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.

PhyteByte: identification of foods containing compounds with specific pharmacological properties.

BACKGROUND: Phytochemicals and other molecules in foods elicit positive health benefits, often by poorly established or unknown mechanisms. While there is a wealth of data on the biological and biophysical properties of drugs and therapeutic compounds, there is a notable lack of similar data for compounds commonly present in food. Computational methods for high-throughput identification of food compounds with specific biological effects, especially when accompanied by relevant food composition data, could enable more effective and more personalized dietary planning. We have created a machine learning-based tool (PhyteByte) to leverage existing pharmacological data to predict bioactivity across a comprehensive molecular database of foods and food compounds. RESULTS: PhyteByte uses a cheminformatic approach to structure-based activity prediction and applies it to uncover the putative bioactivity of food compounds. The tool takes an input protein target and develops a random forest classifier to predict the effect of an input molecule based on its molecular fingerprint, using structure and activity data available from the ChEMBL database. It then predicts the relevant bioactivity of a library of food compounds with known molecular structures from the FooDB database. The output is a list of food compounds with high confidence of eliciting relevant biological effects, along with their source foods and associated quantities in those foods, where available. Applying PhyteByte to the human PPARG gene, we identified irigenin, sesamin, fargesin, and delta-sanshool as putative agonists of PPARG, along with previously identified agonists of this important metabolic regulator. CONCLUSIONS: PhyteByte identifies food-based compounds that are predicted to interact with specific protein targets. The identified relationships can be used to prioritize food compounds for experimental or epidemiological follow-up and can contribute to the rapid development of precision approaches to new nutraceuticals as well as personalized dietary planning.

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.

Dietary epicatechin improves survival and delays skeletal muscle degeneration in aged mice.

We recently reported that epicatechin, a bioactive compound that occurs naturally in various common foods, promoted general health and survival of obese diabetic mice. It remains to be determined whether epicatechin extends health span and delays the process of aging. In the present study, epicatechin or its analogue epigallocatechin gallate (EGCG) (0.25% w/v in drinking water) was administered to 20-mo-old male C57BL mice fed a standard chow. The goal was to determine the antiaging effect. The results showed that supplementation with epicatechin for 37 wk strikingly increased the survival rate from 39 to 69%, whereas EGCG had no significant effect. Consistently, epicatechin improved physical activity, delayed degeneration of skeletal muscle (quadriceps), and shifted the profiles of the serum metabolites and skeletal muscle general mRNA expressions in aging mice toward the profiles observed in young mice. In particular, we found that dietary epicatechin significantly reversed age-altered mRNA and protein expressions of extracellular matrix and peroxisome proliferator-activated receptor pathways in skeletal muscle, and reversed the age-induced declines of the nicotinate and nicotinamide pathway both in serum and skeletal muscle. The present study provides evidence that epicatechin supplementation can exert an antiaging effect, including an increase in survival, an attenuation of the aging-related deterioration of skeletal muscles, and a protection against the aging-related decline in nicotinate and nicotinamide metabolism.-Si, H., Wang, X., Zhang, L., Parnell, L. D., Admed, B., LeRoith, T., Ansah, T.-A., Zhang, L., Li, J., Ordovás, J. M., Si, H., Liu, D., Lai, C.-Q. Dietary epicatechin improves survival and delays skeletal muscle degeneration in aged mice.

Development of a Genetic Score to Predict an Increase in HDL Cholesterol Concentration After a Dietary Intervention in Adults with Metabolic Syndrome.

