This revised project builds on previous efforts of San Antonio Family Heart Study to detect, characterize, andlocalize the effects of genes on variation in lipoproteins and biomarkers of oxidative stress and inflammationin Mexican American families from San Antonio, Texas. The first of 2 major goals is to identify genes andlikely functional polymorphisms therein that contribute substantively to variation in 3 traits for which we haveprior confidence in QTL localization. These traits are plasma concentrations of high-density lipoproteincholesterol (a QTL on chromosome 9p), oxidized low-density lipoprotein cholesterol (chromosome 15q), andvascular cellular adhesion molecule-1 (chromosome 7q). To achieve this goal for each QTL, we will do thefollowing. (1) Use available high-density tagSNP genotype data from 600 SAFHS individuals in pedigreebasedassociation studies to nominate positional candidate genes for further analyses. (2) Confirm theresults of these analyses by typing and analyzing the 7% tagSNPs showing the most significant associationswithin each QTL's support interval in the 745 remaining SAFHS participants. (3) Further prioritize tagSNPs innominated genes using Bayesian quantitative trait nucleotide (BQTN) analysis of data from all 1345 SAFHSparticipants. (4) Interrogate our existing genome-wide transcriptional profile data to test whether the focalphenotype 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 identifylikely functional variants. (4) Genotype up to 30 identified functional SNPs per gene from these analyses inthe SAFHS and conduct a replication study with data from 741 individuals from the San Antonio FamilyGallbladder Disease Study. The second major goal is characterization and localization of QTLs influencingvariation in oxidative stress and inflammation traits now being assayed at the end of the current fundingcycle. These traits include: advanced glycation endproducts; total antioxidant status; plasma concentrationsof extra-cellular superoxide dismutase; and glutathione peroxidase, erythrocyte glutathione concentrations,and glutathione reductase activities. They also include C-reactive protein; tumor necrosis factor-a andinterleukin-6; intercellular adhesion molecule-1, and P-selectin; and granulocyte macrophage colonystimulating factor.
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