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.

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.

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.

Novel epigenetic determinants of type 2 diabetes in Mexican-American families.

Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina HumanMethylation450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites with age, sex and phenotypic traits related to T2D in 850 pedigreed Mexican-American individuals. Robust statistical analyses showed that (i) 15% of the methylome is significantly heritable, with a median heritability of 0.14; (ii) DNA methylation at 14% of CpG sites is associated with nearby sequence variants; (iii) 22% and 3% of the autosomal CpG sites are associated with age and sex, respectively; (iv) 53 CpG sites were significantly associated with liability to T2D, fasting blood glucose and insulin resistance; (v) DNA methylation levels at five CpG sites, mapping to three well-characterized genes (TXNIP, ABCG1 and SAMD12) independently explained 7.8% of the heritability of T2D (vi) methylation at these five sites was unlikely to be influenced by neighboring DNA sequence variation. Our study has identified novel epigenetic indicators of T2D risk in Mexican Americans who have increased risk for this disease. These results provide new insights into potential treatment targets of T2D.

Engineering brown fat into skeletal muscle using ultrasound-targeted microbubble destruction gene delivery in obese Zucker rats: Proof of concept design.

Ultrasound-targeted microbubble destruction (UTMD) is a novel means of tissue-specific gene delivery. This approach systemically infuses transgenes precoupled to gas-filled lipid microbubbles that are burst within the microvasculature of target tissues via an ultrasound signal resulting in release of DNA and transfection of neighboring cells within the tissue. Previous work has shown that adenovirus containing cDNA of UCP-1, injected into the epididymal fat pads in mice, induced localized fat depletion, improving glucose tolerance, and decreasing food intake in obese diabetic mice. Our group recently demonstrated that gene therapy by UTMD achieved beta cell regeneration in streptozotocin (STZ)-treated mice and baboons. We hypothesized that gene therapy with BMP7/PRDM16/PPARGC1A in skeletal muscle (SKM) of obese Zucker diabetic fatty (fa/fa) rats using UTMD technology would produce a brown adipose tissue (BAT) phenotype with UCP-1 overexpression. This study was designed as a proof of concept (POC) project. Obese Zucker rats were administered plasmid cDNA contructs encoding a gene cocktail with BMP7/PRDM16/PPARGC1A incorporated within microbubbles and intravenously delivered into their left thigh. Controls received UTMD with plasmids driving a DsRed reporter gene. An ultrasound transducer was directed to the thigh to disrupt the microbubbles within the microcirculation. Blood samples were drawn at baseline, and after treatment to measure glucose, insulin, and free fatty acids levels. SKM was harvested for immunohistochemistry (IHC). Our IHC results showed a reliable pattern of effective UTMD-based gene delivery in enhancing SKM overexpression of the UCP-1 gene. This clearly indicates that our plasmid DNA construct encoding the gene combination of PRDM16, PPARGC1A, and BMP7 reprogrammed adult SKM tissue into brown adipose cells in vivo. Our pilot established POC showing that the administration of the gene cocktail to SKM in this rat model of genetic obesity using UTMD gene therapy, engineered a BAT phenotype with UCP-1 over-expression. © 2017 IUBMB Life, 69(9):745-755, 2017.

Genetic variation underlying renal uric acid excretion in Hispanic children: the Viva La Familia Study.

BACKGROUND: Reduced renal excretion of uric acid plays a significant role in the development of hyperuricemia and gout in adults. Hyperuricemia has been associated with chronic kidney disease and cardiovascular disease in children and adults. There are limited genome-wide association studies associating genetic polymorphisms with renal urate excretion measures. Therefore, we investigated the genetic factors that influence the excretion of uric acid and related indices in 768 Hispanic children of the Viva La Familia Study. METHODS: We performed a genome-wide association analysis for 24-h urinary excretion measures such as urinary uric acid/urinary creatinine ratio, uric acid clearance, fractional excretion of uric acid, and glomerular load of uric acid in SOLAR, while accounting for non-independence among family members. RESULTS: All renal urate excretion measures were significantly heritable (p <2 × 10-6) and ranged from 0.41 to 0.74. Empirical threshold for genome-wide significance was set at p <1 × 10-7. We observed a strong association (p < 8 × 10-8) of uric acid clearance with a single nucleotide polymorphism (SNP) in zinc finger protein 446 (ZNF446) (rs2033711 (A/G), MAF: 0.30). The minor allele (G) was associated with increased uric acid clearance. Also, we found suggestive associations of uric acid clearance with SNPs in ZNF324, ZNF584, and ZNF132 (in a 72 kb region of 19q13; p <1 × 10-6, MAFs: 0.28-0.31). CONCLUSION: For the first time, we showed the importance of 19q13 region in the regulation of renal urate excretion in Hispanic children. Our findings indicate differences in inherent genetic architecture and shared environmental risk factors between our cohort and other pediatric and adult populations.