BACKGROUND: Dietary intervention (DI) is a primary strategy to attenuate some of the metabolic abnormalities associated with metabolic syndrome (MetS), including low HDL cholesterol. There is no biomarker that can identify individuals who respond to DI by increasing HDL cholesterol. OBJECTIVE: The aim of this study was to assess the predictive power of a genetic predisposition score (GPS) in Mexican adults with MetS to identify HDL cholesterol responders to DI. METHODS: This study followed a prospective cohort design. Sixty-seven Mexican adults aged 20-60 y (21% men) with BMI ≥25 and ≤39.9 kg/m², who had at least 3 of 5 positive criteria for MetS, were included. Participants consumed a low saturated fat diet for 2.5 mo (<7% energy as saturated fat, <200 mg of cholesterol/d) and reduced their usual diet by ∼440 kcal/d, a reduction in total energy intake of about 25%. Anthropometry and serum biochemical markers, including HDL cholesterol, were measured before and after DI. A multilocus GPS was constructed using previously reported genetic variants associated with response to diet in subjects with MetS. GPS values, designed to predict the response of HDL cholesterol to the DI, were computed for each individual as the sum of the number of effect alleles across 14 SNPs. RESULTS: Individuals were dichotomized as high and low GPS according to median GPS (-2.12) and we observed a difference in HDL cholesterol changes on DI of +3 mg/dL (6.3%) in subjects with low GPS, whereas those with high GPS had HDL cholesterol decreases of -3 mg/dL (-7.9%) (P = 0.04). CONCLUSIONS: Individuals with low GPS showed greater increases in their HDL cholesterol than those with high GPS. Therefore, the GPS can be useful for predicting the HDL cholesterol response to diet.

Environmental and epigenetic regulation of postprandial lipemia.

PURPOSE OF REVIEW: Postprandial lipemia (PPL), the prolonged increase in plasma triglyceride-rich lipoproteins following food consumption, is an independent risk factor for cardiovascular disease. Genetic variation, environment and the interplay between these direct an individual's postprandial lipid response. From such interplay, inducible and reversible epigenetic changes arise. Increasing evidence suggests epigenetic variation contributes to postprandial response in lipids and risk. RECENT FINDINGS: Diet and exercise are central agents affecting postprandial lipemia - triglyceride, but heterogeneity of the findings warrant more and larger studies. Several epigenetic loci identified from a human intervention study account for a substantial proportion of PPL phenotype variation, but the burden to conduct an intervention study of postprandial responses likely limits translation to personalized nutrition. SUMMARY: The impact of both DNA methylation patterns and environmental factors such as diet, exercise, sleep and medication on PPL is multifaceted. Discovery of interactions that modify the association between CpG (oligodeoxydinucleotide) methylation and postprandial phenotypes is unfolding.

Detection of gene-environment interactions in a family-based population using SCAD.

Gene-environment interaction (GxE) is emphasized as one potential source of missing genetic variation on disease traits, and the ultimate goal of GxE research is prediction of individual risk and prevention of complex diseases. However, there are various challenges in statistical analysis of GxE. In this paper, we focus on the three methodological challenges: (i) the high dimensions of genes; (ii) the hierarchical structure between interaction effects and their corresponding main effects; and (iii) the correlation among subjects from family-based population studies. In this paper, we propose an algorithm that approaches all three challenges simultaneously. This is the first penalized method focusing on an interaction search based on a linear mixed effect model. For verification, we compare the empirical performance of our new method with other existing methods in simulation study. The results demonstrate the superiority of our method under overall simulation setup. In particular, the outperformance obviously becomes greater as the correlation among subjects increases. In addition, the new method provides a robust estimate for the correlation among subjects. We also apply the new method on Genetics of Lipid Lowering Drugs and Diet Network study data. Copyright © 2017 John Wiley & Sons, Ltd.

Epigenome-wide association study of triglyceride postprandial responses to a high-fat dietary challenge.

Postprandial lipemia (PPL), the increased plasma TG concentration after consuming a high-fat meal, is an independent risk factor for CVD. Individual responses to a meal high in fat vary greatly, depending on genetic and lifestyle factors. However, only a few loci have been associated with TG-PPL response. Heritable epigenomic changes may be significant contributors to the unexplained inter-individual PPL variability. We conducted an epigenome-wide association study on 979 subjects with DNA methylation measured from CD4+ T cells, who were challenged with a high-fat meal as a part of the Genetics of Lipid Lowering Drugs and Diet Network study. Eight methylation sites encompassing five genes, LPP, CPT1A, APOA5, SREBF1, and ABCG1, were significantly associated with PPL response at an epigenome-wide level (P < 1.1 × 10-7), but no methylation site reached epigenome-wide significance after adjusting for baseline TG levels. Higher methylation at LPP, APOA5, SREBF1, and ABCG1, and lower methylation at CPT1A methylation were correlated with an increased TG-PPL response. These PPL-associated methylation sites, also correlated with fasting TG, account for a substantially greater amount of phenotypic variance (14.9%) in PPL and fasting TG (16.3%) when compared with the genetic contribution of loci identified by our previous genome-wide association study (4.5%). In summary, the epigenome is a large contributor to the variation in PPL, and this has the potential to be used to modulate PPL and reduce CVD.

