Novel Insights into the Effects of Genetic Variants on Serum Urate Response to an Acute Fructose Challenge: A Pilot Study

Studies have shown that genetic variations can influence metabolic response to nutrient intake, and that diets rich in fructose contribute to hyperuricemia. In this pilot study, our aim was to determine the variability of serum urate in response to an acute fructose challenge and to investigate if genetic variants would affect this response in young to middle-aged adults who self-reported as Black or White. Fifty-seven participants consumed a fructose-rich beverage after an overnight fast. Blood was drawn at five time points (baseline, 30, 60, 120, and 180 min after consumption). Thirty urate-related single nucleotide polymorphisms (SNPs) were analyzed for their associations with baseline serum urate and its percent changes, using a two-step modeling approach followed by meta-analysis. At baseline, serum urate (mg/dL, mean ± SD) was higher in Whites (5.60 ± 1.01 vs. 5.37 ± 0.96), men (6.17 ± 1.14 vs. 5.24 ± 0.79), and those with obesity (5.69 ± 1.08 vs. 5.42 ± 1.06 vs. 5.34 ± 0.80). Three SNPs were significantly associated with baseline serum urate or its percent changes, and six SNPs were nominally associated with percent changes in serum urate. In summary, our results showed that genetic variants could play a role in short-term urate metabolism

Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study

Background: Genetic research may inform underlying mechanisms for disparities in the burden of type 2 diabetes mellitus among American Indians. Our objective was to assess the association of genetic variants in cardiometabolic candidate genes with B cell dysfunction via HOMA-B, insulin resistance via HOMA-IR, and type 2 diabetes mellitus in the Strong Heart Family Study (SHFS). Methods and Results: We examined the association of variants, previously associated with cardiometabolic traits (∼200,000 from Illumina Cardio MetaboChip), using mixed models of HOMA-B residuals corrected for HOMA-IR (cHOMA-B), log transformed HOMA-IR, and incident diabetes, adjusted for age, sex, population stratification, and familial relatedness. Center-specific estimates were combined using fixed effect meta-analyses. We used Bonferroni correction to account for multiple testing (P \u3c 4.13 × 10−7). We also assessed the association between variants in candidate diabetes genes with these metabolic traits. We explored the top SNPs in an independent, replication sample from Southwestern Arizona. We identified significant associations with cHOMA-B for common variants at 26 loci of which 8 were novel (PRSS7, FCRL5, PEL1, LRP12, IGLL1, ARHGEF10, PARVA, FLJ16686). The most significant variant association with cHOMA-B was observed on chromosome 5 for an intergenic variant near PARP8 (rs2961831, P = 6.39 × 10−9). In the replication study, we found a signal at rs4607517 near GCK/YKT6 (P = 0.01). Variants near candidate diabetes genes (especially GCK and KCNQ1) were also nominally associated with HOMA-IR and cHOMA-B. Conclusion: We identified variants at novel loci and confirmed those at known candidate diabetes loci associations for cHOMA-B. This study also provided evidence for association of variants at KCNQ2, CTNAA2, and KCNQ1with cHOMA-B among American Indians. Further studies are needed to account for the high heritability of diabetes among the American Indian participants of the SHFS cohort

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

Background The purpose of this study was to determine if dietary manipulation can reliably induce early-stage atherosclerosis and clinically relevant changes in vascular function in an established, well-characterized nonhuman 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 to 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

Successful β cells islet regeneration in streptozotocin-induced diabetic baboons using ultrasound-targeted microbubble gene therapy with cyclinD2/CDK4/GLP1

