Genome-wide association study of osteoporosis identifies genetic risk and interactions with DASH diet and sugar sweetened beverages in a Hispanic cohort of older adults.

BACKGROUND: 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 symptoms develop unnoticed until fracture occurs. Therefore, gaining understanding of the genetic risk associated with these conditions could be beneficial for healthcare professionals in early detection and prevention. METHODS: 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. Osteoporosis was defined as T-score ≤ -2.5 (2.5 SD or more below peak bone mass). Dietary variables were collected at the second wave of the BPRHS via food frequency questionnaire. We conducted genome-wide associations with bone outcomes including bone mineral density (BMD) and OP for 978 participants. We also examined 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. RESULTS: Four variants were associated with OP: rs114829316 (IQCJ), rs76603051, rs12214684 (MCHR2), and rs77303493 (RIN2), and two variants with BMD of lumbar spine (rs11855618, CGNL1) and hip (rs73480593, NTRK2), reaching the genome-wide significance threshold of P ≤ 5E-08. In a gene-diet interaction analysis, we found that one SNP showed a significant interaction with the overall DASH score, and 7 SNPs with sugar-sweeten beverages, a major contributor to the DASH score. CONCLUSION: This study identifies new genetic markers related to osteoporosis and BMD in older Hispanic adults. Additionally, we uncovered unique genetic markers that interact with dietary quality, specifically sugar-sweetened beverages, in relation to bone health. These findings may be useful to guide early detection and preventative care.

Rate-Limiting Enzymes in Cardiometabolic Health and Aging in Humans.

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.

The impact of alcoholic drinks and dietary factors on epigenetic markers associated with triglyceride levels.

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.

Dietary Responses of Dementia-Related Genes Encoding Metabolic Enzymes.

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.

Metabolomic profiling in dogs with dilated cardiomyopathy eating non-traditional or traditional diets and in healthy controls.

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.

Diet Quality Scores Are Positively Associated with Whole Blood-Derived Mitochondrial DNA Copy Number in the Framingham Heart Study.

BACKGROUND: The association between diet quality and mitochondrial DNA copy number (mtDNA-CN) remains to be examined. OBJECTIVES: We aimed to study the relation between diet quality and mtDNA-CN. METHODS: We analyzed data from 2931 Framingham Heart Study (FHS) participants (mean age of 57 y, 55% females). Whole-genome sequencing was used to calculate mtDNA-CN from whole-blood samples. We examined the cross-sectional associations between 3 diet quality scores, the Dietary Approaches to Stop Hypertension (DASH) score, the Alternative Healthy Eating Index (AHEI), and the Mediterranean diet score (MDS), and mtDNA-CN. Linear mixed models were used to account for maternal lineage. RESULTS: We observed that a higher DASH score was positively associated with mtDNA-CN after adjusting for sex, age, energy intake, smoking status, alcohol intake, and physical activity level. A 1-SD increase in the DASH score was associated with a 0.042-SD greater mtDNA-CN (95% CI: 0.007, 0.077; P = 0.02). Similarly, for each SD increase in AHEI and MDS, the mtDNA-CN SD increased by 0.056 (95% CI: 0.019, 0.092; P = 0.003) and 0.047 (95% CI: 0.01, 0.083; P = 0.01), respectively. Diet quality scores were associated with neutrophil and lymphocyte counts but not platelet counts, e.g., for a 1-SD increase in the DASH, neutrophils decreased by 0.8% (95% CI: 0.5%, 1.1%; P = 4.1 × 10-6), lymphocytes increased by 0.7% (95% CI: 0.4%, 1%, P = 1.2 × 10-5), and there was no significant change in platelet number (0.1 × 1000/µL; 95% CI: -1.6, 1.9; P = 0.89). Further adjustment for neutrophil, lymphocyte, and platelet counts and the associations between diet quality scores and mtDNA-CN were completely attenuated to nonsignificant (P = 0.95, 0.54, and 0.91, respectively). CONCLUSIONS: We observed that higher diet quality is associated with a greater whole-blood derived mtDNA-CN in middle-aged to older adult FHS participants, and that blood cell composition, particularly neutrophil counts, attenuated the association between diet quality and mtDNA-CN.