Interactions between the colonic transcriptome, metabolome, and microbiome in mouse models of obesity-induced intestinal cancer.

Obesity is a significant risk factor for colorectal cancer (CRC); however, the relative contribution of high-fat (HF) consumption and excess adiposity remains unclear. It is becoming apparent that obesity perturbs both the intestinal microbiome and metabolome, and each has the potential to induce protumorigenic changes in the epithelial transcriptome. The physiological consequences and the degree to which these different biologic systems interact remain poorly defined. To understand the mechanisms by which obesity drives colonic tumorigenesis, we profiled the colonic epithelial transcriptome of HF-fed and genetically obese (DbDb) mice with a genetic predisposition to intestinal tumorigenesis (Apc(1638N)); 266 and 584 genes were differentially expressed in the colonic mucosa of HF and DbDb mice, respectively. These genes mapped to pathways involved in immune function, and cellular proliferation and cancer. Furthermore, Akt was central within the networks of interacting genes identified in both gene sets. Regression analyses of coexpressed genes with the abundance of bacterial taxa identified three taxa, previously correlated with tumor burden, to be significantly correlated with a gene module enriched for Akt-related genes. Similarly, regression of coexpressed genes with metabolites found that adenosine, which was negatively associated with inflammatory markers and tumor burden, was also correlated with a gene module enriched with Akt regulators. Our findings provide evidence that HF consumption and excess adiposity result in changes in the colonic transcriptome that, although distinct, both appear to converge on Akt signaling. Such changes could be mediated by alterations in the colonic microbiome and metabolome.

Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site.

Genome-wide association studies (GWAS) have identified hundreds of genetic variants that are associated with lipid phenotypes. However, data supporting a functional role for these variants in the context of lipid metabolism are scarce. We investigated the association of the lipoprotein lipase (LPL) variant rs13702 with plasma lipids and explored its potential for functionality. The rs13702 minor allele had been predicted to disrupt a microRNA (miR) recognition element (MRE) seed site (MRESS) for the human microRNA-410 (miR-410). Furthermore, rs13702 is in linkage disequilibrium (LD) with several SNPs identified by GWAS. We performed a meta-analysis across ten cohorts of participants that showed a statistically significant association of rs13702 with triacylglycerols (TAG) (p = 3.18 × 10(-42)) and high-density lipoprotein cholesterol (HDL-C) (p = 1.35 × 10(-32)) with each copy of the minor allele associated with 0.060 mmol/l lower TAG and 0.041 mmol/l higher HDL-C. Our data showed that an LPL 3' UTR luciferase reporter carrying the rs13702 major T allele was reduced by 40% in response to a miR-410 mimic. We also evaluated the interaction between intake of dietary fatty acids and rs13702. Meta-analysis demonstrated a significant interaction between rs13702 and dietary polyunsaturated fatty acid (PUFA) with respect to TAG concentrations (p = 0.00153), with the magnitude of the inverse association between dietary PUFA intake and TAG concentration showing -0.007 mmol/l greater reduction. Our results suggest that rs13702 induces the allele-specific regulation of LPL by miR-410 in humans. This work provides biological and potential clinical relevance for previously reported GWAS variants associated with plasma lipid phenotypes.

CD209a expression on dendritic cells is critical for the development of pathogenic Th17 cell responses in murine schistosomiasis.

In murine schistosomiasis, immunopathology and cytokine production in response to parasite eggs are uneven and strain dependent. CBA/J (CBA) mice develop severe hepatic granulomatous inflammation associated with prominent Th17 cell responses driven by dendritic cell (DC)-derived IL-1ß and IL-23. Such Th17 cells fail to develop in low-pathology C57BL/6 (BL/6) mice, and the reasons for these strain-specific differences in APC reactivity to eggs remain unclear. We show by gene profiling that CBA DCs display an 18-fold higher expression of the C-type lectin receptor CD209a, a murine homolog of human DC-specific ICAM-3-grabbing nonintegrin, compared with BL/6 DCs. Higher CD209a expression was observed in CBA splenic and granuloma APC subpopulations, but only DCs induced Th17 cell differentiation in response to schistosome eggs. Gene silencing in CBA DCs and overexpression in BL/6 DCs demonstrated that CD209a is essential for egg-elicited IL-1ß and IL-23 production and subsequent Th17 cell development, which is associated with SRC, RAF-1, and ERK1/2 activation. These findings reveal a novel mechanism controlling the development of Th17 cell-mediated severe immunopathology in helminthic disease.

