Hepatic transcript signatures predict atherosclerotic lesion burden prior to a 2-year high cholesterol, high fat diet challenge.

The purpose of this study was to identify molecular mechanisms by which the liver influences total lesion burden in a nonhuman primate model (NHP) of cardiovascular disease with acute and chronic feeding of a high cholesterol, high fat (HCHF) diet. Baboons (47 females, 64 males) were fed a HCHF diet for 2 years (y); liver biopsies were collected at baseline, 7 weeks (w) and 2y, and lesions were quantified in aortic arch, descending aorta, and common iliac at 2y. Unbiased weighted gene co-expression network analysis (WGCNA) revealed several modules of hepatic genes correlated with lesions at different time points of dietary challenge. Pathway and network analyses were performed to study the roles of hepatic module genes. More significant pathways were observed in males than females. In males, we found modules enriched for genes in oxidative phosphorylation at baseline, opioid signaling at 7w, and EIF2 signaling and HNF1A and HNF4A networks at baseline and 2y. One module enriched for fatty acid ß oxidation pathway genes was found in males and females at 2y. To our knowledge, this is the first study of a large NHP cohort to identify hepatic genes that correlate with lesion burden. Correlations of baseline and 7w module genes with lesions at 2y were observed in males but not in females. Pathway analyses of baseline and 7w module genes indicate EIF2 signaling, oxidative phosphorylation, and µ-opioid signaling are possible mechanisms that predict lesion formation induced by HCHF diet consumption in males. Our findings of coordinated hepatic transcriptional response in male baboons but not female baboons indicate underlying molecular mechanisms differ between female and male primate atherosclerosis.

Genetic variants in ALDH1L1 and GLDC influence the serine-to-glycine ratio in Hispanic children.

BACKGROUND: Glycine is a proteogenic amino acid that is required for numerous metabolic pathways, including purine, creatine, heme, and glutathione biosynthesis. Glycine formation from serine, catalyzed by serine hydroxy methyltransferase, is the major source of this amino acid in humans. Our previous studies in a mouse model have shown a crucial role for the 10-formyltetrahydrofolate dehydrogenase enzyme in serine-to-glycine conversion. OBJECTIVES: We sought to determine the genomic influence on the serine-glycine ratio in 803 Hispanic children from 319 families of the Viva La Familia cohort. METHODS: We performed a genome-wide association analysis for plasma serine, glycine, and the serine-glycine ratio in Sequential Oligogenic Linkage Analysis Routines while accounting for relationships among family members. RESULTS: All 3 parameters were significantly heritable (h2 = 0.22-0.78; P < 0.004). The strongest associations for the serine-glycine ratio were with single nucleotide polymorphisms (SNPs) in aldehyde dehydrogenase 1 family member L1 (ALDH1L1) and glycine decarboxylase (GLDC) and for glycine with GLDC (P < 3.5 × 10-8; effect sizes, 0.03-0.07). No significant associations were found for serine. We also conducted a targeted genetic analysis with ALDH1L1 exonic SNPs and found significant associations between the serine-glycine ratio and rs2886059 (ß = 0.68; SE, 0.25; P = 0.006) and rs3796191 (ß = 0.25; SE, 0.08; P = 0.003) and between glycine and rs3796191 (ß = -0.08; SE, 0.02; P = 0.0004). These exonic SNPs were further associated with metabolic disease risk factors, mainly adiposity measures (P < 0.006). Significant genetic and phenotypic correlations were found for glycine and the serine-glycine ratio with metabolic disease risk factors, including adiposity, insulin sensitivity, and inflammation-related phenotypes [estimate of genetic correlation = -0.37 to 0.35 (P < 0.03); estimate of phenotypic correlation = -0.19 to 0.13 (P < 0.006)]. The significant genetic correlations indicate shared genetic effects among glycine, the serine-glycine ratio, and adiposity and insulin sensitivity phenotypes. CONCLUSIONS: Our study suggests that ALDH1L1 and GLDC SNPs influence the serine-to-glycine ratio and metabolic disease risk.