Metabolite patterns link diet, obesity, and type 2 diabetes in a Hispanic population.

INTRODUCTION: Obesity is a precursor of type 2 diabetes (T2D). OBJECTIVES: Our aim was to identify metabolic signatures of T2D and dietary factors unique to obesity. METHODS: We examined a subsample of the Boston Puerto Rican Health Study (BPRHS) population with a high prevalence of obesity and T2D at baseline (n = 806) and participants (without T2D at baseline) at 5-year follow-up (n = 412). We determined differences in metabolite profiles between T2D and non-T2D participants of the whole sample and according to abdominal obesity status. Enrichment analysis was performed to identify metabolic pathways that were over-represented by metabolites that differed between T2D and non-T2D participants. T2D-associated metabolites unique to obesity were examined for correlation with dietary food groups to understand metabolic links between dietary intake and T2D risk. False Discovery Rate method was used to correct for multiple testing. RESULTS: Of 526 targeted metabolites, 179 differed between T2D and non-T2D in the whole sample, 64 in non-obese participants and 120 unique to participants with abdominal obesity. Twenty-four of 120 metabolites were replicated and were associated with T2D incidence at 5-year follow-up. Enrichment analysis pointed to three metabolic pathways that were overrepresented in obesity-associated T2D: phosphatidylethanolamine (PE), long-chain fatty acids, and glutamate metabolism. Elevated intakes of three food groups, energy-dense takeout food, dairy intake and sugar-sweetened beverages, associated with 13 metabolites represented by the three pathways. CONCLUSION: Metabolic signatures of lipid and glutamate metabolism link obesity to T2D, in parallel with increased intake of dairy and sugar-sweetened beverages, thereby providing insight into the relationship between dietary habits and T2D risk.

Investigation of diets associated with dilated cardiomyopathy in dogs using foodomics analysis.

Dilated cardiomyopathy (DCM) is a disease of the heart muscle that affects both humans and dogs. Certain canine diets have been associated with DCM, but the diet-disease link is unexplained, and novel methods are needed to elucidate mechanisms. We conducted metabolomic profiling of 9 diets associated with canine DCM, containing ≥ 3 pulses, potatoes, or sweet potatoes as main ingredients, and in the top 16 dog diet brands most frequently associated with canine DCM cases reported to the FDA (3P/FDA diets), and 9 non-3P/FDA diets. We identified 88 named biochemical compounds that were higher in 3P/FDA diets and 23 named compounds that were lower in 3P/FDA diets. Amino acids, amino acid-derived compounds, and xenobiotics/plant compounds were the largest categories of biochemicals that were higher in 3P/FDA diets. Random forest analyses identified the top 30 compounds that distinguished the two diet groups with 100% predictive accuracy. Four diet ingredients distinguished the two diet groups (peas, lentils, chicken/turkey, and rice). Of these ingredients, peas showed the greatest association with higher concentrations of compounds in 3P/FDA diets. Moreover, the current foodomics analyses highlight relationships between diet and DCM in dogs that can identify possible etiologies for understanding diet-disease relationships in dogs and humans.

Associations of network-derived metabolite clusters with prevalent type 2 diabetes among adults of Puerto Rican descent.

