Genetic Epidemiology of NAFLD and T2DM

描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)是一种以肝脏脂肪渗透(脂肪变性)为特征的一系列疾病，有时还会出现炎症(脂肪性肝炎)的组织学证据，但没有过量饮酒的病史。NAFLD很常见，并与肥胖、胰岛素抵抗(IR)和2型糖尿病(T2 DM)密切相关，这三种疾病都有很强的遗传发病机制证据；然而，NAFLD的遗传流行病学尚未得到很好的描述。这项研究的中心假设是，对于任何给定的肥胖程度，NAFLD都是高度家族性的，基因变异不仅可以解释肝脏脂肪变性的风险和严重程度的差异，还可以解释个体之间患T2 DM的风险的差异。为了验证这一假设，我们提出了以下具体目标：(1)使用非对比电子束计算机断层扫描(ECT)在阿米什家族钙化研究(AFCS)的1000名参与者中表征NAFLD的分布；2)估计NAFLD的基因和测量的环境危险因素标记物的相对贡献；3)评估肥胖、IR、NAFLD、T2 DM之间的家族聚集性，并确定共同遗传因素对这些性状变异的共同影响程度(即多效性)；(4)在AFCS中进行NAFLD和T2 DM标记的全基因组连锁分析；(5)在AFCS中进行NAFLD和T2 DM标记的遗传关联分析，以及AFCS中连锁分析确定的染色体区域候选基因的单核苷酸多态性与糖尿病健康行动(展望未来)研究中的一组个体的单核苷酸多态性。这项拟议的研究建立在高博士对肥胖症和2型糖尿病遗传流行病学的关注基础上。她将得到具有医学、流行病学、统计学和分子遗传学专业知识的导师的帮助。作为职业发展奖的结果，获得的新方法和专业知识将为高博士提供必要的工具，以便在遗传流行病学研究领域开始完全独立的职业生涯。这一建议得到以下方面的加强：侧重于一种新的糖尿病相关内表型；用于连锁分析(AFCS)的高信息量家系的大样本；可用于关联分析的确诊的无关NAFLD病例(展望未来)、对多种心血管和环境风险因素的评估；最先进的肝脏成像；以及全面的遗传分析，包括全基因组和候选基因方法。深入了解肥胖、胰岛素抵抗、非酒精性脂肪肝和2型糖尿病的分子发病机制，可能为预防和治疗这些疾病提供新的方法。

DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is a spectrum of conditions marked by fatty infiltration of the liver (steatosis) and sometimes histologic evidence of inflammation (steatohepatitis) without a history of excessive alcohol ingestion. NAFLD is common and is strongly associated with obesity, insulin resistance (IR), and T2DM, three conditions with strong evidence for genetic pathogenesis; however, the genetic epidemiology of NAFLD is not well characterized. The central hypothesis of the proposed research is that NAFLD, for any given degree of adiposity, is highly familial and that genetic variations can explain not only difference in risk and severity of hepatic steatosis but also risk of T2DM between individuals. To test this hypothesis, we propose the following specific aims: (1) characterize the distribution of NAFLD using non-contrast electron beam computed tomography in a cohort of 1,000 participants of the Amish Family Calcification Study [AFCS]; 2) estimate the relative contributions of genes and measured environmental risk factors markers of NAFLD; 3) evaluate familial clustering among obesity, IR, NAFLD, T2DM and to determine the extent to which common genetic factors influence variation in these traits jointly (i.e. pleiotropy), (4) perform a genome-wide linkage analyses of markers of NAFLD and T2DM in the AFCS, (5) perform genetic association analyses of markers of NAFLD and T2DM and single nucleotide polymorphisms from candidate genes in chromosome regions identified by linkage analysis in AFCS and a subgroup of individuals from the Action for Health in Diabetes (Look AHEAD) Study. The proposed research builds on Dr. Kao's focus on the genetic epidemiology of obesity and T2DM. She will be assisted by mentors with expertise in medicine, epidemiology, statistics and molecular genetics. The new methods and expertise acquired as a result of this Career Development Award will equip Dr. Kao with the tools necessary to launch a fully independent career in genetic epidemiological research. This proposal is strengthened by: focus on a novel diabetes-related endophenotype; large sample of highly-informative families for linkage analyses (AFCS); availability of confirmed unrelated NAFLD cases for association analyses (Look AHEAD), assessment of a multitude of cardiovascular and environmental risk factors; state-of-the-art imaging of the liver; and comprehensive genetic analyses, including both genome-wide and candidate gene approaches. A deeper understanding of the molecular pathogenesis of obesity, IR, NAFLD, and T2DM may suggest new approaches for the prevention and treatment of these conditions.