Obesity And Diabetes Familial Risk In Hispanic Children
Nancy F Butte, Associate Professor Of Pediatrics
Pediatricsbaylor College Of Medicine
Grant 1R01DK080457-01A2 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: CIDO
Abstract: Familial risk for obesity and diabetes in Hispanic children is due to a number of genes, each with multiple disease-predisposing alleles of low to intermediate population frequency. The overall goal of this project is to identify one or more variants in gene(s) that is/are responsible for the linkage signals on chromosome13q for fasting serum glucose and on chromosome 1p for fasting serum insulin, ghrelin and IGFBP-1 in Hispanic children by use of large scale SNP typing, exhaustive DNA resequencing and statistical functional genomics. The specific aims of this project are Specific Aim 1 To identify genetic variants responsible for the statistically significant (LOD=4.6) quantitative trait locus (QTL) on chromosome 13q for fasting serum glucose in Hispanic children. a. To prioritize genes based on association analysis, a custom, dense panel of ~2200 SNPs in a 5 MB region on chromosome 13q will be genotyped in 1030 children. b. To identify genetic variants responsible for the significant QTL on chromosome 13q, the genes prioritized by association analysis (~four genes) will be extensively resequenced in 376 children. c. To determine the frequency distribution in the entire VIVA LA FAMILIA cohort, the identified variants will be genotyped in the remaining children (n=654). d. To statistically identify potentially functional genetic variants influencing fasting serum glucose in Hispanic children, Bayesian quantitative trait nucleotide (BQTN) analyses will be performed. e. To replicate the potentially functional genetic variants in independent cohorts, we will genotype and analyze the SNPs´ effects in cohorts of Hispanic children (SAFARI) and Hispanic adults (SAFHS). Specific Aim 2 To identify genetic variants responsible for the statistically significant (LOD=3.2-3.4) QTLs on chromosome 1p for fasting serum insulin, ghrelin and IGFBP-1 in Hispanic children. a. To prioritize genes based on association analysis, a custom, dense panel of ~5200 SNPs in a 9 MB region on chromosome 1p will be genotyped in 1030 children. b. To identify genetic variants responsible for the significant QTL on chromosome 1p, the genes prioritized by association analysis (~twelve genes) will be extensively resequenced in 376 children. c. To determine the frequency distribution in the entire VIVA LA FAMILIA cohort, the identified variants will be genotyped in the remaining children (n=654). d. To statistically identify potentially functional genetic variants influencing fasting serum insulin, ghrelin and IGFBP-1 in Hispanic children, BQTN analyses will be performed. e. To replicate the potentially functional genetic variants in independent cohorts, we will genotype and analyze the SNPs´ effects in cohorts of Hispanic children (SAFARI) and Hispanic adults (SAFHS). Hispanic youth in the United States are at increased risk for obesity and type 2 diabetes, and yet the genetic variants underlying this heightened susceptibility have not been identified. In this project, we propose to identify variants in genes that influence fasting glucose, insulin, ghrelin and IGFBP1 in Hispanic children. The identification of genes that influence childhood obesity and type 2 diabetes will advance the detection and treatment of obesity and its comorbidities in children
Project start date: 2009-04-15
Project end date: 2013-02-28
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Nancy F Butte
PREDICTION OF ENERGY EXPENDITURE/PHYSICAL ACTIVITY IN CHILDREN AND ADOLESCENTS
Nancy F Butte, Professor
Baylor College Of Medicine, 1 Baylor Plaza, Houston, Tx 77030-3498
Grant 5R01DK074387-04 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: In the proposed project, we will develop a model to predict minute-by-minute energy expenditure (EE) in children and adolescents using a new device called Actiheart, which simultaneously records heart rate (HR) and (PA). Total energy expenditure (TEE) will be derived from the summation of EE over a 24-h period and activity energy expenditure (AEE) will be computed from TEE using an estimate of resting metabolic rate (0.9 TEE-RMR). This method will be developed in a sample of 50 normal-weight and 50 overweight children and adolescents using 24-h room respiration calorimetry, and validated in an independent sample (n=46) using 24-h room respiration calorimetry and 7-day free-living measurements of TEE by the doubly labeled water (DLW) method. The overall goal will be to predict 24-h TEE and AEE of individuals from combined HR and PA within 10% of independently measured values by respiration calorimetry and DLW. Therefore, the specific aims of the proposed project are 1. To develop multivariate adaptive regression splines (MARS) and cross-sectional time series models for the prediction of EE and hence 24-h TEE and AEE from HR in 50 normal-weight and 50 overweight children and adolescents using Actiheart and 24-h room respiration calorimetry. 