Genetic correlation of the plasma lipidome with type 2 diabetes, prediabetes and insulin resistance in Mexican American families.

BACKGROUND: Differential plasma concentrations of circulating lipid species are associated with pathogenesis of type 2 diabetes (T2D). Whether the wide inter-individual variability in the plasma lipidome contributes to the genetic basis of T2D is unknown. Here, we investigated the potential overlap in the genetic basis of the plasma lipidome and T2D-related traits. RESULTS: We used plasma lipidomic data (1202 pedigreed individuals, 319 lipid species representing 23 lipid classes) from San Antonio Family Heart Study in Mexican Americans. Bivariate trait analyses were used to estimate the genetic and environmental correlation of all lipid species with three T2D-related traits: risk of T2D, presence of prediabetes and homeostatic model of assessment - insulin resistance. We found that 44 lipid species were significantly genetically correlated with one or more of the three T2D-related traits. Majority of these lipid species belonged to the diacylglycerol (DAG, 17 species) and triacylglycerol (TAG, 17 species) classes. Six lipid species (all belonging to the triacylglycerol class and containing palmitate at the first position) were significantly genetically correlated with all the T2D-related traits. CONCLUSIONS: Our results imply that: a) not all plasma lipid species are genetically informative for T2D pathogenesis; b) the DAG and TAG lipid classes partially share genetic basis of T2D; and c) 1-palmitate containing TAGs may provide additional insights into the genetic basis of T2D.

Effect of moderate, 30 percent global maternal nutrient reduction on fetal and postnatal baboon phenotype.

BACKGROUND: Most developmental programming studies on maternal nutrient reduction (MNR) are in altricial rodents whose maternal nutritional burden and offspring developmental trajectory differ from precocial non-human primates and humans. METHODS: Control (CTR) baboon mothers ate ad libitum; MNR mothers ate 70% global control diet in pregnancy and lactation. RESULTS: We present offspring morphometry, blood cortisol, and adrenocorticotropin (ACTH) during second half of gestation (G) and first three postnatal years. Moderate MNR produced intrauterine growth restriction (IUGR). IUGR males (n=43) and females (n=28) were smaller than CTR males (n=50) and females (n=47) in many measurements at many ages. In CTR, fetal ACTH increased 228% and cortisol 48% between 0.65G and 0.9G. IUGR ACTH was elevated at 0.65G and cortisol at 0.9G. 0.9G maternal gestational weight gain, fetal weight, and placenta weight were correlated. CONCLUSIONS: Moderate IUGR decreased body weight and morphometric measurements at key time points and altered hypothalamo-pituitary-adrenal function.

GWAS and transcriptional analysis prioritize ITPR1 and CNTN4 for a serum uric acid 3p26 QTL in Mexican Americans.

