V. Saroja Voruganti

Novel Genetic Loci Identified for the Pathophysiology of Childhood Obesity in the Hispanic Population

Genetic variants responsible for susceptibility to obesity and its comorbidities among Hispanic children have not been identified. The VIVA LA FAMILIA Study was designed to genetically map childhood obesity and associated biological processes in the Hispanic population. A genome-wide association study (GWAS) entailed genotyping 1.1 million single nucleotide polymorphisms (SNPs) using the Illumina Infinium technology in 815 children. Measured genotype analysis was performed between genetic markers and obesity-related traits i.e., anthropometry, body composition, growth, metabolites, hormones, inflammation, diet, energy expenditure, substrate utilization and physical activity. Identified genome-wide significant loci: 1) corroborated genes implicated in other studies (MTNR1B, ZNF259/APOA5, XPA/FOXE1 (TTF-2), DARC, CCR3, ABO); 2) localized novel genes in plausible biological pathways (PCSK2, ARHGAP11A, CHRNA3); and 3) revealed novel genes with unknown function in obesity pathogenesis (MATK, COL4A1). Salient findings include a nonsynonymous SNP (rs1056513) in INADL (p = 1.2E-07) for weight; an intronic variant in MTNR1B associated with fasting glucose (p = 3.7E-08); variants in the APOA5-ZNF259 region associated with triglycerides (p = 2.5-4.8E-08); an intronic variant in PCSK2 associated with total antioxidants (p = 7.6E-08); a block of 23 SNPs in XPA/FOXE1 (TTF-2) associated with serum TSH (p = 5.5E-08 to 1.0E-09); a nonsynonymous SNP (p = 1.3E-21), an intronic SNP (p = 3.6E-13) in DARC identified for MCP-1; an intronic variant in ARHGAP11A associated with sleep duration (p = 5.0E-08); and, after adjusting for body weight, variants in MATK for total energy expenditure (p = 2.7E-08) and in CHRNA3 for sleeping energy expenditure (p = 6.0E-08). Unprecedented phenotyping and high-density SNP genotyping enabled localization of novel genetic loci associated with the pathophysiology of childhood obesity.

Physiological and Molecular Determinants of Insulin Action in the Baboon

OBJECTIVE—To quantitate insulin sensitivity in lean and obese nondiabetic baboons and examine the underlying cellular/molecular mechanisms responsible for impaired insulin action to characterize a baboon model of insulin resistance. RESEARCH DESIGN AND METHODS—Twenty baboons received a hyperinsulinemic-euglycemic clamp with skeletal muscle and visceral adipose tissue biopsies at baseline and at 30 and 120 min after insulin. Genes and protein expression of key molecules involved in the insulin signaling cascade (insulin receptor, insulin receptor substrate-1, p85, phosphatidylinositol 3-kinase, Akt, and AS160) were sequenced, and insulin-mediated changes were analyzed. RESULTS—Overall, baboons show a wide range of insulin sensitivity (6.2 ± 4.8 mg · kg−1 · min−1), and there is a strong inverse correlation between indexes of adiposity and insulin sensitivity (r = −0.946, P < 0.001 for % body fat; r = −0.72, P < 0.001 for waist circumference). The genes and protein sequences analyzed were found to have ∼98% identity to those of man. Insulin-mediated changes in key signaling molecules were impaired both in muscle and adipose tissue in obese insulin-resistant compared with lean insulin-sensitive baboons. CONCLUSIONS—The obese baboon is a pertinent nonhuman primate model to examine the underlying cellular/molecular mechanisms responsible for insulin resistance and eventual development of type 2 diabetes.

Low-Income, Overweight and Obese Mothers as Agents of Change to Improve Food Choices, Fat Habits, and Physical Activity in their 1-to-3-Year-Old Children

Objective: To examine the effects of a weight loss program for mothers on the diet and activity of mothers and their 1–3 year old children. Design: Overweight and obese mothers participated in an 8-week weight loss intervention encompassing diet, physical activity, and behavioral modification. Anthropometrics, demographic, dietary, and physical activity questionnaires were administered at weeks 0 and 8; anthropometrics were re-evaluated at week 24. Subjects: Mothers (N=91) of a 1–3 year old child; body mass index (BMI) ≥ 25 kg/m2; non-breastfeeding; age 18–45 years; income < 200% of federal poverty index; Hispanic, African American, or white; and English-speaking were recruited from Special Supplemental Program for Women Infants and Children (WIC) and public health clinics. Intervention Measures of Outcome: Weight loss in mothers and improvements in diet (reduction in calories, fat, snacks/desserts, sweetened beverages, and increases in fruit, vegetables) and activity in mothers and children. Results: Weight loss in mothers was modest (−2.7 kg, p < 0.001) and sustained at week 24 (−2.8 kg, p < 0.001), and children gained in height and weight as expected for normal growth (p < 0.001). Initial energy intakes of children exceeded Estimated Energy Requirements (123%) and were reduced to acceptable levels post-intervention (102%, p < 0.001); additional beneficial changes in childrens diets were decreased total (47.7 to 39.9 g/day) and saturated fat (19.2 to 16.6 g/day), high-fat snacks/desserts (1.6 to 0.9 servings/day), added fats (81.8 to 40.9% using), sweetened beverages (0.8 to 0.4 servings/day), and fast food consumption (11.6 to 6.6% of meals), and increased home-prepared meals (63.2 to 71.6% of meals) (p < 0.01 for all). Physical activity scores improved by 7% in children (p < 0.05). Comparable changes in food choices and activity also were seen in mothers. Conclusion: Offering weight loss classes was a successful method of enticing low-income women to participate in an educational intervention that benefited their children. Overweight and obese mothers who modified their food choices and fat habits made comparable changes for their child.

Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children

BACKGROUND Melanocortin-4-receptor (MC4R) haploinsufficiency is the most common form of monogenic obesity; however, the frequency of MC4R variants and their functional effects in general populations remain uncertain. OBJECTIVE The aim was to identify and characterize the effects of MC4R variants in Hispanic children. DESIGN MC4R was resequenced in 376 parents, and the identified single nucleotide polymorphisms (SNPs) were genotyped in 613 parents and 1016 children from the Viva la Familia cohort. Measured genotype analysis (MGA) tested associations between SNPs and phenotypes. Bayesian quantitative trait nucleotide (BQTN) analysis was used to infer the most likely functional polymorphisms influencing obesity-related traits. RESULTS Seven rare SNPs in coding and 18 SNPs in flanking regions of MC4R were identified. MGA showed suggestive associations between MC4R variants and body size, adiposity, glucose, insulin, leptin, ghrelin, energy expenditure, physical activity, and food intake. BQTN analysis identified SNP 1704 in a predicted micro-RNA target sequence in the downstream flanking region of MC4R as a strong, probable functional variant influencing total, sedentary, and moderate activities with posterior probabilities of 1.0. SNP 2132 was identified as a variant with a high probability (1.0) of exerting a functional effect on total energy expenditure and sleeping metabolic rate. SNP rs34114122 was selected as having likely functional effects on the appetite hormone ghrelin, with a posterior probability of 0.81. CONCLUSION This comprehensive investigation provides strong evidence that MC4R genetic variants are likely to play a functional role in the regulation of weight, not only through energy intake but through energy expenditure.

Genome Scan for Determinants of Serum Uric Acid Variability

Elevated serum uric acid level is associated with obesity, insulin resistance, diabetes, nephropathy, and hypertension. Epidemiologic studies suggest that serum uric acid levels are heritable. We sought to identify chromosomal regions harboring quantitative trait loci that influence serum uric acid in Mexican Americans using data from 644 participants in the San Antonio Family Heart Study. Serum uric acid was found to exhibit significant heritability (0.42) in this population (P = 2 x 10(-7)) after accounting for covariate effects. In addition, genetic correlations between serum uric acid and other cardiovascular risk factors, such as body mass index, waist circumference, systolic BP, and pulse pressure, were identified, suggesting that the genes associated with uric acid level are also associated with these phenotypes. Multipoint linkage analysis identified quantitative trait loci with measurable effects on serum uric acid variability. The highest multipoint logarithm of odds score of 3.3 was found at 133 cM on chromosome 6q22-23, a region that also contains genes that seem to influence familial IgA nephropathy, obesity, BP, insulin resistance, and type 2 diabetes. Given the relationship between uric acid level and these conditions, future studies should investigate potential candidate susceptibility genes found in this region.

Consistent Directions of Effect for Established Type 2 Diabetes Risk Variants Across Populations: The Population Architecture using Genomics and Epidemiology (PAGE) Consortium

Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69% in American Indians to 100% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (Pheterogeneity < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.

Global metabolomic profiling targeting childhood obesity in the Hispanic population