Genetic determinants of metabolic biomarkers and their associations with cardiometabolic traits in Hispanic/Latino adolescents.

BACKGROUND: Metabolic regulation plays a significant role in energy homeostasis, and adolescence is a crucial life stage for the development of cardiometabolic disease (CMD). This study aims to investigate the genetic determinants of metabolic biomarkers-adiponectin, leptin, ghrelin, and orexin-and their associations with CMD risk factors. METHODS: We characterized the genetic determinants of the biomarkers among Hispanic/Latino adolescents of the Santiago Longitudinal Study (SLS) and identified the cumulative effects of genetic variants on adiponectin and leptin using biomarker polygenic risk scores (PRS). We further investigated the direct and indirect effect of the biomarker PRS on downstream body fat percent (BF%) and glycemic traits using structural equation modeling. RESULTS: We identified putatively novel genetic variants associated with the metabolic biomarkers. A substantial amount of biomarker variance was explained by SLS-specific PRS, and the prediction was improved by including the putatively novel loci. Fasting blood insulin and insulin resistance were associated with PRS for adiponectin, leptin, and ghrelin, and BF% was associated with PRS for adiponectin and leptin. We found evidence of substantial mediation of these associations by the biomarker levels. CONCLUSIONS: The genetic underpinnings of metabolic biomarkers can affect the early development of CMD, partly mediated by the biomarkers. IMPACT: This study characterized the genetic underpinnings of four metabolic hormones and investigated their potential influence on adiposity and insulin biology among Hispanic/Latino adolescents. Fasting blood insulin and insulin resistance were associated with polygenic risk score (PRS) for adiponectin, leptin, and ghrelin, with evidence of some degree of mediation by the biomarker levels. Body fat percent (BF%) was also associated with PRS for adiponectin and leptin. This provides important insight on biological mechanisms underlying early metabolic dysfunction and reveals candidates for prevention efforts. Our findings also highlight the importance of ancestrally diverse populations to facilitate valid studies of the genetic architecture of metabolic biomarker levels.

Replication of Integrative Data Analysis for Adipose Tissue Dysfunction, Low-Grade Inflammation, Postprandial Responses and OMICs Signatures in Symptom-Free Adults.

We previously reported preliminary characterization of adipose tissue (AT) dysfunction through the adiponectin/leptin ratio (ALR) and fasting/postprandial (F/P) gene expression in subcutaneous (SQ) adipose tissue (AT) biopsies obtained from participants in the GEMM study, a precision medicine research project. Here we present integrative data replication of previous findings from an increased number of GEMM symptom-free (SF) adults (N = 124) to improve characterization of early biomarkers for cardiovascular (CV)/immunometabolic risk in SF adults with AT dysfunction. We achieved this goal by taking advantage of the rich set of GEMM F/P 5 h time course data and three tissue samples collected at the same time and frequency on each adult participant (F/P blood, biopsies of SQAT and skeletal muscle (SKM)). We classified them with the presence/absence of AT dysfunction: low (<1) or high (>1) ALR. We also examined the presence of metabolically healthy (MH)/unhealthy (MUH) individuals through low-grade chronic subclinical inflammation (high sensitivity C-reactive protein (hsCRP)), whole body insulin sensitivity (Matsuda Index) and Metabolic Syndrome criteria in people with/without AT dysfunction. Molecular data directly measured from three tissues in a subset of participants allowed fine-scale multi-OMIC profiling of individual postprandial responses (RNA-seq in SKM and SQAT, miRNA from plasma exosomes and shotgun lipidomics in blood). Dynamic postprandial immunometabolic molecular endophenotypes were obtained to move towards a personalized, patient-defined medicine. This study offers an example of integrative translational research, which applies bench-to-bedside research to clinical medicine. Our F/P study design has the potential to characterize CV/immunometabolic early risk detection in support of precision medicine and discovery in SF individuals.