Diminished skeletal muscle microRNA expression with aging is associated with attenuated muscle plasticity and inhibition of IGF-1 signaling.

Older individuals have a reduced capacity to induce muscle hypertrophy with resistance exercise (RE), which may contribute to the age-induced loss of muscle mass and function, sarcopenia. We tested the novel hypothesis that dysregulation of microRNAs (miRNAs) may contribute to reduced muscle plasticity with aging. Skeletal muscle expression profiling of protein-coding genes and miRNA was performed in younger (YNG) and older (OLD) men after an acute bout of RE. 21 miRNAs were altered by RE in YNG men, while no RE-induced changes in miRNA expression were observed in OLD men. This striking absence in miRNA regulation in OLD men was associated with blunted transcription of mRNAs, with only 42 genes altered in OLD men vs. 175 in YNG men following RE, demonstrating a reduced adaptability of aging muscle to exercise. Integrated bioinformatics analysis identified miR-126 as an important regulator of the transcriptional response to exercise and reduced lean mass in OLD men. Manipulation of miR-126 levels in myocytes, in vitro, revealed its direct effects on the expression of regulators of skeletal muscle growth and activation of insulin growth factor 1 (IGF-1) signaling. This work identifies a mechanistic role of miRNA in the adaptation of muscle to anabolic stimulation and reveals a significant impairment in exercise-induced miRNA/mRNA regulation with aging.

The association between genetic variants of RUNX2, ADIPOQ and vertebral fracture in Korean postmenopausal women.

Contrary to the traditional belief that obesity acts as a protective factor for bone, recent epidemiologic studies have shown that body fat might be a risk factor for osteoporosis and bone fracture. Accordingly, we evaluated the association between the phenotypes of osteoporosis or vertebral fracture and variants of obesity-related genes, peroxisome proliferator-activated receptor-gamma (PPARG), runt-related transcription factor 2 (RUNX2), leptin receptor (LEPR), and adiponectin (ADIPOQ). In total, 907 postmenopausal healthy women, aged 60-79 years, were included in this study. BMD and biomarkers of bone health and adiposity were measured. We genotyped for four single nucleotide polymorphisms (SNPs) from four genes (PPARG, RUNX2, LEPR, ADIPOQ). A general linear model for continuous dependent variables and a logistic regression model for categorical dependent variables were used to analyze the statistical differences among genotype groups. Compared with the TT subjects at rs7771980 in RUNX2, C-carrier (TC + CC) subjects had a lower vertebral fracture risk after adjusting for age, smoking, alcohol, total calorie intake, total energy expenditure, total calcium intake, total fat intake, weight, body fat. Odds ratio (OR) and 95% interval (CI) for the vertebral fracture risk was 0.55 (95% CI 0.32-0.94). After adjusting for multiple variables, the prevalence of vertebral fracture was highest in GG subjects at rs1501299 in ADIPOQ (p = 0.0473). A high calcium intake (>1000 mg/day) contributed to a high bone mineral density (BMD) in GT + TT subjects at rs1501299 in ADIPOQ (p for interaction = 0.0295). Even if the mechanisms between obesity-related genes and bone health are not fully established, the results of our study revealed the association of certain SNPs from obesity-related genes with BMD or vertebral fracture risk in postmenopausal Korean women.

S-adenosylmethionine mediates inhibition of inflammatory response and changes in DNA methylation in human macrophages.

