Lipoprotein-Related CVD Risk Factors: QTL Identification

该修订项目建立在圣安东尼奥家庭心脏研究之前的努力之上，旨在检测、表征和 定位基因对脂蛋白变异的影响以及氧化应激和炎症的生物标志物 来自德克萨斯州圣安东尼奥的墨西哥裔美国家庭。两个主要目标中的第一个是识别基因， 其中可能的功能多态性，实质上有助于3个性状的变异，我们已经 QTL定位的先验置信度。这些特征是高密度脂蛋白的血浆浓度 胆固醇（染色体9 p上的QTL），氧化低密度脂蛋白胆固醇（染色体15 q），和 血管细胞粘附分子-1（染色体7 q）。为了实现每个QTL的目标，我们将 以下. (1)使用来自600名SAFHS个体的可用高密度tagSNP基因型数据， 关联研究以提名位置候选基因用于进一步分析。(2)确认 这些分析的结果通过分型和分析7%的tagSNPs显示出最显著的关联 在每个QTL的支持区间内的745个剩余的SAFHS参与者。(3)进一步优先考虑tagSNPs， 使用贝叶斯数量性状核苷酸（BQTN）分析来自所有1345个SAFHS的数据的提名基因 参与者(4)询问我们现有的全基因组转录谱数据，以测试焦点是否 表型与位于QTL支持区间内的任何基因相关（表型上或遗传上）。 (3)对每个QTL的2个优先基因中的所有SNP进行测序和分型，以进行详尽的BQTN分析， 可能的功能变体。(4)基因型多达30个确定的功能SNP每个基因从这些分析中， SAFHS，并对来自圣安东尼奥家族的741名个体的数据进行复制研究 胆囊疾病研究。第二个主要目标是表征和定位影响 在目前的资助结束时， 周期这些特征包括：晚期糖基化终产物;总抗氧化状态;血浆浓度 细胞外超氧化物歧化酶和谷胱甘肽过氧化物酶，红细胞谷胱甘肽浓度， 和谷胱甘肽还原酶活性。它们还包括C-反应蛋白、肿瘤坏死因子-a和 白细胞介素-6、细胞间粘附分子-1和P-选择素以及粒细胞巨噬细胞集落 刺激因素

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.