Genetic variants and physical activity interact to affect bone density in Hispanic children.

BACKGROUND: Our aim was to investigate if moderate to vigorous physical activity (MVPA), calcium intake interacts with bone mineral density (BMD)-related single nucleotide polymorphisms (SNPs) to influence BMD in 750 Hispanic children (4-19y) of the cross-sectional Viva La Familia Study. METHODS: Physical activity and dietary intake were measured by accelerometers and multiple-pass 24 h dietary recalls, respectively. Total body and lumbar spine BMD were measured by dual energy X-ray absorptiometry. A polygenic risk score (PRS) was computed based on SNPs identified in published literature. Regression analysis was conducted with PRSs, MVPA and calcium intake with total body and lumbar spine BMD. RESULTS: We found evidence of statistically significant interaction effects between the PRS and MVPA on total body BMD and lumbar spine BMD (p < 0.05). Higher PRS was associated with a lower total body BMD (ß = - 0.040 ± 0.009, p = 1.1 × 10- 5) and lumbar spine BMD (ß = - 0.042 ± 0.013, p = 0.0016) in low MVPA group, as compared to high MVPA group (ß = - 0.015 ± 0.006, p = 0.02; ß = 0.008 ± 0.01, p = 0.4, respectively). DISCUSSION: The study indicated that calcium intake does not modify the relationship between genetic variants and BMD, while it implied physical activity interacts with genetic variants to affect BMD in Hispanic children. Due to limited sample size of our study, future research on gene by environment interaction on bone health and functional studies to provide biological insights are needed. CONCLUSIONS: Bone health in Hispanic children with high genetic risk for low BMD is benefitted more by MVPA than children with low genetic risk. Our results may be useful to predict disease risk and tailor dietary and physical activity advice delivery to people, especially children.

Towards precision medicine: defining and characterizing adipose tissue dysfunction to identify early immunometabolic risk in symptom-free adults from the GEMM family study.

Interactions between macrophages and adipocytes are early molecular factors influencing adipose tissue (AT) dysfunction, resulting in high leptin, low adiponectin circulating levels and low-grade metaflammation, leading to insulin resistance (IR) with increased cardiovascular risk. We report the characterization of AT dysfunction through measurements of the adiponectin/leptin ratio (ALR), the adipo-insulin resistance index (Adipo-IRi), fasting/postprandial (F/P) immunometabolic phenotyping and direct F/P differential gene expression in AT biopsies obtained from symptom-free adults from the GEMM family study. AT dysfunction was evaluated through associations of the ALR with F/P insulin-glucose axis, lipid-lipoprotein metabolism, and inflammatory markers. A relevant pattern of negative associations between decreased ALR and markers of systemic low-grade metaflammation, HOMA, and postprandial cardiovascular risk hyperinsulinemic, triglyceride and GLP-1 curves was found. We also analysed their plasma non-coding microRNAs and shotgun lipidomics profiles finding trends that may reflect a pattern of adipose tissue dysfunction in the fed and fasted state. Direct gene differential expression data showed initial patterns of AT molecular signatures of key immunometabolic genes involved in AT expansion, angiogenic remodelling and immune cell migration. These data reinforce the central, early role of AT dysfunction at the molecular and systemic level in the pathogenesis of IR and immunometabolic disorders.

Heritability and genetic correlations of obesity indices with ambulatory and office beat-to-beat blood pressure in the Oman Family Study.