BACKGROUND Metabolomics may unravel important biological pathways involved in the pathophysiology of childhood obesity. OBJECTIVES We aimed to 1) identify metabolites that differ significantly between nonobese and obese Hispanic children; 2) collapse metabolites into principal components (PCs) associated with obesity and metabolic risk, specifically hyperinsulinemia, hypertriglyceridemia, hyperleptinemia, and hyperuricemia; and 3) identify metabolites associated with energy expenditure and fat oxidation. DESIGN This trial was a cross-sectional observational study of metabolomics by using gas chromatography-mass spectrometry and ultrahigh-performance liquid chromatography-tandem mass spectrometry analyses performed on fasting plasma samples from 353 nonobese and 450 obese Hispanic children. RESULTS Branched-chained amino acids (BCAAs) (Leu, Ile, and Val) and their catabolites, propionylcarnitine and butyrylcarnitine, were significantly elevated in obese children. Strikingly lower lysolipids and dicarboxylated fatty acids were seen in obese children. Steroid derivatives were markedly higher in obese children as were markers of inflammation and oxidative stress. PC6 (BCAAs and aromatic AAs) and PC10 (asparagine, glycine, and serine) made the largest contributions to body mass index, and PC10 and PC12 (acylcarnitines) made the largest contributions to adiposity. Metabolic risk factors and total energy expenditure were associated with PC6, PC9 (AA and tricarboxylic acid cycle metabolites), and PC10. Fat oxidation was inversely related to PC8 (lysolipids) and positively related to PC16 (acylcarnitines). CONCLUSIONS Global metabolomic profiling in nonobese and obese children replicates the increased BCAA and acylcarnitine catabolism and changes in nucleotides, lysolipids, and inflammation markers seen in obese adults; however, a strong signature of reduced fatty acid catabolism and increased steroid derivatives may be unique to obese children. Metabolic flexibility in fuel use observed in obese children may occur through the activation of alternative intermediary pathways. Insulin resistance, hyperleptinemia, hypertriglyceridemia, hyperuricemia, and oxidative stress and inflammation evident in obese children are associated with distinct metabolomic profiles.

Association of Functional Polymorphism rs2231142 (Q141K) in the ABCG2 Gene With Serum Uric Acid and Gout in 4 US Populations The PAGE Study

A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008-2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 × 10(-67), P = 3.98 × 10(-5), P = 6.97 × 10(-9), and P = 5.33 × 10(-4) in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 × 10(-10), P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 × 10(-80)) and a 1.75-fold increase in the odds of gout (P = 1.09 × 10(-12)). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.

A nutrition and physical activity intervention promotes weight loss and enhances diet attitudes in low-income mothers of young children.

The purpose of this study was to evaluate a nutrition and physical activity program for reducing body weight and improving nutrition attitudes in mothers of young children. A convenience sample of 114 intervention mothers and 33 comparison mothers was recruited from public health clinics and community centers. Eligibility criteria included Hispanic, African American, or white ethnicity; body mass index of at least 25 kg/m(2); low income (< 200% of the federal poverty index); and youngest child aged 1 to 4 years. For intervention participants, height, weight, percentage of body fat, waist circumference, demographics, nutrition attitudes, and dietary intake were measured at weeks 0 and 8; height, weight, percentage of body fat, and waist circumference were reassessed at 6 months. Overweight mothers in the comparison group provided anthropometric and demographic data at weeks 0 and 8. Changes in anthropometrics, attitudes, and dietary intake were evaluated in intervention mothers. Anthropometric data of intervention vs comparison group mothers were examined. Differences in anthropometrics and attitude scores between weight loss responders (> or = 2.27 kg) and nonresponders (< 2.27 kg) were assessed at week 8. Intervention participants lost weight (x = -2.7 kg; P < .001), whereas comparison mothers gained a slight amount of weight (x = 0.1 kg) by week 8. Weight loss responders had healthier eating attitudes (5.6 vs 5.2; P < .01) and fewer perceived barriers (2.4 vs 2.9; P < .05) than nonresponders postintervention. In conclusion, this dietary and physical activity curriculum is a valuable resource for weight management programs serving low-income women.

Genetics of variation in serum uric acid and cardiovascular risk factors in Mexican Americans

BACKGROUND Elevated serum uric acid is associated with several cardiovascular disease (CVD) risk factors such as hypertension, inflammation, endothelial dysfunction, insulin resistance, dyslipidemia, and obesity. However, the role of uric acid as an independent risk factor for CVD is not yet clear. OBJECTIVE The aim of the study was to localize quantitative trait loci regulating variation in serum uric acid and also establish the relationship between serum uric acid and other CVD risk factors in Mexican Americans (n = 848; men = 310, women = 538) participating in the San Antonio Family Heart Study. METHODS Quantitative genetic analysis was conducted using variance components decomposition method, implemented in the software program SOLAR. RESULTS Mean +/- SD of serum uric acid was 5.35 +/- 1.38 mg/dl. Univariate genetic analysis showed serum uric acid and other CVD risk markers to be significantly heritable (P < 0.005). Bivariate analysis showed significant correlation of serum uric acid with body mass index, waist circumference, waist/hip ratio, total body fat, plasma insulin, serum triglycerides, high-density lipoprotein cholesterol, C-reactive protein, and granulocyte macrophage-colony stimulating factor (P < 0.05). A genome-wide scan for detecting quantitative trait loci regulating serum uric acid variation showed a significant logarithm of odds (LOD) score of 4.72 (empirical LOD score = 4.62; P < 0.00001) on chromosome 3p26. One LOD support interval contains 25 genes, of which an interesting candidate gene is chemokine receptor 2. SUMMARY There is a significant genetic component in the variation in serum uric acid and evidence of pleiotropy between serum uric acid and other cardiovascular risk factors.