Genetics of Gallbladder Disease in Mexican Americans

墨西哥裔美国人胆囊疾病的遗传学

• 批准号: 7877076
• 负责人: RAVINDRANATH DUGGIRALA
• 金额: $ 39.63万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7877076
• 关键词: 1p34.3; 1p36; Accounting; Affect; Age; American; Animal Model; Bile fluid; Candidate Disease Gene; Central obesity; Cholecystectomy; Cholelithiasis; Cholesterol; Chromosomes; Complex; Country; Data; Data Linkages; Diabetes Mellitus; Diet; Digestive System Disorders; Disease; Disease susceptibility; Environmental Risk Factor; Epidemic; Ethnic Origin; Exhibits; Family; Family Study; Female; Gall Bladder Diseases; Gallbladder; Genes; Genetic; Genetic Determinism; Genetic Variation; Genome; Genome Scan; Genotype; Goals; Heart; Hepatobiliary; Heritability; Human; Individual; Lead; Life Expectancy; Link; Linkage Disequilibrium; Lipids; Location; Lod Score; Malignant neoplasm of gallbladder; Maps; Measures; Metabolic Diseases; Metabolic syndrome; Mexican Americans; Minor; Minority; Mucins; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nucleotides; Obesity; Participant; Pathogenesis; Pattern; Pharmaceutical Preparations; Phase; Population; Predisposition; Prevalence; Prevention; Procedures; Research Activity; Research Project Grants; Risk Factors; Sampling; Sampling Studies; Screening procedure; Signal Transduction; Single Nucleotide Polymorphism; Symptoms; System; Testing; Ultrasonography; Variant; age effect; base; density; disease phenotype; disorder risk; ethnic difference; genetic linkage analysis; genome-wide; health disparity; interest; mouse model; parity; public health relevance; sex; trait

DESCRIPTION (provided by applicant): Gallbladder disease (GBD) is a common, economically burdensome digestive disease. An estimated 20 million Americans are affected with GBD, and more than 700,000 cholecystectomies are performed every year. Its risk factors include age, sex, obesity, type 2 diabetes, and the metabolic syndrome (MS). Ethnic differences, familial aggregation of GBD, and the identification of Lith loci for gallstone disease using animal models suggest genetic influences on GBD. Since the major susceptibility loci for GBD in human populations have not been identified, we recently performed a genome-wide search for susceptibility loci for GBD, using data from the San Antonio Family Diabetes/Gallbladder Study (SAFDGS) and multipoint linkage analysis. After accounting for the covariate effects of age, sex, and MS, we found strong linkage signals for symptomatic GBD phenotype. The highest LOD scores (3.7 and 3.5) occurred on chromosome 1p between markers D1S1597 and D1S407 (1p36.21) and near marker D1S255 (1p34.3), respectively. The major goal of this revised competing renewal proposal is to conduct a systematic screening of the 1.5-LOD support interval regions surrounding the two linked regions on chromosome 1p to find the potential functional variant(s) that could relate to our initial linkage findings. We will use a phase-wise single nucleotide polymorphism (SNP) typing strategy to ultimately identify the potential functional variant(s) that influence GBD. Firstly (Aim 1), to cover the two linked regions (~9.5 and ~18 Mb long regions) at high density, but gene-centrically, 4,608 SNPs (~1,600 SNPs in the first region and ~3,000 SNPs in the second) will be typed using high-throughput genotyping procedures and our data (N = 735). The patterns of linkage disequilibrium will be measured, and association analysis with GBD will be performed to prioritize 5 positional candidate genes. These genes will be thoroughly screened by sequencing 150 founders [representing 300 genomes] from SAFDGS families (Aim 2a). After evaluating the genetic variation within these 5 candidate genes, ~250 SNPs will be selected for typing in our samples to perform Bayesian quantitative trait nucleotide (BQTN) analysis in order to identify the most likely functional variants (Aim 2b). Approximately 400 individuals from 10 San Antonio Family Heart Study (SAFHS) families will be recalled as part of a replication sample for this study, and information on GBD phenotypes will be collected (Aim 3a). Selected SNPs that are most strongly associated with GBD in the SAFDGS sample (Aim 2b) will be validated in this replication sample (Aim 3b). This study will lead to identification of genetic factors that influence GBD in Mexican Americans, the fastest growing minority population in the US. These observations could contribute to understanding health disparities among the US populations.Gallbladder disease (GBD) is one of the most prevalent and expensive digestive diseases. The findings from this research project will lead to the identification of genes that influence variation in GBD in Mexican Americans. Ultimately, the proposed research activities may pave the way for prevention and treatment of GBD. PUBLIC HEALTH RELEVANCE: Gallbladder disease (GBD) is one of the most prevalent and expensive digestive diseases. The findings from this research project will lead to the identification of genes that influence variation in GBD in Mexican Americans. Ultimately, the proposed research activities may pave the way for prevention and treatment of GBD.