BACKGROUND: The variation in serum uric acid concentrations is under significant genetic influence. Elevated SUA concentrations have been linked to increased risk for gout, kidney stones, chronic kidney disease, and cardiovascular disease whereas reduced serum uric acid concentrations have been linked to multiple sclerosis, Parkinson's disease and Alzheimer's disease. Previously, we identified a novel locus on chromosome 3p26 affecting serum uric acid concentrations in Mexican Americans from San Antonio Family Heart Study. As a follow up, we examined genome-wide single nucleotide polymorphism data in an extended cohort of 1281 Mexican Americans from multigenerational families of the San Antonio Family Heart Study and the San Antonio Family Diabetes/Gallbladder Study. We used a linear regression-based joint linkage/association test under an additive model of allelic effect, while accounting for non-independence among family members via a kinship variance component. RESULTS: Univariate genetic analysis indicated serum uric acid concentrations to be significant heritable (h (2) = 0.50 ± 0.05, p < 4 × 10(-35)), and linkage analysis of serum uric acid concentrations confirmed our previous finding of a novel locus on 3p26 (LOD = 4.9, p < 1 × 10(-5)) in the extended sample. Additionally, we observed strong association of serum uric acid concentrations with variants in following candidate genes in the 3p26 region; inositol 1,4,5-trisphosphate receptor, type 1 (ITPR1), contactin 4 (CNTN4), decapping mRNA 1A (DCP1A); transglutaminase 4 (TGM4) and rho guanine nucleotide exchange factor (GEF) 26 (ARHGEF26) [p < 3 × 10(-7); minor allele frequencies ranged between 0.003 and 0.42] and evidence of cis-regulation for ITPR1 transcripts. CONCLUSION: Our results confirm the importance of the chromosome 3p26 locus and genetic variants in this region in the regulation of serum uric acid concentrations.

Central GIP signaling stimulates peripheral GIP release and promotes insulin and pancreatic polypeptide secretion in nonhuman primates.

Glucose-dependent insulinotropic polypeptide (GIP) has important actions on whole body metabolic function. GIP and its receptor are also present in the central nervous system and have been linked to neurotrophic actions. Metabolic effects of central nervous system GIP signaling have not been reported. We investigated whether centrally administered GIP could increase peripheral plasma GIP concentrations and influence the metabolic response to a mixed macronutrient meal in nonhuman primates. An infusion and sampling system was developed to enable continuous intracerebroventricular (ICV) infusions with serial venous sampling in conscious nonhuman primates. Male baboons (Papio sp.) that were healthy and had normal body weights (28.9 ± 2.1 kg) were studied (n = 3). Animals were randomized to receive continuous ICV infusions of GIP (20 pmol·kg-1·h-1) or vehicle before and over the course of a 300-min mixed meal test (15 kcal/kg, 1.5g glucose/kg) on two occasions. A significant increase in plasma GIP concentration was observed under ICV GIP infusion (66.5 ± 8.0 vs. 680.6 ± 412.8 pg/ml, P = 0.04) before administration of the mixed meal. Increases in postprandial, but not fasted, insulin (P = 0.01) and pancreatic polypeptide (P = 0.04) were also observed under ICV GIP. Effects of ICV GIP on fasted or postprandial glucagon, glucose, triglyceride, and free fatty acids were not observed. Our data demonstrate that central GIP signaling can promote increased plasma GIP concentrations independent of nutrient stimulation and increase insulin and pancreatic polypeptide responses to a mixed meal.

Chronic continuous exenatide infusion does not cause pancreatic inflammation and ductal hyperplasia in non-human primates.

In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67-positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67-positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67-positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30-positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a ß-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates.

Vitamin D heritability and effect of pregnancy status in Vervet monkeys (Chlorocebus aethiops sabaeus) under conditions of modest and high dietary supplementation.