2. To validate the MARS and cross-sectional time series models for the prediction of minute-by-minute EE and hence 24-h TEE and AEE from HR against 24-h room respiration calorimetry and DLW method in an independent sample of 23 normal-weight and 23 overweight children and adolescents. Free-living measurements of 24-h TEE and AEE are required to better understand the metabolic, physiological, behavioral and environmental factors affecting energy balance and contributing to the global epidemic of childhood obesity. The two primary methods to measure EE (respiration calorimetry and DLW) are impractical for the large-scale epidemiological studies required to address this important public health problem. A new method based on direct ambulatory monitoring of HR and PA will be developed to accurately predict EE, and hence 24-h TEE and AEE in children and adolescents
Keywords: 0-11 years old; Address; Adolescent; Adolescent Youth; Affect; Ambulatory Monitoring; Basal Metabolism; Basal metabolic rate; Behavioral; Calorimetry, Indirect; Calorimetry, Respiration; Child; Child Youth; Childhood; Children (0-21); Chronotropism, Cardiac; Chronotropisms, Cardiac; Devices; Disease regression; Energy Expenditure; Energy Metabolism; Environmental Factor; Environmental Risk Factor; Epidemic; Epidemiologic Research; Epidemiologic Studies; Epidemiological Studies; Epidemiology Research; Expenditure; Goals; Heart Rate; Human, Child; Hydrogen Oxide; Indirect Calorimetry; Individual; Label; Life; Measurement; Measures; Metabolic; Methods; Modeling; Monitoring, Ambulatory; Obesity; Outpatient Monitoring; Over weight; Overweight; Physical activity; Physiologic; Physiological; Public Health; Records; Regression; Sampling; Series; Time; Water; Weight; adiposity; base; children; corpulence; corpulency; corpulentia; day; energy balance; environmental risk; juvenile; juvenile human; obese; obese people; obese person; obese population; pediatric; public health medicine (field); resting metabolic rate; youngster
Project start date: 2005-09-01
Project end date: 2010-08-31
Budget start date: 1-SEP-2008
Budget end date: 31-AUG-2010
PFA/PA: PA-04-088
5R01DK074387-04 (2008): $0
5R01DK074387-03 (2007): $288010
5R01DK074387-02 (2006): $296613
Prediction Of Energy Expenditure/Physical Activity
Nancy F Butte, Associate Professor Of Pediatrics
Baylor College Of Medicine 1 Baylor Plaza Houston, Tx 770303498
Grant 1R01DK074387-01 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: ZRG1
Abstract: In the proposed project, we will develop a model to predict minute-by-minute energy expenditure (EE) in children and adolescents using a new device called Actiheart, which simultaneously records heart rate (HR) and (PA). Total energy expenditure (TEE) will be derived from the summation of EE over a 24-h period and activity energy expenditure (AEE) will be computed from TEE using an estimate of resting metabolic rate (0.9 TEE-RMR). This method will be developed in a sample of 50 normal-weight and 50 overweight children and adolescents using 24-h room respiration calorimetry, and validated in an independent sample (n=46) using 24-h room respiration calorimetry and 7-day free-living measurements of TEE by the doubly labeled water (DLW) method. The overall goal will be to predict 24-h TEE and AEE of individuals from combined HR and PA within 10% of independently measured values by respiration calorimetry and DLW. Therefore, the specific aims of the proposed project are 1. To develop multivariate adaptive regression splines (MARS) and cross-sectional time series models for the prediction of EE and hence 24-h TEE and AEE from HR in 50 normal-weight and 50 overweight children and adolescents using Actiheart and 24-h room respiration calorimetry. 2. To validate the MARS and cross-sectional time series models for the prediction of minute-by-minute EE and hence 24-h TEE and AEE from HR against 24-h room respiration calorimetry and DLW method in an independent sample of 23 normal-weight and 23 overweight children and adolescents. Public Health Relevance Free-living measurements of 24-h TEE and AEE are required to better understand the metabolic, physiological, behavioral and environmental factors affecting energy balance and contributing to the global epidemic of childhood obesity. The two primary methods to measure EE (respiration calorimetry and DLW) are impractical for the large-scale epidemiological studies required to address this important public health problem. A new method based on direct ambulatory monitoring of HR and PA will be developed to accurately predict EE, and hence 24-h TEE and AEE in children and adolescents.