描述（由申请人提供）：胆囊疾病（GBD）是一种常见的、经济负担重的消化系统疾病。据估计，有 2000 万美国人患有 GBD，每年进行超过 70 万例胆囊切除术。其危险因素包括年龄、性别、肥胖、2 型糖尿病和代谢综合征 (MS)。种族差异、GBD 的家族聚集以及使用动物模型鉴定胆石病的 Lith 位点表明遗传对 GBD 的影响。由于尚未确定人群中 GBD 的主要易感位点，我们最近利用圣安东尼奥家庭糖尿病/胆囊研究 (SAFDGS) 的数据和多点连锁分析，对 GBD 的易感位点进行了全基因组搜索。在考虑了年龄、性别和 MS 的协变量效应后，我们发现了症状性 GBD 表型的强烈连锁信号。最高 LOD 得分（3.7 和 3.5）分别出现在标记 D1S1597 和 D1S407 (1p36.21) 之间以及标记 D1S255 (1p34.3) 附近的染色体 1p 上。这一修订后的竞争更新提案的主要目标是对 1p 染色体上两个连锁区域周围的 1.5-LOD 支持区间区域进行系统筛选，以找到可能与我们最初的连锁发现相关的潜在功能变异。我们将使用分阶段单核苷酸多态性 (SNP) 分型策略来最终识别影响 GBD 的潜在功能变异。首先（目标 1），为了以高密度覆盖两个链接区域（约 9.5 Mb 和约 18 Mb 长的区域），但以基因为中心，将使用 4,608 个 SNP（第一个区域约 1,600 个 SNP，第二个区域约 3,000 个 SNP）使用高通量基因分型程序和我们的数据进行分型（N = 735）。将测量连锁不平衡模式，并进行与 GBD 的关联分析，以确定 5 个位置候选基因的优先级。这些基因将通过对来自 SAFDGS 家族的 150 个创始人（代表 300 个基因组）进行测序来彻底筛选（目标 2a）。在评估这 5 个候选基因内的遗传变异后，将选择约 250 个 SNP 在我们的样本中进行分型，以进行贝叶斯数量性状核苷酸 (BQTN) 分析，以确定最可能的功能变异（目标 2b）。来自 10 个圣安东尼奥家庭心脏研究 (SAFHS) 家庭的大约 400 名个体将被召回，作为本研究复制样本的一部分，并将收集有关 GBD 表型的信息（目标 3a）。 SAFDGS 样本中与 GBD 最密切相关的选定 SNP（目标 2b）将在此复制样本中进行验证（目标 3b）。这项研究将确定影响墨西哥裔美国人 GBD 的遗传因素，墨西哥裔美国人是美国增长最快的少数民族人口。这些观察结果可能有助于了解美国人口之间的健康差异。胆囊疾病（GBD）是最普遍和最昂贵的消化系统疾病之一。该研究项目的结果将有助于鉴定影响墨西哥裔美国人 GBD 变异的基因。最终，拟议的研究活动可能为 GBD 的预防和治疗铺平道路。公众健康相关性：胆囊疾病 (GBD) 是最常见和最昂贵的消化系统疾病之一。该研究项目的结果将有助于鉴定影响墨西哥裔美国人 GBD 变异的基因。最终，拟议的研究活动可能为 GBD 的预防和治疗铺平道路。