S-adenosylmethionine (SAM), the unique methyl donor in DNA methylation, has been shown to lower lipopolysaccharide (LPS)-induced expression of the proinflammatory cytokine TNF-α and increase the expression of the anti-inflammatory cytokine IL-10 in macrophages. The aim of this study was to assess whether epigenetic mechanisms mediate the anti-inflammatory effects of SAM. Human monocytic THP1 cells were differentiated into macrophages and treated with 0, 500, or 1,000 µmol/l SAM for 24 h, followed by stimulation with LPS. TNFα and IL-10 expression levels were measured by real-time PCR, cellular concentrations of SAM and S-adenosylhomocysteine (SAH), a metabolite of SAM, were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and DNA methylation was measured with LC-MS/MS and microarrays. Relative to control (0 µmol/l SAM), treatment with 500 µmol/l SAM caused a significant decrease in TNF-α expression (-45%, P < 0.05) and increase in IL-10 expression (+77%, P < 0.05). Treatment with 1,000 µmol/l SAM yielded no significant additional benefits. Relative to control, 500 µmol/l SAM increased cellular SAM concentrations twofold without changes in SAH, and 1,000 µmol/l SAM increased cellular SAM sixfold and SAH fourfold. Global DNA methylation increased 7% with 500 µmol/l SAM compared with control. Following treatment with 500 µmol/l SAM, DNA methylation microarray analysis identified 765 differentially methylated regions associated with 918 genes. Pathway analysis of these genes identified a biological network associated with cardiovascular disease, including a subset of genes that were differentially hypomethylated and whose expression levels were altered by SAM. Our data indicate that SAM modulates the expression of inflammatory genes in association with changes in specific gene promoter DNA methylation.

Genome-wide interaction of genotype by erythrocyte n-3 fatty acids contributes to phenotypic variance of diabetes-related traits.

BACKGROUND: Little is known about the interplay between n-3 fatty acids and genetic variants for diabetes-related traits at the genome-wide level. The present study aimed to examine variance contributions of genotype by environment (GxE) interactions for different erythrocyte n-3 fatty acids and genetic variants for diabetes-related traits at the genome-wide level in a non-Hispanic white population living in the U.S.A. (n = 820). A tool for Genome-wide Complex Trait Analysis (GCTA) was used to estimate the genome-wide GxE variance contribution of four diabetes-related traits: HOMA-Insulin Resistance (HOMA-IR), fasting plasma insulin, glucose and adiponectin. A GxE genome-wide association study (GWAS) was conducted to further elucidate the GCTA results. Replication was conducted in the participants of the Boston Puerto Rican Health Study (BPRHS) without diabetes (n = 716). RESULTS: In GOLDN, docosapentaenoic acid (DPA) contributed the most significant GxE variance to the total phenotypic variance of both HOMA-IR (26.5%, P-nominal = 0.034) and fasting insulin (24.3%, P-nominal = 0.042). The ratio of arachidonic acid to eicosapentaenoic acid + docosahexaenoic acid contributed the most significant GxE variance to the total variance of fasting glucose (27.0%, P-nominal = 0.023). GxE variance of the arachidonic acid/eicosapentaenoic acid ratio showed a marginally significant contribution to the adiponectin variance (16.0%, P-nominal = 0.058). None of the GCTA results were significant after Bonferroni correction (P < 0.001). For each trait, the GxE GWAS identified a far larger number of significant single-nucleotide polymorphisms (P-interaction ≤ 10E-5) for the significant E factor (significant GxE variance contributor) than a control E factor (non-significant GxE variance contributor). In the BPRHS, DPA contributed a marginally significant GxE variance to the phenotypic variance of HOMA-IR (12.9%, P-nominal = 0.068) and fasting insulin (18.0%, P-nominal = 0.033). CONCLUSION: Erythrocyte n-3 fatty acids contributed a significant GxE variance to diabetes-related traits at the genome-wide level.

Circulating 25-hydroxyvitamin D, IRS1 variant rs2943641, and insulin resistance: replication of a gene-nutrient interaction in 4 populations of different ancestries.