Both major forms of diabetes mellitus (DM) involve β-cell destruction and dysfunction. New treatment strategies have focused on replenishing the deficiency of β-cell mass common to both major forms of diabetes by islet transplantation or β-cell regeneration. The pancreas, not the liver, is the ideal organ for islet regeneration, because it is the natural milieu for islets. Since islet mass is known to increase during obesity and pregnancy, the concept of stimulating pancreatic islet regeneration in vivo is both rational and physiologic. This paper proposes a novel approach in which non-viral gene therapy is targeted to pancreatic islets using ultrasound targeted microbubble destruction (UTMD) in a non-human primate model (NHP), the baboon. Treated baboons received a gene cocktail comprised of cyclinD2, CDK, and GLP1, which in rats results in robust and durable islet regeneration with normalization of blood glucose, insulin, and C-peptide levels. We were able to generate important preliminary data indicating that gene therapy by UTMD can achieve in vivo normalization of the intravenous (IV) glucose tolerance test (IVGTT) curves in STZ hyperglycemic-induced conscious tethered baboons. Immunohistochemistry clearly demonstrated evidence of islet regeneration and restoration of β-cell mass

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 b-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

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 (h2 = 0.50 ± 0.05, p 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

Linkage Analysis of Urine Arsenic Species Patterns in the Strong Heart Family Study

Arsenic toxicokinetics are important for disease risks in exposed populations, but genetic determinants are not fully understood. We examined urine arsenic species patterns measured by HPLC-ICPMS among 2189 Strong Heart Study participants 18 years of age and older with data on ∼400 genome-wide microsatellite markers spaced ∼10 cM and arsenic speciation (683 participants from Arizona, 684 from Oklahoma, and 822 from North and South Dakota). We logit-transformed % arsenic species (% inorganic arsenic, %MMA, and %DMA) and also conducted principal component analyses of the logit % arsenic species. We used inverse-normalized residuals from multivariable-adjusted polygenic heritability analysis for multipoint variance components linkage analysis. We also examined the contribution of polymorphisms in the arsenic metabolism gene AS3MT via conditional linkage analysis. We localized a quantitative trait locus (QTL) on chromosome 10 (LOD 4.12 for %MMA, 4.65 for %DMA, and 4.84 for the first principal component of logit % arsenic species). This peak was partially but not fully explained by measured AS3MT variants. We also localized a QTL for the second principal component of logit % arsenic species on chromosome 5 (LOD 4.21) that was not evident from considering % arsenic species individually. Some other loci were suggestive or significant for 1 geographical area but not overall across all areas, indicating possible locus heterogeneity. This genome-wide linkage scan suggests genetic determinants of arsenic toxicokinetics to be identified by future fine-mapping, and illustrates the utility of principal component analysis as a novel approach that considers % arsenic species jointly

Replication of obesity and diabetes-related SNP associations in individuals from Yucatán, México

The prevalence of type 2 diabetes (T2D) is rising rapidly and in Mexicans is ∼19%. T2D is affected by both environmental and genetic factors. Although specific genes have been implicated in T2D risk few of these findings are confirmed in studies of Mexican subjects. Our aim was to replicate associations of 39 single nucleotide polymorphisms (SNPs) from 10 genes with T2D-related phenotypes in a community-based Mexican cohort. Unrelated individuals (n = 259) living in southeastern Mexico were enrolled in the study based at the University of Yucatan School of Medicine in Merida. Phenotypes measured included anthropometric measurements, circulating levels of adipose tissue endocrine factors (leptin, adiponectin, pro-inflammatory cytokines), and insulin, glucose, and blood pressure. Association analyses were conducted by measured genotype analysis implemented in SOLAR, adapted for unrelated individuals. SNP Minor allele frequencies ranged from 2.2 to 48.6%. Nominal associations were found for CNR1, SLC30A8, GCK, and PCSK1 SNPs with systolic blood pressure, insulin and glucose, and for CNR1, SLC30A8, KCNJ11, and PCSK1 SNPs with adiponectin and leptin (p < 0.05). P-values greater than 0.0014 were considered significant. Association of SNPs rs10485170 of CNR1 and rs5215 of KCNJ11 with adiponectin and leptin, respectively, reached near significance (p = 0.002). Significant association (p = 0.001) was observed between plasma leptin and rs5219 of KCNJ11

