyrobetaine showed moderate correlation with crotonobetaine-associated CpGs. In total, these metabolite-linked CpGs were mapped to 108 genes. Gene set enrichment analysis revealed 145 significantly enriched gene sets, including nine highly relevant to CVD risk. Furthermore, CpGs were enriched in 80 immunologic signature gene sets (FDR < 0.05). MR analysis identified three CpGs associated with coronary artery disease (CAD), including hypermethylation at cg18705301 (NDUFAF1), which was inversely associated with betaine levels and linked to a lower risk of CAD (P = 1.8e-5). This study identified specific DNA methylation sites associated with TMAO and related metabolites. These epigenetic changes may contribute to CVD risk through multiple pathways. Future research should validate these findings and explore their clinical implications.

Dietary choices influence both risk and development of type 2 diabetes (T2D), but the precise mechanisms remain incompletely described. Dietary intake and lifestyle behaviors can alter epigenetic states with subsequent modulations on gene expression which then can change the risk of T2D. An epigenome-wide association study was conducted to identify any epigenetic links to diabetes risk by investigating epigenetic changes during a 6-year follow-up in 374 participants who were free of T2D at baseline. The identified epigenetic changes were examined for their association with any dietary and lifestyle factors. Additionally, mediation analysis determined whether the associated dietary factors contribute to diabetes risk through epigenetic changes. The epigenome-wide association study identified significant epigenetic changes during the 6-year follow-up at seven loci within genes REPIN1, BMP2, LINC01723, and SEL1L2, all of which were associated with insulin resistance. Further analysis revealed strong associations between three specific differentially methylated sites (DMSs) cg16400647 in REPIN1, cg12344389, and cg00625573, and dietary vitamin B12 intake. Additionally, cg26719314 on the X chromosome showed separate robust correlations with total sugar intake. Mediation analysis showed that higher vitamin B12 intake might reduce insulin resistance through epigenetic modification in REPIN1 and DNAAF9. Conversely, higher total sugar intake correlated significantly with elevated diabetes risk, with cg26719314 acting as a mediator. Furthermore, increased vitamin B12 supplementation was associated with decreased insulin resistance at 6-year follow-up in the entire cohort. These findings suggest that vitamin B12 intake may influence insulin resistance through specific epigenetic changes, thus describing the epigenetic links between diet and development of T2D.

Background: Obesity is a leading cause of type 2 diabetes (T2D), with particularly high prevalence in Hispanic populations residing in the USA. However, how genetic variation influences obesity-related blood metabolite levels which, in turn, contribute to T2D progression, is not well understood. Our goal was to identify and understand genetic and dietary connections between obesity and T2D in a Hispanic cohort of older adults. Materials and Methods: We conducted a genome-wide association study on 13 specific metabolites previously associated with T2D and characteristic of individuals with abdominal obesity within the Boston Puerto Rican Health Study cohort. We further examined associations of identified metabolite quantitative trait loci (mQTLs) and their interactions with targeted dietary factors on T2D prevalence and related traits. We used gene set and pathway analysis with protein–protein interaction networks to explore the molecular mechanisms underlying the metabolic connections between obesity and T2D. Results: We identified 30 single-nucleotide polymorphisms (SNPs) acting as mQTLs for these 13 metabolites. These mQTLs were located within 19 gene regions, associated with processes such as linoleic acid metabolism, alpha-linolenic acid metabolism, and glycerophospholipid biosynthesis. Although no mQTLs were directly associated with T2D or related traits, 12 demonstrated interactions with certain food groups that affect T2D risk. Moreover, gene set and pathway analysis with protein–protein interaction networks indicated that alpha-linolenic acid metabolism, lipid metabolism, and glycerophospholipid biosynthesis and metabolism among other pathways are potential connections between T2D and obesity. Conclusions: This study identifies biochemical relationships between genetic susceptibility and dietary influences, contributing to our understanding of T2D progression in Hispanic people with obesity.