OBJECTIVE: To more precisely and comprehensively estimate the genetic and environmental correlations between various indices of obesity and BP. METHODS: We estimated heritability and genetic correlations of obesity indices with BP in the Oman family study (n = 1231). Ambulatory and office beat-to-beat BP was measured and mean values for SBP and DBP during daytime, sleep, 24-h and 10 min at rest were calculated. Different indices were used to quantify obesity and fat distribution: BMI, percentage of body fat (%BF), waist circumference and waist-to-height ratio (WHtR). SOLAR software was used to perform univariate and bivariate quantitative genetic analyses adjusting for age, age, sex, age-sex and age--sex interactions. RESULTS: Heritabilities of BP ranged from 30.2 to 38.2% for ambulatory daytime, 16.8--21.4% for sleeping time, 32.1--40.4% for 24-h and 22--24.4% for office beat-to-beat measurements. Heritabilities for obesity indices were 67.8% for BMI, 52.2% for %BF, 37.3% for waist circumference and 37.9% for WHtR. All obesity measures had consistently positive phenotypic correlations with ambulatory and office beat-to-beat SBP and DBP (r-range: 0.14--0.32). Genetic correlations of obesity indices with SBP and DBP were higher than environmental correlations (rG: 0.16--0.50; rE: 0.01--0.31). CONCLUSION: The considerable genetic overlap between a variety of obesity indices and both ambulatory and office beat-to-beat BP highlights the relevance of pleiotropic genes. Future GWAS analyses should discover the specific genes both influencing obesity indices and BP to help unravel their shared genetic background.

Genetic variants affecting bone mineral density and bone mineral content at multiple skeletal sites in Hispanic children.

CONTEXT: Osteoporosis is a major public health burden with significant economic costs. However, the correlates of bone health in Hispanic children are understudied. OBJECTIVE: We aimed to identify genetic variants associated with bone mineral density (BMD) and bone mineral content (BMC) at multiple skeletal sites in Hispanic children. METHODS: We conducted a cross-sectional genome-wide linkage analysis, genome-wide and exome-wide association analysis of BMD and BMC. The Viva La Familia Study is a family-based cohort with a total of 1030 Hispanic children (4-19 years old at baseline) conducted in Houston, TX. BMD and BMC were measured by Dual-energy X-ray absorptiometry. RESULTS: Significant heritability were observed for BMC and BMD at multiple skeletal sites ranging between 44 and 68% (P < 2.8 × 10-9). Significant evidence for linkage was found for BMD of pelvis and left leg on chromosome 7p14, lumbar spine on 20q13 and left rib on 6p21, and BMC of pelvis on chromosome 20q12 and total body on 14q22-23 (logarithm of odds score > 3). We found genome-wide significant association between BMC of right arm and rs762920 at PVALB (P = 4.6 × 10-8), and between pelvis BMD and rs7000615 at PTK2B (P = 7.4 × 10-8). Exome-wide association analysis revealed novel association of variants at MEGF10 and ABRAXAS2 with left arm and lumber spine BMC, respectively (P < 9 × 10-7). CONCLUSIONS: We identified novel loci associated with BMC and BMD in Hispanic children, with strongest evidence for PTK2B. These findings provide better understanding of bone genetics and shed light on biological mechanisms underlying BMD and BMC variation.

Exenatide regulates pancreatic islet integrity and insulin sensitivity in the nonhuman primate baboon Papio hamadryas.

The glucagon-like peptide-1 receptor agonist exenatide improves glycemic control by several and not completely understood mechanisms. Herein, we examined the effects of chronic intravenous exenatide infusion on insulin sensitivity, ß cell and α cell function and relative volumes, and islet cell apoptosis and replication in nondiabetic nonhuman primates (baboons). At baseline, baboons received a 2-step hyperglycemic clamp followed by an l-arginine bolus (HC/A). After HC/A, baboons underwent a partial pancreatectomy (tail removal) and received a continuous exenatide (n = 12) or saline (n = 12) infusion for 13 weeks. At the end of treatment, HC/A was repeated, and the remnant pancreas (head-body) was harvested. Insulin sensitivity increased dramatically after exenatide treatment and was accompanied by a decrease in insulin and C-peptide secretion, while the insulin secretion/insulin resistance (disposition) index increased by about 2-fold. ß, α, and δ cell relative volumes in exenatide-treated baboons were significantly increased compared with saline-treated controls, primarily as the result of increased islet cell replication. Features of cellular stress and secretory dysfunction were present in islets of saline-treated baboons and absent in islets of exenatide-treated baboons. In conclusion, chronic administration of exenatide exerts proliferative and cytoprotective effects on ß, α, and δ cells and produces a robust increase in insulin sensitivity in nonhuman primates.