INTRODUCTION: We investigated whether network analysis revealed clusters of coregulated metabolites associated with prevalent type 2 diabetes (T2D) among Puerto Rican adults. RESEARCH DESIGN AND METHODS: We used liquid chromatography-mass spectrometry to measure fasting plasma metabolites (>600) among participants aged 40-75 years in the Boston Puerto Rican Health Study (BPRHS; discovery) and San Juan Overweight Adult Longitudinal Study (SOALS; replication), with (n=357; n=77) and without (n=322; n=934) T2D, respectively. Among BPRHS participants, we used unsupervised partial correlation network-based methods to identify and calculate metabolite cluster scores. Logistic regression was used to assess cross-sectional associations between metabolite clusters and prevalent T2D at the baseline blood draw in the BPRHS, and significant associations were replicated in SOALS. Inverse-variance weighted random-effect meta-analysis was used to combine cohort-specific estimates. RESULTS: Six metabolite clusters were significantly associated with prevalent T2D in the BPRHS and replicated in SOALS (false discovery rate (FDR) <0.05). In a meta-analysis of the two cohorts, the OR and 95% CI (per 1 SD increase in cluster score) for prevalent T2D were as follows for clusters characterized primarily by glucose transport (0.21 (0.16 to 0.30); FDR <0.0001), sphingolipids (0.40 (0.29 to 0.53); FDR <0.0001), acyl cholines (0.35 (0.22 to 0.56); FDR <0.0001), sugar metabolism (2.28 (1.68 to 3.09); FDR <0.0001), branched-chain and aromatic amino acids (2.22 (1.60 to 3.08); FDR <0.0001), and fatty acid biosynthesis (1.54 (1.29 to 1.85); FDR <0.0001). Three additional clusters characterized by amino acid metabolism, cell membrane components, and aromatic amino acid metabolism displayed significant associations with prevalent T2D in the BPRHS, but these associations were not replicated in SOALS. CONCLUSIONS: Among Puerto Rican adults, we identified several known and novel metabolite clusters that associated with prevalent T2D.

Risk Factors Associated with Vitamin D Status among Older Puerto Rican Adults.

BACKGROUND: Vitamin D deficiency has been associated with health problems globally, but there is limited information on vitamin D status and associated risk factors among adults in underserved populations. OBJECTIVE: This study aimed to identify risk factors for vitamin D deficiency/insufficiency among Puerto Rican adults from the Boston Puerto Rican Health Study (BPRHS). METHODS: A total of 822 adults (45-75 y, at baseline) were included in these analyses. Deficiency was defined as serum 25-hydroxyvitamin D [25(OH)D] <30 and insufficiency as 30 to <50 nmol/L. Dietary intake was assessed with a validated FFQ. Associations between risk factors, including dietary vitamin D, supplement use, ancestry, skin pigmentation, months in the past year spent in a southern climate, and serum 25(OH)D were assessed with multivariable general linear models. RESULTS: Approximately 13% of participants were deficient in 25(OH)D and another 43% insufficient. Skin pigment was associated with 25(OH)D using 3 measures, greater African ancestry (ß ± SE) (-7.74 ± 2.91, P = 0.01); interviewer assessed dark or medium, compared with white, skin tone, (-5.09 ± 2.19, P = 0.02 and -5.89 ± 1.58, P < 0.001, respectively); and melanin index of the upper inner right arm, assessed using a spectrophotometer (-2.04 ± 0.84, P = 0.02). After adjusting for ancestry, factors associated with lower serum 25(OH)D included smoking (-4.49 ± 1.58, P = 0.01); BMI (-0.21 ± 0.10, P = 0.04); and spring compared with autumn blood draw (-4.66 ± 1.68, P = 0.004). Factors associated with higher serum 25(OH)D included female sex compared with male (4.03 ± 1.58, P = 0.01); dietary vitamin D intake µg/d (0.71 ± 0.25, P < 0.004); vitamin D supplement use (4.50 ± 1.87, P = 0.02); income to poverty ratio (0.01 ± 0.01, P = 0.06), and months in a southern climate during the past year (0.96 ± 0.56, P = 0.09). CONCLUSIONS: Vitamin D deficiency/insufficiency was prevalent in this Puerto Rican population living in the northeastern USA. Several factors were associated with this, which may assist in identifying those at risk. Interventions are needed to improve serum 25(OH)D concentration, particularly among those with limited exposure to sunlight.

Using Machine Learning to Predict Obesity Based on Genome-Wide and Epigenome-Wide Gene-Gene and Gene-Diet Interactions.

