Analysis of Fatty Liver in the Framingham Heart Study Cohort

描述(由申请人提供)： 由于肥胖在全球范围内的流行，许多人的肝脏中有脂肪沉积，可能导致肝硬变和肝功能衰竭；然而，人们对脂肪肝的遗传流行病学或代谢后果知之甚少。斯皮里奥特斯博士是马萨诸塞州总医院的胃肠病研究员，也是布罗德研究所的博士后研究员，对肥胖很感兴趣。她在基础科学研究方面有很强的背景，现在的目标是扩大她的分析技能，将人类遗传流行病学包括在内。她的长期目标是能够评估、应用和创造新的信息来治疗人类肥胖和相关疾病。拟议的职业发展计划包括一个明确的、有指导的、以患者为导向的研究方案，并与统计学、流行病学和遗传学的结构化教学课程相一致。她将通过实现以下目标来阐明基于弗雷明翰心脏研究队列的人群中脂肪肝的流行病学和遗传相关性：目的1.确定脂肪肝的患病率和临床相关性。答：她将分析这个样本中的3500多个CT扫描是否存在脂肪肝，并在一项横断面设计的研究中确定这种情况的患病率。她将测试代谢性疾病是否与脂肪肝相关，独立于其他肥胖指标。此外，她将测试亚临床和临床心血管疾病是否与脂肪肝相关，独立于上述肥胖和代谢风险因素的其他衡量标准。目的2.确定脂肪肝的遗传度和连锁关系。她将利用队列中以家族为基础的部分，使用方差成分似然法来估计脂肪肝的A.遗传力和B.连锁。目的3.检测与脂肪肝相关的基因变异。答：她将使用多变量回归技术测试INSIG2、KCNJ11、PPARG和TCF7L2基因中与肥胖或糖尿病相关的单核苷酸多态(SNPs)是否与脂肪肝独立相关。她将使用多变量回归技术测试队列中已经和将要进行基因分型的1QOK/500K SNP标记是否与脂肪肝有关。她将尝试在1124名患者中复制与脂肪肝相关的任何SNP，这些患者在接受胃旁路手术时进行了肝活检，并通过组织学检查患有脂肪肝。在以社区为基础的大样本中了解脂肪肝的最佳独立临床和遗传相关性将有助于我们更好地了解肝脏中脂肪的生物学和临床意义，这将有助于我们更好地识别、管理和治疗许多脂肪肝患者。通过拟议的研究和教育培训，Speliotes博士将获得成为人类遗传流行病学独立科学家的技能。

DESCRIPTION (provided by applicant): As a consequence of the epidemic worldwide increase in obesity, many people have fat deposited in their liver that can lead to liver cirrhosis and liver failure; nevertheless, little is known about the genetic epidemiology or metabolic consequences of fatty liver. Dr. Speliotes is a fellow in gastroenterology at the Massachusetts General Hospital and a post doctoral fellow at the Broad Institute with an interest in obesity. She has a strong background in basic science research and now aims to expand her analytic skills to include human genetic epidemiology. Her long term goals are to be able to evaluate, apply, and create new information to treat obesity and associated illnesses in humans. The proposed career development plan includes a well defined mentored patient-oriented research proposal in concert with a structured didactic curriculum in statistics, epidemiology and genetics. She will elucidate the epidemiologic and genetic correlates of fatty liver in the population based Framingham Heart study cohort by carrying out the following aims: Aim 1. Determine the prevalence and clinical correlates of fatty liver. A. She will analyze the over 3500 CT scans available in this sample for the presence of fatty liver and determine the prevalence of this condition in a cross-sectionally designed study. She will test whether metabolic diseases correlate with fatty liver independent of other measures of adiposity. B. Furthermore, she will test whether subclinical and clinical cardiovascular disease correlate with fatty liver independently of the other measures of adiposity and metabolic risk factors noted above. Aim 2. Determine the heritability and linkage of fatty liver. She will take advantage of the family-based component of the cohort to estimate the A. heritability and B. linkage of fatty liver using variance-components likelihood methods. Aim 3. Test genetic variants for association with fatty liver. A. She will test whether obesity- or diabetes-associated single nucleotide polymorphisms (SNPs) in the genes INSIG2, KCNJ11, PPARG, and TCF7L2 are independently associated with fatty liver using multivariable regression techniques. B. She will test whether the 1QOK/ 500K SNP markers that have been and will be genotyped in the cohort associate with fatty liver using multivariable regression techniques. She will attempt to replicate any SNPs associated with fatty liver in a sample of 1124 individuals that have had liver biopsies while undergoing gastric bypass surgery and have fatty liver by histology. An understanding of the best independent clinical and genetic correlates of fatty liver in a large community based sample will help us to better understand the biology and clinical significance of fat in the liver which will help us to better identify, manage and treat the many individuals that have fatty liver. Through the proposed research and educational training Dr. Speliotes will acquire the skills to become an independent scientist in human genetic epidemiology.