Analysis of Fatty Liver in the Framingham Heart Study Cohort

弗雷明汉心脏研究队列中的脂肪肝分析

• 批准号: 7361956
• 负责人: Elizabeth K Speliotes
• 金额: $ 18.55万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7361956
• 关键词: Abdomen; Adipose tissue; Age; Arteries; Basic Science; Biology; Body Weight decreased; Body mass index; Calcium; Cardiovascular Diseases; Caucasians; Caucasoid Race; Central obesity; Chest; Clinical; Communities; Condition; Congestive Heart Failure; Coronary; Coronary heart disease; Data; Deposition; Development; Development Plans; Diabetes Mellitus; Disease; Disease regression; Dyslipidemias; Educational Curriculum; Epidemic; Epidemiology; Family; Fatty Liver; Fatty acid glycerol esters; Framingham Heart Study; Future; Gastroenterology; General Hospitals; Genes; Genetic; Genetic Determinism; Genome; Genomics; Genotype; Goals; Grant; Heritability; Hispanics; Histology; Human; Human Genetics; Hyperlipidemia; Hypertension; Impaired fasting glycaemia; Individual; Institutes; Lead; Learning; Liver; Liver Cirrhosis; Liver Failure; Liver diseases; Massachusetts; Measures; Mentors; Metabolic; Metabolic Diseases; Metabolic syndrome; Methods; Obesity; PPARG gene; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Population; Postdoctoral Fellow; Prevalence; Rate; Research; Research Design; Research Proposals; Resources; Risk Factors; Sampling; Scanning; Scientist; Single Nucleotide Polymorphism; Stroke; Structure; TCF7L2 gene; Taiwan; Techniques; Testing; Texas; Tomogram; Training; Visceral; bariatric surgery; base; burden of illness; career; clinically significant; cohort; disorder risk; genetic epidemiology; genetic variant; improved; interest; liver biopsy; liver imaging; non-alcoholic fatty liver; patient oriented research; sex; skills; statistics; subcutaneous; waist circumference

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.

描述（由申请人提供）： 由于肥胖症在全球范围内的流行增加，许多人的肝脏中沉积了脂肪，这可能导致肝硬化和肝功能衰竭;然而，人们对脂肪肝的遗传流行病学或代谢后果知之甚少。Speliotes博士是马萨诸塞州总医院的胃肠病学研究员，也是布罗德研究所的博士后研究员，对肥胖感兴趣。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，包括人类遗传流行病学。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、面向病人的研究建议，以及一个结构化的统计学、流行病学和遗传学教学课程。她将阐明脂肪肝的流行病学和遗传学相关性在人口为基础的心脏研究队列通过执行以下目标：目标1。确定脂肪肝的患病率和临床相关性。A.她将分析这个样本中超过3500个CT扫描结果，以确定脂肪肝的存在，并在一项横断面设计的研究中确定这种疾病的患病率。她将测试代谢性疾病是否与脂肪肝相关，而不依赖于其他肥胖指标。B。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，而与上述肥胖和代谢危险因素的其他指标无关。目标2.确定脂肪肝的遗传度和连锁。她将利用队列中以家庭为基础的成分来估计A。遗传力和B.使用方差分量似然方法的脂肪肝的联系。目标3.检测与脂肪肝相关的遗传变异。A.她将使用多变量回归技术测试肥胖或糖尿病相关的单核苷酸多态性（SNP）是否与INSIG 2，KCNJ 11，PPARG和TCF 7 L2基因独立相关。B。她将使用多变量回归技术测试在队列中已经和将要进行基因分型的1 QOK/500 K SNP标记是否与脂肪肝相关。她将尝试在1124例接受胃旁路手术时进行肝活检并通过组织学检查患有脂肪肝的个体样本中复制与脂肪肝相关的任何SNP。了解大型社区样本中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，管理和治疗许多患有脂肪肝的个体。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。