Obesity is associated with many chronic diseases that impair healthy aging and is governed by genetic, epigenetic, and environmental factors and their complex interactions. This study aimed to develop a model that predicts an individual's risk of obesity by better characterizing these complex relations and interactions focusing on dietary factors. For this purpose, we conducted a combined genome-wide and epigenome-wide scan for body mass index (BMI) and up to three-way interactions among 402,793 single nucleotide polymorphisms (SNPs), 415,202 DNA methylation sites (DMSs), and 397 dietary and lifestyle factors using the generalized multifactor dimensionality reduction (GMDR) method. The training set consisted of 1,573 participants in exam 8 of the Framingham Offspring Study (FOS) cohort. After identifying genetic, epigenetic, and dietary factors that passed statistical significance, we applied machine learning (ML) algorithms to predict participants' obesity status in the test set, taken as a subset of independent samples (n = 394) from the same cohort. The quality and accuracy of prediction models were evaluated using the area under the receiver operating characteristic curve (ROC-AUC). GMDR identified 213 SNPs, 530 DMSs, and 49 dietary and lifestyle factors as significant predictors of obesity. Comparing several ML algorithms, we found that the stochastic gradient boosting model provided the best prediction accuracy for obesity with an overall accuracy of 70%, with ROC-AUC of 0.72 in test set samples. Top predictors of the best-fit model were 21 SNPs, 230 DMSs in genes such as CPT1A, ABCG1, SLC7A11, RNF145, and SREBF1, and 26 dietary factors, including processed meat, diet soda, French fries, high-fat dairy, artificial sweeteners, alcohol intake, and specific nutrients and food components, such as calcium and flavonols. In conclusion, we developed an integrated approach with ML to predict obesity using omics and dietary data. This extends our knowledge of the drivers of obesity, which can inform precision nutrition strategies for the prevention and treatment of obesity. Clinical Trial Registration: [www.ClinicalTrials.gov], the Framingham Heart Study (FHS), [NCT00005121].

Dietary Epicatechin, A Novel Anti-aging Bioactive Small Molecule.

Epicatechin (EC), a flavonoid present in various foods including cocoa, dark chocolate, berries, and tea, has recently been reported to promote general health and survival of old mice fed a standard chow diet. This is considered a novel discovery in the field of identifying natural compounds to extend lifespan, given that presumably popular anti-aging natural agents including resveratrol, green tea extract, and curcumin had failed in extending the lifespan of standard chow-diet-fed mice. However, the anti-aging mechanism of EC is not fully understood, thus impeding the potential application of this natural compound in improving a healthy lifespan in humans. In this review, we first summarized the main dietary sources that contain a significant amount of EC and recent research regarding the absorption, metabolism and distribution of EC in humans and rodents. The review is then focused on the anti-aging effects of EC in cultured cells, animals and humans with the possible physiological, cellular and molecular mechanisms underlying its lifespan-extending effects.

Diet-derived fruit and vegetable metabolites show sex-specific inverse relationships to osteoporosis status.

BACKGROUND: The impact of nutrition on the metabolic profile of osteoporosis (OS) is unknown. OBJECTIVE: Identify biochemical factors driving the association of fruit and vegetable (FV) intakes with OS prevalence using an untargeted metabolomics approach. DESIGN: Cross-sectional dietary, anthropometric and plasma metabolite data were examined from the Boston Puerto Rican Osteoporosis Study, n = 600 (46-79 yr). METHODS: Bone mineral density was assessed by DXA. OS was defined by clinical standards. A culturally adapted FFQ assessed usual dietary intake. Principal components analysis (PCA) of 42 FV items created 6 factors. Metabolomic profiles derived from plasma samples were assessed on a commercial platform. Differences in levels of 525 plasma metabolites between disease groups (OS vs no-OS) were compared using logistic regression; and associations with FV intakes by multivariable linear regression, adjusted for covariates. Metabolites significantly associated with OS status or with total FV intake were analyzed for enrichment in various biological pathways using Mbrole 2.0, MetaboAnalyst, and Reactome, using FDR correction of P-values. Correlation coefficients were calculated as Spearman's rho rank correlations, followed by hierarchical clustering of the resulting correlation coefficients using PCA FV factors and sex-specific sets of OS-associated metabolites. RESULTS: High FV intake was inversely related to OS prevalence (Odds Ratio = 0.73; 95% CI = 0.57, 0.94; P = 0.01). Several biological processes affiliated with the FV-associating metabolites, including caffeine metabolism, carnitines and fatty acids, and glycerophospholipids. Important processes identified with OS-associated metabolites were steroid hormone biosynthesis in women and branched-chain amino acid metabolism in men. Factors derived from PCA were correlated with the OS-associated metabolites, with high intake of dark leafy greens and berries/melons appearing protective in both sexes. CONCLUSIONS: These data warrant investigation into whether increasing intakes of dark leafy greens, berries and melons causally affect bone turnover and BMD among middle-aged and older adults at risk for osteoporosis via sex-specific metabolic pathways, and how gene-diet interactions alter these sex-specific metabolomic-osteoporosis links. ClinicalTrials.gov Identifier: NCT01231958.