OBJECTIVES: The two objectives of the current study were to: 1) investigate the genetic contributions to variations in serum vitamin D concentrations under two dietary conditions (a standard monkey biscuit diet vs. a diet designed to model typical American consumption); and 2) explore the interaction of vitamin D with pregnancy status using a cohort of pedigreed female vervet/African green monkeys. METHODS: This study includes 185 female (≥3.5 years) vervet/African green monkeys (Chlorocebus aethiops sabaeus) from a multi-generational, pedigreed breeding colony. The 25(OH)D3 concentrations were first measured seven to eight weeks after consuming a "typical American" diet (TAD), deriving 37, 18, and 45% of calories from fat, protein sources, and carbohydrates, and supplemented with vitamin D to a human equivalent of 1,000 IU/day. Vitamin D concentrations were assessed again when animals were switched to a low-fat, standard biscuit diet (LabDiet 5038) for 8 months, which provided a human equivalent of approximately 4,000 IU/day of vitamin D. All statistical analyses were implemented in SOLAR. RESULTS: Pregnancy was associated with reduced 25(OH)D3 concentrations. Heritability analyses indicated a significant genetic contribution to 25(OH)D3 concentrations in the same monkeys consuming the biscuit diet (h(2) =0.66, P=0.0004) and TAD (h(2) =0.67, P=0.0078) diets, with higher 25(OH)D3 concentrations in animals consuming the biscuit diet. Additionally, there was a significant genotype-by-pregnancy status interaction on 25(OH)D3 concentrations (P<0.05) only among animals consuming the TAD diet. DISCUSSION: These results support the existence of a genetic contribution to differences in serum 25(OH)D3 concentrations by pregnancy status and emphasize the role of diet (including vitamin D supplementation) in modifying genetic signals as well as vitamin D concentrations.

Assessment of cardiovascular disease risk factors in a genetically homogenous population of Parsi Zoroastrians in the United States: A pilot study.

OBJECTIVE: Genetically isolated and homogenous populations are ideal for detecting genes underlying common complex diseases. The use of isolated populations with reduced disease heterogeneity has led to significant gene discoveries in the past. The aim of this pilot study was to assess the prevalence of cardiovascular disease (CVD) risk phenotypes in a genetically homogenous population of Parsi Zoroastrians in the United States. METHODS: Anthropometrics, blood pressure, and medical history were collected from 152 men and 186 women participating in a pilot study as part of the Parsi Family Study. The relative pairs used in the study included 60 parent-off springs, 28 siblings, 6 grandparent-grandchild, 7 avuncular, 18 half-siblings, 7 half-avuncular, and one half-first cousin. Estimates of genetic and environmental influence were calculated using a maximum likelihood-based variance components method implemented in SOLAR. RESULTS: The prevalence of overweight/obesity in adults (62%) was on par with current US prevalence. Hypertension and prehypertension were prevalent in 16% and 46% of the participants, respectively. The quantitative genetic analysis revealed significant heritabilities for all anthropometric phenotypes (P < 0.05). Significant phenotypic correlations were found between blood pressure and anthropometric phenotypes (P < 0.001), whereas significant genetic correlation was found for only diastolic blood pressure and fat free mass (rhoG = -0.88, P < 0.05). CONCLUSION: These preliminary data show significant additive genetic effects on CVD-related phenotypes in this population. Our findings represent the first epidemiological data in Parsi Zoroastrians in the United States and offer excellent promise for future genetic studies in this population. Am. J. Hum. Biol. 28:440-443, 2016. © 2016 Wiley Periodicals, Inc.

Lipidomic risk score independently and cost-effectively predicts risk of future type 2 diabetes: results from diverse cohorts.

BACKGROUND: Detection of type 2 diabetes (T2D) is routinely based on the presence of dysglycemia. Although disturbed lipid metabolism is a hallmark of T2D, the potential of plasma lipidomics as a biomarker of future T2D is unknown. Our objective was to develop and validate a plasma lipidomic risk score (LRS) as a biomarker of future type 2 diabetes and to evaluate its cost-effectiveness for T2D screening. METHODS: Plasma LRS, based on significantly associated lipid species from an array of 319 lipid species, was developed in a cohort of initially T2D-free individuals from the San Antonio Family Heart Study (SAFHS). The LRS derived from SAFHS as well as its recalibrated version were validated in an independent cohort from Australia--the AusDiab cohort. The participants were T2D-free at baseline and followed for 9197 person-years in the SAFHS cohort (n = 771) and 5930 person-years in the AusDiab cohort (n = 644). Statistically and clinically improved T2D prediction was evaluated with established statistical parameters in both cohorts. Modeling studies were conducted to determine whether the use of LRS would be cost-effective for T2D screening. The main outcome measures included accuracy and incremental value of the LRS over routinely used clinical predictors of T2D risk; validation of these results in an independent cohort and cost-effectiveness of including LRS in screening/intervention programs for T2D. RESULTS: The LRS was based on plasma concentration of dihydroceramide 18:0, lysoalkylphosphatidylcholine 22:1 and triacyglycerol 16:0/18:0/18:1. The score predicted future T2D independently of prediabetes with an accuracy of 76%. Even in the subset of initially euglycemic individuals, the LRS improved T2D prediction. In the AusDiab cohort, the LRS continued to predict T2D significantly and independently. When combined with risk-stratification methods currently used in clinical practice, the LRS significantly improved the model fit (p < 0.001), information content (p < 0.001), discrimination (p < 0.001) and reclassification (p < 0.001) in both cohorts. Modeling studies demonstrated that LRS-based risk-stratification combined with metformin supplementation for high-risk individuals was the most cost-effective strategy for T2D prevention. CONCLUSIONS: Considering the novelty, incremental value and cost-effectiveness of LRS it should be used for risk-stratification of future T2D.

