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). PUBLIC HEALTH RELEVANCE: 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.

R01DK080457

2009-04-15

2015-02-28