Carbohydrate and fat intake associated with risk of metabolic diseases through epigenetics of CPT1A.

BACKGROUND: Epigenome-wide association studies identified the cg00574958 DNA methylation site at the carnitine palmitoyltransferase-1A (CPT1A) gene to be associated with reduced risk of metabolic diseases (hypertriglyceridemia, obesity, type 2 diabetes, hypertension, metabolic syndrome), but the mechanism underlying these associations is unknown. OBJECTIVES: We aimed to elucidate whether carbohydrate and fat intakes modulate cg00574958 methylation and the risk of metabolic diseases. METHODS: We examined associations between carbohydrate (CHO) and fat (FAT) intake, as percentages of total diet energy, and the CHO/FAT ratio with CPT1A-cg00574958, and the risk of metabolic diseases in 3 populations (Genetics of Lipid Lowering Drugs and Diet Network, n = 978; Framingham Heart Study, n = 2331; and REgistre GIroní del COR study, n = 645) while adjusting for confounding factors. To understand possible causal effects of dietary intake on the risk of metabolic diseases, we performed meta-analysis, CPT1A transcription analysis, and mediation analysis with CHO and FAT intakes as exposures and cg00574958 methylation as the mediator. RESULTS: We confirmed strong associations of cg00574958 methylation with metabolic phenotypes (BMI, triglyceride, glucose) and diseases in all 3 populations. Our results showed that CHO intake and CHO/FAT ratio were positively associated with cg00574958 methylation, whereas FAT intake was negatively correlated with cg00574958 methylation. Meta-analysis further confirmed this strong correlation, with ß = 58.4 ± 7.27, P = 8.98 x 10-16 for CHO intake; ß = -36.4 ± 5.95, P = 9.96 x 10-10 for FAT intake; and ß = 3.30 ± 0.49, P = 1.48 x 10-11 for the CHO/FAT ratio. Furthermore, CPT1A mRNA expression was negatively associated with CHO intake, and positively associated with FAT intake, and metabolic phenotypes. Mediation analysis supports the hypothesis that CHO intake induces CPT1A methylation, hence reducing the risk of metabolic diseases, whereas FAT intake inhibits CPT1A methylation, thereby increasing the risk of metabolic diseases. CONCLUSIONS: Our results suggest that the proportion of total energy supplied by CHO and FAT can have a causal effect on the risk of metabolic diseases via the epigenetic status of CPT1A.Study registration at https://www.clinicaltrials.gov/: the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)-NCT01023750; and the Framingham Heart Study (FHS)-NCT00005121.

Statin Use Associates With Risk of Type 2 Diabetes via Epigenetic Patterns at ABCG1.

Statin is the medication most widely prescribed to reduce plasma cholesterol levels. Yet, how the medication contributes to diabetes risk and impaired glucose metabolism is not clear. This study aims to examine the epigenetic mechanisms of ABCG1 through which statin use associates with risk of type 2 diabetes. We determined the association between the statin use, DNA methylation at ABCG1 and type 2 diabetes/glycemic traits in the Framingham Heart Study Offspring (FHS, n = 2741), with validation in the Women's Health Initiative Study (WHI, n = 2020). The causal effect of statin use on the risk of type 2 diabetes was examined using a two-step Mendelian randomization approach. Next, based on transcriptome analysis, we determined the links between the medication-associated epigenetic status of ABCG1 and biological pathways on the pathogenesis of type 2 diabetes. Our results showed that DNA methylation levels at cg06500161 of ABCG1 were positively associated with the use of statin, type 2 diabetes and related traits (fasting glucose and insulin) in FHS and WHI. Two-step Mendelian randomization suggested a causal effect of statin use on type 2 diabetes and related traits through epigenetic mechanisms, specifically, DNA methylation at cg06500161. Our results highlighted that gene expression of ABCG1, ABCA1 and ACSL3, involved in both cholesterol metabolism and glycemic pathways, was inversely associated with statin use, CpG methylation, and diabetic signatures. We concluded that DNA methylation site cg06500161 at ABCG1 is a mediator of the association between statins and risk of type 2 diabetes.