Analysis of serum changes in response to a high fat high cholesterol diet challenge reveals metabolic biomarkers of atherosclerosis.

Atherosclerotic plaques are characterized by an accumulation of macrophages, lipids, smooth muscle cells, and fibroblasts, and, in advanced stages, necrotic debris within the arterial walls. Dietary habits such as high fat and high cholesterol (HFHC) consumption are known risk factors for atherosclerosis. However, the key metabolic contributors to diet-induced atherosclerosis are far from established. Herein, we investigate the role of a 2-year HFHC diet challenge in the metabolic changes of development and progression of atherosclerosis. We used a non-human primate (NHP) model (baboons, n = 60) fed a HFHC diet for two years and compared metabolomic profiles in serum from animals on baseline chow with serum collected after the challenge diet using two-dimensional gas chromatography time-of-flight mass-spectrometry (2D GC-ToF-MS) for untargeted metabolomic analysis, to quantify metabolites that contribute to atherosclerotic lesion formation. Further, clinical biomarkers associated with atherosclerosis, lipoprotein measures, fat indices, and arterial plaque formation (lesions) were quantified. Using two chemical derivatization (i.e., silylation) approaches, we quantified 321 metabolites belonging to 66 different metabolic pathways, which revealed significantly different metabolic profiles of HFHC diet and chow diet fed baboon sera. We found heritability of two important metabolites, lactic acid and asparagine, in the context of diet-induced metabolic changes. In addition, abundance of cholesterol, lactic acid, and asparagine were sex-dependent. Finally, 35 metabolites correlated (R2, 0.068-0.271, P < 0.05) with total lesion burden assessed in three arteries (aortic arch, common iliac artery, and descending aorta) which could serve as potential biomarkers pending further validation. This study demonstrates the feasibility of detecting sex-specific and heritable metabolites in NHPs with diet-induced atherosclerosis using untargeted metabolomics allowing understanding of atherosclerotic disease progression in humans.

Genomewide association study of C-peptide surfaces key regulatory genes in Indians.

Insulin is a commonly used measure of pancreatic ß-cell function but exhibits a short half-life in the human body. During biosynthesis, insulin release is accompanied by C-peptide at an equimolar concentration which has a much higher plasma half-life and is therefore projected as a precise measure of ß-cell activity than insulin. Despite this, genetic studies of metabolic traits haveneglected the regulatory potential of C-peptide for therapeutic intervention of type-2 diabetes. The present study is aimed to search genomewide variants governing C-peptide levels in genetically diverse and high risk population for metabolic diseases-Indians. We performed whole genome genotyping in 877 healthy Indians of Indo-European origin followed by replication of variants with P ≤ 1 × 10-3 in an independent sample-set of 1829 Indians. Lead-associated signals were also tested in-silico in 773 Hispanics. To secure biological rationale for observed association, we further carried out DNA methylation quantitative trait loci analysis in 233 Indians and publicly available regulatory data was mined. We discovered novel lncRNA gene AC073333.8 with the strongest association with C-peptide levels in Indians that however missed genomewide significance. Also, noncoding genes, RP1-209A6.1 and RPS3AP5; protein gene regulators, ZNF831 and ETS2; and solute carrier protein gene SLC15A5 retained robust association with C-peptide after meta-analysis. Integration of methylation data revealed ETS2 and ZNF831 single-nucleotide polymorphisms as significant meth-QTLs in Indians. All genes showed reasonable expression in the human lung, signifying alternate important organs for C-peptide biology. Our findings mirror polygenic nature of C-peptide where multiple small-effect size variants in the regulatory genome principally govern the trait biology.

Heritability and genetic and environmental correlations of heart rate variability and baroreceptor reflex sensitivity with ambulatory and beat-to-beat blood pressure.