Evaluation of neurotrophic tyrosine receptor kinase 2 (NTRK2) as a positional candidate gene for variation in estimated glomerular filtration rate (eGFR) in Mexican American participants of San Antonio Family Heart study.

BACKGROUND: The estimated glomerular filtration rate (eGFR) is a well-known measure of kidney function and is commonly used for the diagnosis and management of patients with chronic kidney disease. The inter-individual variation in eGFR has significant genetic component. However, the identification of underlying genetic susceptibility variants has been challenging. In an attempt to identify and characterize susceptibility genetic variant(s) we previously identified the strongest evidence for linkage of eGFR occurring on chromosome 9q21 in the Mexican American participants of San Antonio Family Heart Study (SAFHS). The objective of the present study was to examine whether the common genetic variants in Neurotrophic Tyrosine Receptor Kinase 2 (NTRK2), a positional candidate gene on 9q21, contribute to variation in eGFR. RESULTS: Twelve tagging single nucleotide polymorphisms (SNPs) across the NTRK2 gene region were selected (r2 ≥ 0.80, minor allele frequency of ≥ 0.05) from the Hapmap database. SNPs were genotyped by TaqMan assay in the 848 Mexican American subjects participated in the SAFHS. Association analysis between the genotypes and eGFR (estimated by the Modification of Diet in Renal Disease equation) were performed by measured genotype approach as implemented in the program SOLAR. Of the 12 common genetic variants examined, the rs1036915 (located in 3'UTR) and rs1187274 (located in intron-14), present in perfect linkage disequilibrium, exhibited an association (P = 0.017) with eGFR after accounting for the effects of age, sex, diabetes, diabetes duration, systolic blood pressure and blood pressure medication. The carriers of minor allele of rs1036915 (G; 38%) had increased eGFR (104 ± 25 ml/min/1.73 m(2)) in comparison to the carriers of major allele A (98 ± 25 ml/min/1.73 m(2)). CONCLUSION: Together, our results suggest for the first time that the genetic variants in NTRK2 may regulate eGFR.

Genetic influences on response to novel objects and dimensions of personality in Papio baboons.

Behavioral variation within and between populations and species of the genus Papio has been studied extensively, but little is known about the genetic causes of individual- or population-level differences. This study investigates the influence of genetic variation on personality (sometimes referred to as temperament) in baboons and identifies a candidate gene partially responsible for the variation in that phenotype. To accomplish these goals, we examined individual variation in response to both novel objects and an apparent novel social partner (using a mirror test) among pedigreed baboons (n = 578) from the Southwest National Primate Research Center. We investigated the frequency and duration of individual behaviors in response to novel objects and used multivariate factor analysis to identify trait-like dimensions of personality. Exploratory factor analysis identified two distinct dimensions of personality within this population. Factor 1 accounts for 46.8 % of the variance within the behavioral matrix, and consists primarily of behaviors related to the "boldness" of the subject. Factor 2 accounts for 18.8 % of the variation, and contains several "anxiety" like behaviors. Several specific behaviors, and the two personality factors, were significantly heritable, with the factors showing higher heritability than most individual behaviors. Subsequent analyses show that the behavioral reactions observed in the test protocol are associated with animals' social behavior observed later in their home social groups. Finally we used linkage analysis to map quantitative trait loci for the measured phenotypes. Single nucleotide polymorphisms in a positional candidate gene (SNAP25) are associated with variation in one of the personality factors, and CSF levels of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol. This study documents heritable variation in personality among baboons and suggests that sequence variation in SNAP25 may influence differences in behavior and neurochemistry in these nonhuman primates.

