Lipoprotein-Related CVD Risk Factors: QTL Identification

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This revised project builds on previous efforts of San Antonio Family Heart Study to detect, characterize, and localize the effects of genes on variation in lipoproteins and biomarkers of oxidative stress and inflammation in Mexican American families from San Antonio, Texas. The first of 2 major goals is to identify genes and likely functional polymorphisms therein that contribute substantively to variation in 3 traits for which we have prior confidence in QTL localization. These traits are plasma concentrations of high-density lipoprotein cholesterol (a QTL on chromosome 9p), oxidized low-density lipoprotein cholesterol (chromosome 15q), and vascular cellular adhesion molecule-1 (chromosome 7q). To achieve this goal for each QTL, we will do the following. (1) Use available high-density tagSNP genotype data from 600 SAFHS individuals in pedigreebased association studies to nominate positional candidate genes for further analyses. (2) Confirm the results of these analyses by typing and analyzing the 7% tagSNPs showing the most significant associations within each QTL's support interval in the 745 remaining SAFHS participants. (3) Further prioritize tagSNPs in nominated genes using Bayesian quantitative trait nucleotide (BQTN) analysis of data from all 1345 SAFHS participants. (4) Interrogate our existing genome-wide transcriptional profile data to test whether the focal phenotype is correlated (phenotypically or genetically) with any gene located within the QTL support interval. (3) Sequence and type all SNPs in 2 prioritized genes per QTL for exhaustive BQTN analyses to identify likely functional variants. (4) Genotype up to 30 identified functional SNPs per gene from these analyses in the SAFHS and conduct a replication study with data from 741 individuals from the San Antonio Family Gallbladder Disease Study. The second major goal is characterization and localization of QTLs influencing variation in oxidative stress and inflammation traits now being assayed at the end of the current funding cycle. These traits include: advanced glycation endproducts; total antioxidant status; plasma concentrations of extra-cellular superoxide dismutase; and glutathione peroxidase, erythrocyte glutathione concentrations, and glutathione reductase activities. They also include C-reactive protein; tumor necrosis factor-a and interleukin-6; intercellular adhesion molecule-1, and P-selectin; and granulocyte macrophage colony stimulating factor.