OBJECTIVE:This study aimed to determine whether APOA2 genotypes and saturated fatty acid (SAT) intake affect weight-loss response to healthy low-carbohydrate (HLC) and healthy low-fat (HLF) diets. METHODS:This is a secondary analysis of the Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) study, a 12-month randomized clinical trial of HLC or HLF diets in 609 adults aged 18 to 50 years with BMI values between 28 and 40 kg/m2. The current study examined 3-, 6-, and 12-month weight loss in participants with different APOA2 genotypes (TT vs. C allele carriers, CT + CC) at variant rs5082 who met the SAT intake criterion of ≥22 g/day for an HLC diet and < 22 g/day for an HLF diet at all three study time points. RESULTS:Participants with the TT APOA2 genotype lost significantly more weight consistently on an HLC diet than on an HLF diet at 3, 6, and 12 months, whereas C allele carriers lost more weight only at 3 months and not at 6 or 12 months. APOA2 genotype-by-SAT intake interaction affecting weight loss was observed only at 12 months. Among participants who did not consistently meet the SAT intake criterion, there were no significant weight-loss differences among APOA2 genotypes. CONCLUSIONS:This study highlights the importance of evaluating genotype-diet interactions in weight-loss trials to better inform precision nutrition interventions. CLINICAL TRIAL REGISTRATION:NCT01826591.

Valid measures of dietary intake are essential for health and nutrition research, but typical forms- or interview-based measurements are susceptible to random and systematic errors. Although many biomarkers of food intake (BFIs) have been validated, we aimed to explore how food-BFI relationships are affected by genetic and lifestyle factors among Caribbean Hispanic adults. Dietary, clinical, anthropometric, blood metabolomics, and genotype data from 782 Puerto Rican adults were available. Thirty-one BFI-food intake relationships were assessed using linear regression, including covariates based on significant covariate-BFI associations (i.e., age, body weight, physical activity, and sex). We observed 12 known BFI-food pairs that reached statistical significance, of which 11 remained significant after adjustment. Applying genome-wide association tests of blood metabolites to BFI-food pairs, genetic variants rs7078243 and rs62501664 were identified as modifying relationships with 3-methylxanthine-coffee and 3-methylhistidine-poultry, respectively. Eleven validated biomarker-food intake pairs remained statistically significant after adjusting for covariates. Identification of genotype-BFI associations accentuates that the implementation of certain BFIs will depend on common genetic differences.

Background Diet quality is a key determinant of healthy aging, yet fully assessing dietary intake remains a challenge partly because of data limitations and difficulty in integrating information from methodologically distinct datasets. Different nationally representative datasets can offer complementary perspectives: the National Health and Nutrition Examination Survey (NHANES) captures self-reported dietary intake using 1 to 2 d of 24-h recall, whereas the Circana Consumer Network (CN) is a national retail dataset that records year-long grocery purchases from ∼60,000 United States households. Objectives This study aimed to evaluate whether dietary intake reported in NHANES 2017–2018 aligns with food purchase trends in CN 2018 among United States adults aged ≥55 y. Methods We examined self-reported dietary intake of grocery/store-bought foods from 24-h recalls in NHANES (n = 1950 individuals) and, separately, household grocery purchases from 1- and 2-person households in CN (n = 29,192 households), analyzed by sex and age group (55–64 y, 65–74 y, and 75+ y). For each dataset, healthfulness of food intakes or purchases was assessed using the 2015 Healthy Eating Index (HEI) and food group proportions were evaluated by percent mass (grams) and energy (kilocalorie). Results Mean total HEI scores were modest and comparable across datasets (NHANES: 55.7 ± 0.9; CN: 51.3 ± 0.1; P = 0.004). Both sources demonstrated moderate agreement among the 13 HEI component scores, revealing consistent shortfalls in total/whole fruit, greens and beans, whole grains, and saturated fat moderation. Food group proportions had <10% difference across most categories by both mass and energy, although there were higher discrepancies for mixed dishes, condiments, and snacks/sweets. Conclusions In United States adults aged ≥55 y, grocery/store-sourced intake from NHANES and household grocery purchases from CN showed broadly similar but not interchangeable patterns of diet quality, indicating that purchase data can complement, but not replace, recall-based dietary surveillance. Integrating purchase records with recalls could provide deeper insights into older adults’ dietary behaviors and strengthen precision nutrition research.