This family study from Oman (n = 1231) explored the heritability and genetic and environmental correlations of heart rate variability (HRV) and baroreceptor reflex sensitivity (BRS) with ambulatory and beat-to-beat blood pressure (BP). Ambulatory BP was measured for 24 hours to calculate mean values for daytime and sleep separately. Time and frequency domain HRV indices, BRS, office beat-to-beat BP, and heart rate (HR) were measured for 10 minutes at rest. SOLAR software was used to perform univariate and bivariate quantitative genetic analyses adjusting for age, age2, sex, their interactions and BMI. Heritability of SBP and DBP ranged from 16.8% to 40.4% for daytime, sleeping, 24-hour and office beat-to-beat measurements. HR and BRS showed a heritability of 31.9% and 20.6%, respectively, and for HRV indices heritability ranged from 11.1% to 20.5%. All HRV measurements and BRS were found to be negatively correlated with BP, but phenotypic correlation coefficients were relatively weak; HR was positively correlated with BP. None of the genetic correlations were statistically significant while environmental factors explained most of the correlations for all HRV indices with BP. Our study found consistent but weak correlations among HRV, HR, BRS and ambulatory/office beat-to-beat BP. However, environmental rather than genetic factors contributed most to those correlations.

Duodenal adipose tissue is associated with obesity in baboons (Papio sp): a novel site of ectopic fat deposition in non-human primates.

AIMS: Ectopic fat is a recognized contributor to insulin resistance and metabolic dysfunction, while the role of fat deposition inside intestinal wall tissue remains understudied. We undertook this study to directly quantify and localize intramural fat deposition in duodenal tissue and determine its association with adiposity. METHODS: Duodenal tissues were collected from aged (21.2 ± 1.3 years, 19.5 ± 3.1 kg, n = 39) female baboons (Papio sp.). Fasted blood was collected for metabolic profiling and abdominal circumference (AC) measurements were taken. Primary tissue samples were collected at the major duodenal papilla at necropsy: one full cross section was processed for hematoxylin and eosin staining and evaluated; a second full cross section was processed for direct chemical lipid analysis on which percentage duodenal fat content was calculated. RESULTS: Duodenal fat content obtained by direct tissue quantification showed considerable variability (11.95 ± 6.93%) and was correlated with AC (r = 0.60, p < 0.001), weight (r = 0.38, p = 0.02), leptin (r = 0.63, p < 0.001), adiponectin (r = - 0.32, p < 0.05), and triglyceride (r = 0.41, p = 0.01). The relationship between duodenal fat content and leptin remained after adjusting for body weight and abdominal circumference. Intramural adipocytes were found in duodenal sections from all animals and were localized to the submucosa. Consistent with the variation in tissue fat content, the submucosal adipocytes were non-uniformly distributed in clusters of varying size. Duodenal adipocytes were larger in obese vs. lean animals (106.9 vs. 66.7 µm2, p = 0.02). CONCLUSIONS: Fat accumulation inside the duodenal wall is strongly associated with adiposity and adiposity related circulating biomarkers in baboons. Duodenal tissue fat represents a novel and potentially metabolically active site of ectopic fat deposition.

Assessment of DNA Methylation Patterns in the Bone and Cartilage of a Nonhuman Primate Model of Osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) affects humans and several other animals. Thus, the mechanisms underlying this disorder, such as specific skeletal tissue DNA methylation patterns, may be evolutionary conserved. However, associations between methylation and OA have not been readily studied in nonhuman animals. Baboons serve as important models of disease and develop OA at rates similar to those in humans. Therefore, this study investigated the associations between methylation and OA in baboons to advance the evolutionary understanding of OA. DESIGN: Trabecular bone and cartilage was collected from the medial condyles of adult female baboon femora, 5 with and 5 without knee OA. The Infinium HumanMethylation450 BeadChip (450K array) was used to identify DNA methylation patterns in these tissues. RESULTS: Approximately 44% of the 450K array probes reliably align to the baboon genome, contain a CpG site of interest, and maintain a wide distribution throughout the genome. Of the 2 filtering methods tested, both identified significantly differentially methylated positions (DMPs) between healthy and OA individuals in cartilage tissues, and some of these patterns overlap with those previously identified in humans. Conversely, no DMPs were found between tissue types or between disease states in bone tissues. CONCLUSIONS: Overall, the 450K array can be used to measure genome-wide DNA methylation in baboon tissues and identify significant associations with complex traits. The results of this study indicate that some DNA methylation patterns associated with OA are evolutionarily conserved, while others are not. This warrants further investigation in a larger and more phylogenetically diverse sample set.