BACKGROUND: Associations of either insulin receptor substrate 1 (IRS1) variants or circulating 25-hydroxyvitamin D [25(OH)D] with type 2 diabetes (T2D) and insulin resistance (IR) are inconsistent. This study sought to determine whether circulating 25(OH)D modulates the association of a potentially functional variant at IRS1 (rs2943641) with insulin resistance. METHOD: Interaction between IRS1 rs2943641 and circulating 25(OH)D on homeostasis model assessment for IR (HOMA-IR) was examined in the Boston Puerto Rican Health Study (BPRHS) (n = 1144). Replication was performed in the African-American (n = 1126), non-Hispanic white (n = 1967), and Hispanic (n = 1241) populations of the Multi-Ethnic Study of Atherosclerosis (MESA) with genotypes of 3 IRS1 variants, rs2972144, rs1515104, and rs2673142, which are tag single nucleotide polymorphisms (SNPs) and in strong linkage disequilibrium with rs2943641. RESULTS: Higher circulating 25(OH)D was associated with lower risk of T2D and IR in BPRHS women homozygous for minor allele rs2943641T. Consistently, in each of 3 MESA populations, HOMA-IR and insulin decreased more evidently with higher circulating 25(OH)D in women of the rs2943641TT genotype than in carriers of the major allele (rs2943641C). Metaanalysis indicated significant and consistent interactions between circulating 25(OH)D and IRS1 variants on HOMA-IR (log transformed) [pooled ß = -0.008, 95% CI: -0.016 to -0.001, P interaction = 0.004] and insulin (log transformed) (pooled ß = -0.006, 95% CI: -0.011 to -0.002, P interaction = 0.023) in 3065 women of the 4 populations. CONCLUSIONS: Participants with different genotypes of IRS1 rs2943641 exhibit differential benefit from high circulating 25(OH)D for the reduction of insulin resistance and T2D risk. This gene-nutrient interaction, which appears to be limited to women, warrants further examination in randomized controlled trials of vitamin D supplementation.

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.

Genetic variants at PSMD3 interact with dietary fat and carbohydrate to modulate insulin resistance.

PSMD3 encodes subunit 3 of the 26S proteasome, which is involved in regulating insulin signal transduction, and dietary factors could potentially regulate the function of this gene. We aimed to investigate the associations of PSMD3 variants with glucose-related traits and the interactions of those variants with dietary fat and carbohydrate for glucose-related traits in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study and to replicate the findings in the Boston Puerto Rican Health Study (BPRHS). Ten single nucleotide polymorphisms (SNPs) were selected, covering 90% the genetic variations in or near PSMD3. Minor allele (C) carriers of rs4065321 had higher homeostasis model assessment of insulin resistance (HOMA-IR) than noncarriers in males of both the GOLDN (P = 0.022) and BPRHS (P = 0.036). Minor allele (T) carriers of rs709592 had significantly higher HOMA-IR (P = 0.032) than C homozygotes in the GOLDN, whereas the T allele carriers of rs709592 tended to have higher HOMA-IR (P = 0.08) than C homozygotes in the BPRHS. In the GOLDN, there was an interaction between rs709592 and dietary carbohydrate on HOMA-IR (P = 0.049). Subjects carrying the T allele of rs709592 had higher HOMA-IR compared only with noncarriers with low carbohydrate intake (≤49.1% energy; P = 0.004). SNPs rs4065321 and rs709592 both significantly interacted with dietary MUFAs and carbohydrate on glucose concentrations in the GOLDN. Our study suggests that PSMD3 variants are associated with insulin resistance in populations of different ancestries and that these relationships may also be modified by dietary factors.

Apolipoprotein A2 polymorphism interacts with intakes of dairy foods to influence body weight in 2 U.S. populations.

The interaction between a functional apolipoprotein A2 gene (APOA2) variant and saturated fatty acids (SFAs) for the outcome of body mass index (BMI) is among the most widely replicated gene-nutrient interactions. Whether this interaction can be extrapolated to food-based sources of SFAs, specifically dairy foods, is unexplored. Cross-sectional analyses were performed in 2 U.S. population-based samples. We evaluated interactions between dairy foods and APOA2 -265T > C (rs5082) for BMI in the Boston Puerto Rican Health Study (n = 955) and tested for replication in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 1116). Dairy products were evaluated as total dairy, higher-fat dairy (>1%), and low-fat dairy (≤ 1%) in servings per day, dichotomized into high and low based on each population median and also as continuous variables. We identified a statistically significant interaction between the APOA2 -265T > C variant and higher-fat dairy food intake in the Boston Puerto Ricans (P-interaction = 0.028) and replicated this relation in the GOLDN study (P-interaction = 0.001). In both groups, individuals with the previously demonstrated SFA-sensitive genotype (CC) who consumed a greater amount of higher-fat dairy foods had greater BMI (P = 0.013 in Boston Puerto Ricans; P = 0.0007 in GOLDN women) compared with those consuming less of the higher-fat dairy foods. The results expand the understanding of the metabolic influence of dairy products, an important food group for which variable relations to body weight may be in part genetically based. Moreover, these findings suggest that other strongly demonstrated gene-nutrient relations might be investigated through appropriate food-based, translatable avenues and may be relevant to dietary management of obesity.