Introduction: Previous studies identified genetic links between the TCF7L2 C/T variant rs7903146, type 2 diabetes (T2D), and obesity. We wished to deepen our understanding of how specific diets interact with this variant to affect blood metabolites, an aspect not previously investigated. Hence, we conducted a controlled study where individuals with different genotypes followed a Mediterranean (Med) or low-fat (LF) diet for 1 week. Methods: Participants were recruited from the Boston, MA (USA) area. Anthropometric and clinical measures were taken. Genotypes at rs7903146 were ascertained, with homozygous carriers of the more common and protective CC or risk TT genotype invited to participate. Participants followed both diets (LF or Med) for 1 week with ∼10 days’ washout between diets. Blood samples taken at the beginning and end of each diet period underwent metabolomics analysis using nuclear magnetic resonance spectroscopy. We evaluated how the diet affected different metabolites based on genetic profile. Results: The cohort of 35 persons was 43% female, aged 18–70 y, with BMI between 26.4 and 33.9 kg/m2. Focusing on fatty acids (FAs) and other lipid metabolic factors (n = 23), we observed a greater number and stronger correlations among these factors in the CC genotype-Med diet group than in the other three genotype-diet combinations. An aggregate of 11 factors, each negatively correlating with delta-saturated fatty acids (SFA), showed a significant genotype-Med diet interaction on delta-SFA in CC individuals on the Med diet (p = 0.0046). A similar genotype-Med diet interaction was observed for delta-monounsaturated fatty acids (p = 0.0078). These interactions were not statistically significant at the end of the LF intervention. Conclusion: Our findings suggest that the Med diet has a stronger influence on regulating lipid factors in individuals with the CC genotype at the TCF7L2 variant rs7903146. This diet-genotype interaction may have significant implications for understanding the inter-individual variation of metabolic response on specific dietary regimens.

The TCF7L2 gene is a significant genetic factor contributing to the risk of metabolic and cardiovascular diseases (CVD). We previously found that subjects with the TT genotype of TCF7L2 rs7903146 variant, who consume a low-fat diet (LF) had a higher incidence of stroke than subjects with the CC genotype. Yet this association was abolished in subjects with the TT genotype who consumed a Mediterranean-type diet (MetD). However, the mechanism by which MetD diet modulates the association between TCF7L2 and CVD risk is unclear. This study aims to validate these findings under real-world conditions and clinical practice to elucidate the biological mechanisms involved in this correlation. Thirty-five participants with BMI ranging from 27 to 34 kg/m2 were recruited based on rs7903146 genotype. Of those consented to participate, 21 had the CC and 14 had the TT genotype. Participants were randomly assigned to two dietary intervention groups, ensuring an equal distribution of CC and TT carriers. Each participant followed one of two diets (LF or MetD) for one week, followed by a 10-day washout period before switching to the other diet for one week. Blood samples were collected before and after each diet for metabolomic analysis using nuclear magnetic resonance (NMR) spectroscopy. The differential effect of the diets on triglyceride-rich lipoproteins was determined based on TCF7L2 genotype. The MetD significantly reduced triglyceride-rich lipoprotein concentrations compared to the LF diet. After consuming the LF diet, TT carriers exhibited more small VLDL particles, potentially contributing to CVD risk compared to CC carriers. However, this difference in risk was not observed with the MetD. Furthermore, the order in which the two diets were crossed affected the triglyceride-rich lipoprotein profile, with LF-MetD regimen showing a stronger effect on triglyceride-rich lipoproteins (TRL) levels than the MetD-LF regimen. Our findings suggest that rs7903146 TT carriers benefit more from a MetD than a LF diet in terms of their triglyceride-rich lipoprotein profile, which may reduce their risk of CVD. These results support the notion that genotype is a factor in determining the extent to which the MetD affects cardiovascular health.