Heritability and genetic correlations of heart rate variability at rest and during stress in the Oman Family Study.

INTRODUCTION: Individual differences in heart rate variability (HRV) can be partly attributed to genetic factors that may be more pronounced during stress. Using data from the Oman Family Study (OFS), we aimed to estimate and quantify the relative contribution of genes and environment to the variance of HRV at rest and during stress; calculate the overlap in genetic and environmental influences on HRV at rest and under stress using bivariate analyses of HRV parameters and heart rate (HR). METHODS: Time and frequency domain HRV variables and average HR were measured from beat-to-beat HR obtained from electrocardiogram recordings at rest and during two stress tests [mental: Word Conflict Test (WCT) and physical: Cold Pressor Test (CPT)] in the OFS - a multigenerational pedigree consisting of five large Arab families with a total of 1326 participants. SOLAR software was used to perform quantitative genetic modelling. RESULTS: Heritability estimates for HRV and HR ranged from 0.11 to 0.31 for rest, 0.09-0.43 for WCT, and 0.07-0.36 for CPT. A large part of the genetic influences during rest and stress conditions were shared with genetic correlations ranging between 0.52 and 0.86 for rest-WCT and 0.60-0.92 for rest-CPT. Nonetheless, genetic rest-stress correlations for most traits were significantly smaller than 1 indicating some stress-specific genetic effects. CONCLUSION: Genetic factors significantly influence HRV and HR at rest and under stress. Most of the genetic factors that influence HRV at rest also influence HRV during stress tests, although some unique genetic variance emerges during these challenging conditions.

Genetic and environmental (physical fitness and sedentary activity) interaction effects on cardiometabolic risk factors in Mexican American children and adolescents.

Knowledge on genetic and environmental (G × E) interaction effects on cardiometabolic risk factors (CMRFs) in children is limited.  The purpose of this study was to examine the impact of G × E interaction effects on CMRFs in Mexican American (MA) children (n = 617, ages 6-17 years). The environments examined were sedentary activity (SA), assessed by recalls from "yesterday" (SAy) and "usually" (SAu) and physical fitness (PF) assessed by Harvard PF scores (HPFS). CMRF data included body mass index (BMI), waist circumference (WC), fat mass (FM), fasting insulin (FI), homeostasis model of assessment-insulin resistance (HOMA-IR), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), systolic (SBP) and diastolic (DBP) blood pressure, and number of metabolic syndrome components (MSC). We examined potential G × E interaction in the phenotypic expression of CMRFs using variance component models and likelihood-based statistical inference. Significant G × SA interactions were identified for six CMRFs: BMI, WC, FI, HOMA-IR, MSC, and HDL, and significant G × HPFS interactions were observed for four CMRFs: BMI, WC, FM, and HOMA-IR. However, after correcting for multiple hypothesis testing, only WC × SAy, FM × SAy, and FI × SAu interactions became marginally significant. After correcting for multiple testing, most of CMRFs exhibited significant G × E interactions (Reduced G × E model vs. Constrained model). These findings provide evidence that genetic factors interact with SA and PF to influence variation in CMRFs, and underscore the need for better understanding of these relationships to develop strategies and interventions to effectively reduce or prevent cardiometabolic risk in children.

