Genetics of Gallbladder Disease in Mexican Americans

描述（申请人提供）：胆囊疾病（GBD）是一种常见的、经济负担沉重的消化系统疾病。据估计，有2000万美国人患有GBD，每年有超过70万人接受胆囊切除术。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的家族聚集性，以及通过动物模型确定胆结石疾病的Lith位点，提示基因对GBD的影响。由于GBD在人群中的主要易感位点尚未确定，我们最近使用来自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进行了GBD易感位点的全基因组搜索。在考虑了年龄、性别和多发性硬化症的协变量效应后，我们发现症状性GBD表型有很强的关联信号。最高的LOD评分分别出现在1p染色体D1S1597和D1S407之间（1p36.21）和D1S255附近（1p34.3）。这项修订后的竞争性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支持间隔区域进行系统筛选，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，最终确定影响GBD的潜在功能变异。首先（目标1），为了高密度地覆盖两个连接区域（~9.5和~18 Mb长区域），但以基因为中心，将使用高通量基因分型程序和我们的数据（N = 735）对4,608个snp（第一个区域约1,600个snp，第二个区域约3,000个snp）进行分型。将测量连锁不平衡模式，并进行与GBD的关联分析，以优先考虑5个位置候选基因。这些基因将通过对来自SAFDGS家族的150位创始人（代表300个基因组）进行测序来彻底筛选（Aim 2a）。在评估这5个候选基因的遗传变异后，我们将在样本中选择约250个snp进行分型，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（Aim 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的复制样本的一部分，并收集GBD表型信息（Aim 3a）。在SAFDGS样本（Aim 2b）中与GBD最密切相关的选定snp将在该复制样本（Aim 3b）中进行验证。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。这些观察结果有助于理解美国人群之间的健康差异。胆囊疾病（GBD）是最常见和最昂贵的消化系统疾病之一。这项研究项目的发现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。公共卫生相关性：胆囊疾病（GBD）是最普遍和最昂贵的消化系统疾病之一。这项研究项目的发现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。

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.