Metabolomic Links between Sugar-Sweetened Beverage Intake and Obesity.

Background: Sugar-sweetened beverage (SSB) consumption is highly associated with obesity, but the metabolic mechanism underlying this correlation is not understood. Objective: Our objective was to examine metabolomic links between SSB intake and obesity to understand metabolic mechanisms. Design: We examined the association of plasma metabolomic profiles with SSB intake and obesity risk in 781 participants, aged 45-75 y, in the Boston Puerto Rican Health Study (BPRHS) using generalized linear models, controlling for potential confounding factors. Based on identified metabolites, we conducted pathway enrichment analysis to identify potential metabolic pathways that link SSB intake and obesity risk. Variants in genes encoding enzymes known to function in identified metabolic pathways were examined for their interactions with SSB intake on obesity. Results: SSB intake was correlated with BMI (ß = 0.607, P=0.045). Among 526 measured metabolites, 86 showed a significant correlation with SSB intake and 148 with BMI (P ≤ 0.05); 28 were correlated with both SSB intake and BMI (P ≤ 0.05). Pathway enrichment analysis identified the phosphatidylcholine and lysophospholipid pathways as linking SSB intake to obesity, after correction for multiple testing. Furthermore, 8 of 10 genes functioning in these two pathways showed strong interaction with SSB intake on BMI. Our results further identified participants who may exhibit an increased risk of obesity when consuming SSB. Conclusions: We identified two key metabolic pathways that link SSB intake to obesity, revealing the potential of phosphatidylcholine and lysophospholipid to modulate how SSB intake can increase obesity risk. The interaction between genetic variants related to these pathways and SSB intake on obesity further supports the mechanism.

Salivary AMY1 Copy Number Variation Modifies Age-Related Type 2 Diabetes Risk.

BACKGROUND: Copy number variation (CNV) in the salivary amylase gene (AMY1) modulates salivary α-amylase levels and is associated with postprandial glycemic traits. Whether AMY1-CNV plays a role in age-mediated change in insulin resistance (IR) is uncertain. METHODS: We measured AMY1-CNV using duplex quantitative real-time polymerase chain reaction in two studies, the Boston Puerto Rican Health Study (BPRHS, n = 749) and the Genetics of Lipid-Lowering Drug and Diet Network study (GOLDN, n = 980), and plasma metabolomic profiles in the BPRHS. We examined the interaction between AMY1-CNV and age by assessing the relationship between age with glycemic traits and type 2 diabetes (T2D) according to high or low copy numbers of the AMY1 gene. Furthermore, we investigated associations between metabolites and interacting effects of AMY1-CNV and age on T2D risk. RESULTS: We found positive associations of IR with age among subjects with low AMY1-copy-numbers in both studies. T2D was marginally correlated with age in participants with low AMY1-copy-numbers but not with high AMY1-copy-numbers in the BPRHS. Metabolic pathway enrichment analysis identified the pentose metabolic pathway based on metabolites that were associated with both IR and the interactions between AMY1-CNV and age. Moreover, in older participants, high AMY1-copy-numbers tended to be associated with lower levels of ribonic acid, erythronic acid, and arabinonic acid, all of which were positively associated with IR. CONCLUSIONS: We found evidence supporting a role of AMY1-CNV in modifying the relationship between age and IR. Individuals with low AMY1-copy-numbers tend to have increased IR with advancing age.

Curcumin supplementation improves heat-stress-induced cardiac injury of mice: physiological and molecular mechanisms.