Keywords: adolescence (12-20), bioenergetics, body physical activity, heart rate, middle childhood (6-11), monitoring device, basal metabolism, body composition, body height, body weight, obesity, physical fitness, calorimetry, clinical research, human subject, photon absorptiometry, statistics /biometry
Project start date: 2005-09-01
Project end date: 2009-08-31
1R01DK074387-01 (2005): $303750
Nancy F Butte, Associate Professor Of Pediatrics
Baylor College Of Medicine 1 Baylor Plaza Houston, Tx 770303498
Grant 5R01DK059264-05 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: MGN
Abstract: Childhood obesity in the United States has dramatically increased in the past decade. The proportion of children exceeding the 95th and 85th percentiles for body mass index (BMI) is among the greatest in Mexican- Americans. Despite the high prevalence of obesity among Hispanic children, the genes underlying the heightened susceptibility to childhood- onset obesity in Hispanic populations have not been investigated. The specific goal of this project is to test the hypothesis that a number of genes, each with a measurable effect on the expression of childhood obesity, can be identified by the use of a systematic genomic screen. The specific aims are l) to identify and phenotype 300 obese Hispanic probands (ages 4-18 y) and their biological parents and siblings, 2) to construct a 10 cM map for 1600 Hispanic individuals to be used in a genome-wide scan for loci that affect quantitative phenotypes of adiposity and energy expenditure using high-throughput genotyping techniques, 3) to perform a multipoint genome scan to find and localize QTLs that influence quantitative variation in adiposity. and energy expenditure in children by performing variance component linkage analysis, and 4) to use multivariate quantitative trait linkage analysis to test whether QTLs localized in Aim 3 have measurable pleiotropic effects across phenotypes. Our target sample will include 1600 genotyped individuals dispersed over 300 nuclear families with a minimum of three children, ascertained on the obese proband using a bivariate scheme (i.e., >95th percentile for BMI and >85th percentile for fat mass). Phenotyping will include anthropometry and body composition, as well as factors associated with the development of obesity energy partitioning during growth, energy expenditure, physical fitness and activity. hormones, metabolites, and neurotransmitters. Anthropometry and body composition measurements will be repeated after 1y to determine body weight and fat change in the children. Approximately 360 hyper-variable STR markers will be typed for each individual to produce a 10 cM genome map. Multipoint linkage analysis using variance components methods will be applied to nuclear family data to search for QTLs influencing obesity-related phenotypes in Hispanic children. We will test the null hypothesis that the additive genetic variance due to a QTL equals zero (no linkage) by comparing the likelihood of this restricted model with that of a model in which the variance is estimated. This QTL method will be implemented in the program package SOLAR using estimation procedures from FISHER. Lastly, we will test for pleiotropic effects of obesity-related QTLs across phenotypes.
Keywords: Hispanic American, adolescence (12-20), gene expression, genetic screening, genetic susceptibility, middle childhood (6-11), obesity, preschool child (1-5), adipose tissue, bioenergetics, body composition, family genetics, genetic marker, linkage mapping, phenotype, blood chemistry, calorimetry, clinical research, genotype, high throughput technology, human subject, interview, nucleic acid repetitive sequence, polymerase chain reaction
Project start date: 2000-09-30
Project end date: 2006-06-30
5R01DK059264-05 (2004): $459385
5R01DK059264-02 (2001): $554748
1R01DK059264-01 (2000): $552590
Nonalcoholic Fatty Liver Disease In Hispanic Obese Youth
Nancy F Butte, Associate Professor Of Pediatrics
Baylor College Of Medicine 1 Baylor Plaza Houston, Tx 770303498
Grant 5R03DK066109-02 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: ZDK1
Abstract: Childhood obesity and type II diabetes are reaching epidemic proportions in the U.S. particularly among Hispanic and African-American children, and the consequences of this epidemic in terms of nonalcoholic fatty liver disease (NAFLD) are understudied and under appreciated. Hispanic and African-American children are at greater risk for the development of obesity and type II diabetes which are major risk factors for NAFLD. The full impact of this metabolic syndrome will not be realized until these children become adults and develop the long-term consequences of obesity, diabetes and liver disease. The primary objective of this grant is to characterize children at risk for NAFLD and explore possible mechanisms underlying the development of NAFLD in 1000 Hispanic children enrolled in an on-going NIH genome-wide linkage study designed to identify genes that influence the expression of childhood obesity. The long-term objective is to develop an clinical intervention trial to treat the adverse effects of NAFLD in obese children. Hypothesis Oxidative stress, endotoxemia and systemic inflammation superimposed on hepatic fat accumulation may lead to liver damage in obese children. Specific Aims 1. To characterize Hispanic children at high risk of developing NAFLD in terms of age, gender, body composition, diet, physical activity, and severity and duration of obesity. 2. To determine the relationships between fasting hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hyperleptinemia, and elevations in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). 3. To obtain evidence that oxidative stress, endotoxemia and measures of systemic inflammation are associated with elevations in serum ALT and AST. Design Obese Hispanic children and their nonobese siblings will be screened for NAFLD using serum liver function tests; total sample size will be 1000. We will characterize children at risk for NAFLD and explore possible mechanisms of oxidative stress, endotoxemia and systemic inflammation underlying NAFLD. Methods Liver function tests, ALT and AST will be analyzed in relation to in-depth phenotyping and genetic linkage analysis performed under the on-going NIH study. Newly proposed tests include chromogenic assays to measure lipid peroxidation end products and endotoxins, and ELISA and RIA to measure cytokine and markers of systemic inflammation.
Keywords: Hispanic American, alanine transaminase, aspartate transaminase, children, disease /disorder proneness /risk, fatty liver, liver disorder, obesity, diabetes mellitus, gene expression, hypercholesterolemia, hyperinsulinism, hypertriglyceridemia, adolescence (12-20), child (0-11), clinical research, enzyme linked immunosorbent assay, human subject
Project start date: 2004-01-15
Project end date: 2006-12-31
5R03DK066109-02 (2005): $150500
1R03DK066109-01 (2004): $150500