Molecular Profiling of Diabetes and its Complications

在目前的项目中，正在使用经典流行病学和遗传流行病学的技术来确定2型糖尿病的决定因素、其危险因素及其并发症。遗传因素的影响在其他项目中进行了评估(DK069028-24，糖尿病和肥胖的遗传流行病学和DK069094-06，糖尿病并发症的遗传流行病学)；目前的研究重点是遗传因素下游的分子过程，如基因转录、蛋白质表达和细胞代谢。在凤凰城，正在对2型糖尿病的高危人群进行纵向研究。收集的样本用于基因组DNA的研究，这些样本也适用于表观遗传因素的研究，如DNA甲基化和组蛋白修饰。收集适合于RNA提取以及蛋白质水平和代谢组学大规模研究的样本。收集关于家庭成员的信息，以便纳入基于家庭的分析。 最近对骨骼肌组织全基因组转录的分析表明，少数转录本具有明显的双峰频率分布；其中绝大多数是由于转录本编码区域附近的遗传多态的影响。从密集的基因类型数据中使用经验性同一性下降估计进行的分析表明，基因表达中的大量遗传性是由于编码转座子的区域内或附近的变异体的作用。与德克萨斯生物医学研究所的研究人员合作，还在外周血液样本中测量了大规模基因组范围的转录图谱。初步分析显示，大量转录本与年龄、性别和炎症标志物(C-反应蛋白)有关，这些数据正在与其他队列中的数据进行协作性荟萃分析比较。此外，还对与血小板计数相关的遗传多态与全血转录的关系进行了分析。对全血转录本的研究表明，SLC16A11中已建立的2型糖尿病变异体的作用是通过附近RNASEK的表达来调节的。 目前正在分析外周血样本转录与糖尿病、肥胖症和相关因素的关系，以及遗传力和父母来源影响的评估。招募更多的个人和家庭以及纵向后续行动也在进行中。

In the current project, the techniques of classic epidemiology and of genetic epidemiology are being used to identify determinants of type 2 diabetes, its risk factors and its complications. The effects of genetic factors are assessed in other projects (DK069028-24, Genetic Epidemiology of Diabetes and Obesity and DK069094-06, Genetic Epidemiology of Diabetic Complications); the present study focuses on molecular processes that are downstream of genetic factors, such as gene transcription, protein expression and cellular metabolism. Longitudinal studies are being conducted in individuals at high risk for type 2 diabetes in urban Phoenix. Samples are collected for studies of genomic DNA, and these samples are also suitable for studies of epigenetic factors, such as DNA methylation and histone modification. Samples are collected that suitable for RNA extraction and for large scale studies of protein levels and metabolomics. Information on family membership is collected for inclusion in family-based analyses. Recent analyses of genome-wide transcription in skeletal muscle tissue have shown that a small number of transcripts have a clearly bimodal frequency distribution; the vast majority of these are accounted for by the effect of a genetic polymorphism in close proximity the region encoding for the transcript. Analyses using empirical identity by descent estimates from dense genotypic data suggest that a large amount of the heritability in gene expression is due to the action of variants within or near the region coding for the transcipt. Large scale genome-wide transcription profiles are also being measured in peripheral blood samples in collaboration with investigators from Texas Biomedical Research Institute. Initial analyses have shown a large number of transcripts associated with age, sex and markers of inflammation (C-reactive protein), and these data are being compared with those from other cohorts in a collaborative meta-analysis. Additional analyses of the relationship of genetic polymorphisms associated with platelet count with whole blood transcription have been performed. Studies of whole blood transcripts suggest that the effect of an established type 2 diabetes variant in SLC16A11 is mediated by expression of the nearby RNASEK. Analyses of the relationship of transcription in peripheral blood samples with diabetes, obesity and related factors are currently in process, as is the assessment of heritability and parent-of-origin effects. Recruitment of additional individuals and families and longitudinal follow-up are also ongoing.