Heat stress (HS) causes serious physiological dysfunction associated with cardiovascular diseases. Curcumin (CUR) may increase animal survival and lifespan under HS. However, its effects and mechanism on mammal are underexplored. The goal of this study was to examine the protective effect of CUR on the cardiac health of mice exposed to HS. Mice were divided into six groups (n=8 per group): no-heat treatment (NHT), heat treatment (HT), aspirin, CUR 50 mg/kg/day, CUR 100 mg/kg/day and CUR 200 mg/kg/day. After administration for 4 weeks, except for NHT, other groups were exposed once to HS at 41°C for 20 min. After HS treatment, the physiological-related indexes of blood pressure, rectal temperature and heart rate were measured. Serum biochemical indexes and the levels of cardiac troponin I (cTn-I) in serum and angiotensin II (Ang II) in cardiomyocytes were analyzed. Furthermore, the mRNA and proteins levels of angiotensin receptor 1 (AT1), 78-kDa glucose-regulated protein (GRP78), C/EBP homologous protein (CHOP) and B-cell lymphoma 2 (Bcl-2) were measured. Our results indicated that CUR supplementation could alleviate HS-induced physiological disorders and the increasing of cTn-I and Ang II. The expression of AT1 gene in HT group was significantly higher than that of CUR groups, indicating the cardioprotective effects of CUR. Moreover, the levels of GRP78 and CHOP proteins in the HT group were significantly higher than those of CUR groups, indicating that CUR supplementation reversed the endoplasmic reticulum HS-mediated apoptosis. In summary, CUR supplementation alleviates physiological stress and cardiac damage caused by HS.

Mediterranean Diet Adherence Modulates Anthropometric Measures by TCF7L2 Genotypes among Puerto Rican Adults.

BACKGROUND: Transcription factor 7-like 2 (TCF7L2) genetic variants that predispose individuals to type 2 diabetes (T2D) show inconsistent associations with anthropometric traits. Interaction between TCF7L2 genotypes and dietary factors may help explain these observations. OBJECTIVE: We aimed to examine the potential modulation of TCF7L2-rs7903146 and rs12255372 on anthropometric markers by a Mediterranean diet (MedDiet). METHODS: Cross-sectional analysis was conducted in 1120 participants (aged 45-75 y) of the Boston Puerto Rican Health Study. Anthropometric variables were measured, and polymorphisms were genotyped using standardized protocols. Diet was assessed using a validated FFQ. The MedDiet was defined based on adherence to 9 food and nutrient components using sex-specific population-based median cut-offs; high adherence was defined as meeting ≥4 components. Haplotypes were tested for association with obesity traits, independently and via interaction with the MedDiet. RESULTS: TCF7L2-rs7903146 showed significant interaction with the MedDiet influencing BMI, weight, and waist circumference. The T risk-allele carriers (CT + TT) with a high MedDiet score had lower weight (77.3 ± 1.0 compared with CC 80.9 ± 1.0 kg; P = 0.013) and waist circumference (99.2 ± 0.9 compared with CC 102.2 ± 0.9 cm; P = 0.021), when compared with CC participants. A low MedDiet score resulted in no significant differences between genotypes. For TCF7L2-rs12255372, we found significant interactions with the MedDiet for weight (P-interaction = 0.034) and BMI (P-interaction = 0.036). The T allele carriers with a higher MedDiet score showed a trend of lower but no significant differences when compared with CC participants for BMI (P = 0.19), weight (P = 0.09), and waist circumference (P = 0.11). We found significant interactions between the 2 risk-carrying haplotypes and the MedDiet compared with the common haplotype (GC), with lower BMI (ß ± SE, TT: -1.53 ± 0.68; P-interaction = 0.024), weight (TT: -4.16 ± 1.77; P-interaction = 0.019), and waist circumference (GT: -5.07 ± 2.50; P-interaction = 0.042) at a high MedDiet score. CONCLUSION: Puerto Ricans with the TCF7L2-rs7903146 and rs12255372 T2D risk genotypes, although still high, had better anthropometric profiles when adhering to a MedDiet, suggesting that this diet may offset unfavorable genetic predisposition.

Association of Birth Weight With Type 2 Diabetes and Glycemic Traits: A Mendelian Randomization Study.

Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations. Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis. Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included. Main Outcomes and Measures: Type 2 diabetes and glycemic traits. Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (ß = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration. Conclusions and Relevance: In this study, a genetic predisposition to lower birth weight was associated with increased risk of T2D and higher fasting glucose concentration, suggesting genetic effects on retarded fetal growth and increased diabetes risk that either are independent of each other or operate through alterations of integrated biological mechanisms.