Phenotype-Genotype Interactions and Type 2 Diabetes

描述（由申请人提供）：2型糖尿病在世界范围内呈上升趋势。控制糖尿病需要了解其发病机制中涉及的基因和基因-环境相互作用。连锁分析是识别糖尿病等复杂疾病基因的关键初始策略，但许多研究仅提供了与2型糖尿病或相关特征的基因组联系的暗示证据。异质性2型糖尿病表型有助于适度的连锁信号。特别是，三种主要的表型糖尿病危险因素：父母糖尿病、后代肥胖和年龄相关性发病，都引入了异质性，削弱了基因与糖尿病表达的关联。弗雷明汉心脏研究（FHS）收集了来自一个相对同质群体的330个系谱中的1702个父母和后代的广泛的横断面和纵向表型数据和基因组微卫星标记分型。在这个R21申请中，我们建议对现有的FHS数据进行二次分析，作为一种经济有效的方法来检验关于糖尿病遗传学的假设，并指导下一步的位置克隆。我们将重点关注染色体Iq、lOq和1iq，在非分层分析中，它们与糖尿病特征有暗示的联系。我们将通过定义表型亚层来减少表型异质性，包括有和没有父亲和/或母亲糖尿病的家庭，相对瘦弱和相对肥胖的家庭，或相对年轻和相对年长的糖尿病家庭。糖尿病表型包括偶发糖尿病或与糖尿病相关的数量性状（血浆HbAic、葡萄糖和胰岛素水平）。分析将使用分层有序子集的方差成分（VC）模型，或将包括基因-分层相互作用的正式测试，或考虑印迹效应、可变发病年龄表型（在生存分析中）或时变性状（在VC纵向性状分析中）。我们的假设是，减少异质性的连锁分析将完善Iq， 10q， 1iq相关的证据，并将确定糖尿病基因更有可能分离的亚层。结果将为未来的实验室工作提供基础，并将增加对糖尿病发病机制中表型-基因型相互作用的理解。

DESCRIPTION (provided by applicant): Type 2 diabetes mellitus is increasing in epidemic proportions worldwide. Control of diabetes requires an understanding of the genes and gene-environment interactions involved in its pathogenesis. Linkage analysis is a key initial strategy to identify genes for complex disorders like diabetes, but many studies provide only suggestive evidence for genomic linkage to type 2 diabetes or related traits. The heterogeneous type 2 diabetes phenotype contributes to modest linkage signals. In particular, three major phenotypic diabetes risk factors: parental diabetes, offspring obesity, and older age-related onset, all introduce heterogeneity that weakens the association of genes with expression of diabetes. The Framingham Heart Study (FHS) has collected extensive cross-sectional and longitudinal phenotypic data and typed genomic micro satellite markers on 1702 parents and offspring within 330 pedigrees from a relatively homogeneous community. In this R21 application we propose secondary analyses of existing FHS data as a cost-effective means to test hypotheses about diabetes genetics and to guide next steps for positional cloning. We will focus on chromosomes Iq, lOq, and 1 Iq, where there is suggestive linkage to diabetes traits in unstratified analyses. We will reduce phenotypic heterogeneity by defining phenotypic sub-strata, including families with and without paternal and/or maternal diabetes, relatively lean vs. relatively obese families, or families with relatively younger vs. relatively older-onset diabetes. Diabetes phenotypes include incident diabetes or diabetes-related quantitative traits (plasma levels of HbAic, glucose and insulin). Analyses will use variance components (VC) models of ordered subsets of strata, or will include formal tests of gene-by-strata interaction, or account for imprinting effects, variable age-of-onset phenotypes (in survival analyses), or for time-varying traits (in VC longitudinal trait analyses). Our hypothesis is that linkage analyses that reduce heterogeneity will refine evidence for linkage on Iq, 10q, 1 Iq, and will identify sub-strata where diabetes genes are more likely to be segregating. Results will provide a foundation for future laboratory efforts and will increase understanding of phenotype-genotype interactions in diabetes pathogenesis.