Osteoporosis (OP) and low bone mass can be debilitating and costly conditions if not acted on quickly. This disease is also difficult to diagnose as the symptoms develop unnoticed until fracture occurs. Therefore, gaining understanding of the genetic risk associated with these conditions could be beneficial for health-care professionals in early detection and prevention. The Boston Puerto Rican Osteoporosis (BPROS) study, an ancillary study to the Boston Puerto Rican Health Study (BPRHS), collected information regarding bone and bone health. All bone measurements were taken during regular BPROS visits using dual-energy X-ray absorptiometry. The OP was defined as T-score ≤ -2.5 (≥2.5 SDs below peak bone mass). Dietary variables were collected at the second wave of the BPRHS via a food frequency questionnaire. We conducted genome-wide associations with bone outcomes, including BMD and OP for 978 participants. We also examined the interactions with dietary quality on the relationships between genotype and bone outcomes. We further tested if candidate genetic variants described in previous GWAS on OP and BMD contribute to OP risk in this population. Four variants were associated with OP: rs114829316 (IQ motif containing J gene), rs76603051, rs12214684 (melanin-concentrating hormone receptor 2 gene), and rs77303493 (Ras and Rab interactor 2 gene), and 2 variants were associated with BMD of lumbar spine (rs11855618, cingulin-like 1 gene) and hip (rs73480593, NTRK2), reaching the genome-wide significance threshold of P ≤ 5E-08. In a gene-diet interaction analysis, we found that 1 SNP showed a significant interaction with the overall Dietary Approaches to Stop Hypertension (DASH) score, and 7 SNPs with sugar-sweetened beverages (SSBs), a major contributor to the DASH score. This study identifies new genetic markers related to OP and BMD in older Hispanic adults. Additionally, we uncovered unique genetic markers that interact with dietary quality, specifically SSBs, in relation to bone health. These findings may be useful to guide early detection and preventative care.

The age-related loss of the cognitive function is a growing concern for global populations. Many factors that determine cognitive resilience or dementia also have metabolic functions. However, this duality is not universally appreciated when the action of that factor occurs in tissues external to the brain. Thus, we examined a set of genes involved in dementia, i.e., those related to vascular dementia, Alzheimer’s disease, Parkinson’s disease, and the human metabolism for activity in 12 metabolically active tissues. Mining the Genotype-Tissue Expression (GTEx) data showed that most of these metabolism–dementia (MD) genes (62 of 93, 67%) exhibit a higher median expression in any of the metabolically active tissues than in the brain. After identifying that several MD genes served as blood-based biomarkers of longevity in other studies, we examined the impact of the intake of food, nutrients, and other dietary factors on the expression of MD genes in whole blood in the Framingham Offspring Study (n = 2134). We observed positive correlations between flavonoids and HMOX1, taurine and UQCRC1, broccoli and SLC10A2, and myricetin and SLC9A8 (p < 2.09 × 10−4). In contrast, dairy protein, palmitic acid, and pie were negatively correlated, respectively, with the expression of IGF1R, CSF1R, and SLC9A8, among others (p < 2.92 × 10−4). The results of this investigation underscore the potential contributions of metabolic enzyme activity in non-brain tissues to the risk of dementia. Specific epidemiological or intervention studies could be designed using specific foods and nutrients or even dietary patterns focused on these foods and nutrients that influence the expression of some MD genes to verify the findings presented here.

Background: Many epigenetic loci have been associated with plasma triglyceride (TG) levels, but epigenetic connections between those loci and dietary exposures are largely unknown. This study aimed to characterize the epigenetic links between diet, lifestyle, and TG.Methods: We first conducted an epigenome-wide association study (EWAS) for TG in the Framingham Heart Study Offspring population (FHS, n = 2,264). We then examined relationships between dietary and lifestyle-related variables, collected four times in 13 years, and differential DNA methylation sites (DMSs) associated with the last TG measures. Third, we conducted a mediation analysis to evaluate the causal relationships between diet-related variables and TG. Finally, we replicated three steps to validate identified DMSs associated with alcohol and carbohydrate intake in the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) study (n = 993).Results: In the FHS, the EWAS revealed 28 TG-associated DMSs at 19 gene regions. We identified 102 unique associations between these DMSs and one or more dietary and lifestyle-related variables. Alcohol and carbohydrate intake showed the most significant and consistent associations with 11 TG-associated DMSs. Mediation analyses demonstrated that alcohol and carbohydrate intake independently affect TG via DMSs as mediators. Higher alcohol intake was associated with lower methylation at seven DMSs and higher TG. In contrast, increased carbohydrate intake was associated with higher DNA methylation at two DMSs (CPT1A and SLC7A11) and lower TG. Validation in the GOLDN further supports the findings.Conclusion: Our findings imply that TG-associated DMSs reflect dietary intakes, particularly alcoholic drinks, which could affect the current cardiometabolic risk via epigenetic changes. This study illustrates a new method to map epigenetic signatures of environmental factors for disease risk. Identification of epigenetic markers of dietary intake can provide insight into an individual’s risk of cardiovascular disease and support the application of precision nutrition.Clinical Trial Registration:www.ClinicalTrials.gov, the Framingham Heart Study (FHS), NCT00005121; the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN), NCT01023750.