Genetic variants associated with fasting glucose and insulin concentrations in an ethnically diverse population: results from the Population Architecture using Genomics and Epidemiology (PAGE) study

Background: Multiple genome-wide association studies (GWAS) within European populations have implicated common genetic variants associated with insulin and glucose concentrations. In contrast, few studies have been conducted within minority groups, which carry the highest burden of impaired glucose homeostasis and type 2 diabetes in the U.S. Methods: As part of the 'Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we investigated the association of up to 10 GWAS-identified single nucleotide polymorphisms (SNPs) in 8 genetic regions with glucose or insulin concentrations in up to 36,579 non-diabetic subjects including 23,323 European Americans (EA) and 7,526 African Americans (AA), 3,140 Hispanics, 1,779 American Indians (AI), and 811 Asians. We estimated the association between each SNP and fasting glucose or log-transformed fasting insulin, followed by meta-analysis to combine results across PAGE sites. Results: Overall, our results show that 9/9 GWAS SNPs are associated with glucose in EA (p = 0.04 to 9 × 10-15), versus 3/9 in AA (p= 0.03 to 6 × 10-5), 3/4 SNPs in Hispanics, 2/4 SNPs in AI, and 1/2 SNPs in Asians. For insulin we observed a significant association with rs780094/GCKR in EA, Hispanics and AI only. Conclusions: Generalization of results across multiple racial/ethnic groups helps confirm the relevance of some of these loci for glucose and insulin metabolism. Lack of association in non-EA groups may be due to insufficient power, or to unique patterns of linkage disequilibrium

Obesity-associated phenotypes and circulating levels of ghrelin, cholecystokinin, low-density lipoprotein and zinc: genetic and observational studies

textObesity is a complex problem that is believed to result from both genetic and environmental factors. This condition greatly increases the risk of developing serious health consequences, such as metabolic syndrome and cardiovascular disease. The primary goal of this research was to study the genetic influence on plasma ghrelin, cholecystokinin (CCK), and low-density lipoprotein (LDL), and their relationship with obesity. A secondary goal was to investigate the effect of weight loss on plasma zinc and other risk factors for metabolic syndrome. Aims 1 and 2 were to estimate the additive heritabilities and to localize the responsible chromosomal quantitative trait loci associated with circulating levels of the appetite regulating hormones, ghrelin and CCK, in baboons. Plasma ghrelin and CCK were higher in baboons than humans, with males exhibiting greater levels. Ghrelin was inversely linked to body weight (r = 0.23, p < 0.001), insulin (r = - 0.19, p < 0.05), and leptin (r = - 0.14, p < 0.05). Significant heritabilities were observed for ghrelin and CCK. A strong signal was detected for plasma CCK on chromosome 17p12 (LOD = 3.1, p < 0.01). Aim 3 was to detect heritability and pleiotropy between the obesity-related anthropometric phenotypes and low- density lipoproteins (LDL) in humans. Effect of genes on LDL size was evident, with substantial heritability and strong genetic correlations between LDL and obesity-related traits; small LDL and weight (rhoG = 0.65, p < 0.001), waist (rhoG = 0.80, p < 0.001), and BMI (rhoG = 0.67, p < 0.001), respectively. Aim 4 was to study the impact of weight loss on plasma zinc and risk factors for metabolic syndrome in humans. Weight reduction significantly increased the low plasma zinc observed in obese women, and improved risk factors for metabolic syndrome (HDL, BMI, waist and body fat). A negative correlation was observed between changes in zinc and body fat (r = -0.28, p < 0.05). Collectively, these results demonstrate significant influence of genetic factors on plasma ghrelin, CCK, LDL and obesity phenotypes. In addition, weight loss produced beneficial effects of weight loss on plasma zinc and risk factors for metabolic syndrome.Human Ecolog