Diet-induced early-stage atherosclerosis in baboons: Lipoproteins, atherogenesis, and arterial compliance.

BACKGROUND: The purpose of this study was to determine whether dietary manipulation can reliably induce early-stage atherosclerosis and clinically relevant changes in vascular function in an established, well-characterized non-human primate model. METHODS: We fed 112 baboons a high-cholesterol, high-fat challenge diet for two years. We assayed circulating biomarkers of cardiovascular disease (CVD) risk, at 0, 7, and 104 weeks into the challenge; assessed arterial compliance noninvasively at 104 weeks; and measured atherosclerotic lesions in three major arteries at necropsy. RESULTS: We observed evidence of atherosclerosis in all but one baboon fed the two-year challenge diet. CVD risk biomarkers, the prevalence, size, and complexity of arterial lesions, plus consequent arterial stiffness, were increased in comparison with dietary control animals. CONCLUSIONS: Feeding baboons a high-cholesterol, high-fat diet for two years reliably induces atherosclerosis, with risk factor profiles, arterial lesions, and changes in vascular function also seen in humans.

Use and Importance of Nonhuman Primates in Metabolic Disease Research: Current State of the Field.

Obesity and its multiple metabolic sequelae, including type 2 diabetes, cardiovascular disease, and fatty liver disease, are becoming increasingly widespread in both the developed and developing world. There is an urgent need to identify new approaches for the prevention and treatment of these costly and prevalent metabolic conditions. Accomplishing this will require the use of appropriate animal models for preclinical and translational investigations in metabolic disease research. Although studies in rodent models are often useful for target/pathway identification and testing hypotheses, there are important differences in metabolic physiology between rodents and primates, and experimental findings in rodent models have often failed to be successfully translated into new, clinically useful therapeutic modalities in humans. Nonhuman primates represent a valuable and physiologically relevant model that serve as a critical translational bridge between basic studies performed in rodent models and clinical studies in humans. The purpose of this review is to evaluate the evidence, including a number of specific examples, in support of the use of nonhuman primate models in metabolic disease research, as well as some of the disadvantages and limitations involved in the use of nonhuman primates. The evidence taken as a whole indicates that nonhuman primates are and will remain an indispensable resource for evaluating the efficacy and safety of novel therapeutic strategies targeting clinically important metabolic diseases, including dyslipidemia and atherosclerosis, type 2 diabetes, hepatic steatosis, steatohepatitis, and hepatic fibrosis, and potentially the cognitive decline and dementia associated with metabolic dysfunction, prior to taking these therapies into clinical trials in humans.

Nonhuman Primates and Translational Research-Cardiovascular Disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Human epidemiological studies provide challenges for understanding mechanisms that regulate initiation and progression of CVD due to variation in lifestyle, diet, and other environmental factors. Studies describing metabolic and physiologic aspects of CVD, and those investigating genetic and epigenetic mechanisms influencing CVD initiation and progression, have been conducted in multiple Old World nonhuman primate (NHP) species. Major advantages of NHPs as models for understanding CVD are their genetic, metabolic, and physiologic similarities with humans, and the ability to control diet, environment, and breeding. These NHP species are also genetically and phenotypically heterogeneous, providing opportunities to study gene by environment interactions that are not feasible in inbred animal models. Each Old World NHP species included in this review brings unique strengths as models to better understand human CVD. All develop CVD without genetic manipulation providing multiple models to discover genetic variants that influence CVD risk. In addition, as each of these NHP species age, their age-related comorbidities such as dyslipidemia and diabetes are accelerated proportionally 3 to 4 times faster than in humans.In this review, we discuss current CVD-related research in NHPs focusing on selected aspects of CVD for which nonprimate model organism studies have left gaps in our understanding of human disease. We include studies on current knowledge of genetics, epigenetics, calorie restriction, maternal calorie restriction and offspring health, maternal obesity and offspring health, nonalcoholic steatohepatitis and steatosis, Chagas disease, microbiome, stem cells, and prevention of CVD.