Introduction: Rate-limiting enzymes (RLEs) are innate slow points in metabolic pathways, and many function in bio-processes related to nutrient sensing. Many RLEs carry causal mutations relevant to inherited metabolic disorders. Because the activity of RLEs in cardiovascular health is poorly characterized, our objective was to assess their involvement in cardiometabolic health and disease and where altered biophysical and biochemical functions can promote disease. Methods: A dataset of 380 human RLEs was compared to protein and gene datasets for factors likely to contribute to cardiometabolic disease, including proteins showing significant age-related altered expression in blood and genetic loci with variants that associate with common cardiometabolic phenotypes. The biochemical reactions catalyzed by RLEs were evaluated for metabolites enriched in RLE subsets associating with various cardiometabolic phenotypes. Most significance tests were based on Z-score enrichment converted to p values with a normal distribution function. Results: Of 380 RLEs analyzed, 112 function in mitochondria, and 53 are assigned to inherited metabolic disorders. There was a depletion of RLE proteins known as aging biomarkers. At the gene level, RLEs were assessed for common genetic variants that associated with important cardiometabolic traits of LDL-cholesterol or any of the five outcomes pertinent to metabolic syndrome. This revealed several RLEs with links to cardiometabolic traits, from a minimum of 26 for HDL-cholesterol to a maximum of 45 for plasma glucose. Analysis of these GWAS-linked RLEs for enrichment of the molecular constituents of the catalyzed reactions disclosed a number of significant phenotype-metabolite links. These included blood pressure with acetate (p = 2.2 × 10−4) and NADP+ (p = 0.0091), plasma HDL-cholesterol and triglyceride with diacylglycerol (p = 2.6 × 10−5, 6.4 × 10−5, respectively) and diolein (p = 2.2 × 10−6, 5.9 × 10−6), and waist circumference with d-glucosamine-6-phosphate (p = 1.8 × 10−4). Conclusion: In the context of cardiometabolic health, aging, and disease, these results highlight key diet-derived metabolites that are central to specific rate-limited processes that are linked to cardiometabolic health. These metabolites include acetate and diacylglycerol, pertinent to blood pressure and triglycerides, respectively, as well as diacylglycerol and HDL-cholesterol.

Dilated cardiomyopathy (DCM), caused by genetic and environmental factors, usually progresses to heart failure, a major cause of death in elderly people. A diet-associated form of DCM was recently identified in pet dogs eating non-traditional (NT) diets. To identify potential dietary causes, we analyzed metabolomic signatures and gene set/pathway enrichment in (1) all dogs based on disease, diet, and their interactions and (2) dogs with DCM based on diet. Metabolomic analysis was performed in 38 dogs with DCM eating NT diets (DCM-NT), 8 dogs with DCM eating traditional diets, 12 healthy controls eating NT diets, and 17 healthy controls eating traditional diets. Overall, 153 and 63 metabolites differed significantly between dogs with DCM versus healthy controls and dogs eating NT versus traditional diets, respectively, with 12 metabolites overlapping both analyses. Protein–protein interaction networks and gene set enrichment analysis identified 105 significant pathways and gene sets including aging-related pathways (e.g., nuclear factor-kappa B, oxidative damage, inflammation). Seventeen metabolites differed significantly in dogs with DCM eating NT versus traditional diets (e.g., fatty acids, amino acids, legume biomarkers), suggesting different mechanisms for primary versus diet-associated DCM. Our multifaceted metabolomic assessment of DCM in dogs highlighted diet’s role in some forms of DCM.

Recommended Citation Lai, Chao-Qiang; Wojczynski, Mary K.; Parnell, Laurence D.; Hidalgo, Bertha A.; Irvin, Marguerite Ryan; Aslibekyan, Stella; Province, Michael A.; Absher, Devin M.; Arnett, Donna K.; and Ordovas, Jose M., ,"Epigenome-wide association study of triglyceride postprandial responses to a high-fat dietary challenge." Journal of Lipid Research. 57,12. 2200-2207. (2016). https://digitalcommons.wustl.edu/open_access_pubs/5586