Successful pharmaceutical-grade streptozotocin (STZ)-induced hyperglycemia in a conscious tethered baboon (Papio hamadryas) model.

BACKGROUND: Non-human primate (NHP) diabetic models using chemical ablation of ß-cells with STZ have been achieved by several research groups. Chemotherapeutic STZ could lead to serious adverse events including nephrotoxicity, hepatotoxicity, and mortality. METHODS: We implemented a comprehensive therapeutic strategy that included the tether system, permanent indwelling catheter implants, an aggressive hydration protocol, management for pain with IV nubain and anxiety with IV midazolam, moment-by-moment monitoring of glucose levels post-STZ administration, and continuous intravenous insulin therapy. RESULTS: A triphasic response in blood glucose after STZ administration was fully characterized. A dangerous hypoglycemic phase was also detected in all baboons. Other significant findings were hyperglycemia associated with low levels of plasma leptin, insulin and C-peptide concentrations, hyperglucagonemia, and elevated non-esterified fatty acids (NEFA) concentrations. CONCLUSIONS: We successfully induced frank diabetes by IV administering a single dose of pharmaceutical-grade STZ safely and without adverse events in conscious tethered baboons.

Molecular evolution and expression profile of the chemerine encoding gene RARRES2 in baboon and chimpanzee.

BACKGROUND: Chemerin, encoded by the retinoic acid receptor responder 2 (RARRES2) gene is an adipocytesecreted protein with autocrine/paracrine functions in adipose tissue, metabolism and inflammation with a recently described function in vascular tone regulation, liver, steatosis, etc. This molecule is believed to represent a critical endocrine signal linking obesity to diabetes. There are no data available regarding evolution of RARRES2 in non-human primates and great apes. Expression profile and orthology in RARRES2 genes are unknown aspects in the biology of this multigene family in primates. Thus; we attempt to describe expression profile and phylogenetic relationship as complementary knowledge in the function of this gene in primates. To do that, we performed A RT-PCR from different tissues obtained during necropsies. Also we tested the hypotheses of positive evolution, purifying selection, and neutrality. And finally a phylogenetic analysis was made between primates RARRES2 protein. RESULTS: RARRES2 transcripts were present in liver, lung, adipose tissue, ovary, pancreas, heart, hypothalamus and pituitary tissues. Expression in kidney and leukocytes were not detectable in either species. It was determined that the studied genes are orthologous. CONCLUSIONS: RARRES2 evolution fits the hypothesis of purifying selection. Expression profiles of the RARRES2 gene are similar in baboons and chimpanzees and are also phylogenetically related.

Plasma lipidome is independently associated with variability in metabolic syndrome in Mexican American families.

Plasma lipidome is now increasingly recognized as a potentially important marker of chronic diseases, but the exact extent of its contribution to the interindividual phenotypic variability in family studies is unknown. Here, we used the rich data from the ongoing San Antonio Family Heart Study (SAFHS) and developed a novel statistical approach to quantify the independent and additive value of the plasma lipidome in explaining metabolic syndrome (MS) variability in Mexican American families recruited in the SAFHS. Our analytical approach included two preprocessing steps: principal components analysis of the high-resolution plasma lipidomics data and construction of a subject-subject lipidomic similarity matrix. We then used the Sequential Oligogenic Linkage Analysis Routines software to model the complex family relationships, lipidomic similarities, and other important covariates in a variance components framework. Our results suggested that even after accounting for the shared genetic influences, indicators of lipemic status (total serum cholesterol, TGs, and HDL cholesterol), and obesity, the plasma lipidome independently explained 22% of variability in the homeostatic model of assessment-insulin resistance trait and 16% to 22% variability in glucose, insulin, and waist circumference. Our results demonstrate that plasma lipidomic studies can additively contribute to an understanding of the interindividual variability in MS.