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（DK 069028 -24，糖尿病和肥胖的遗传流行病学和DK 069094 -06，糖尿病并发症的遗传流行病学）;本研究的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。正在凤凰城城市2型糖尿病高危人群中进行纵向研究。收集样品用于基因组DNA的研究，并且这些样品也适用于表观遗传因素的研究，例如DNA甲基化和组蛋白修饰。收集适合于RNA提取和蛋白质水平和代谢组学的大规模研究的样品。收集关于家庭成员的资料，以便纳入以家庭为基础的分析。 最近对骨骼肌组织中全基因组转录的分析表明，少数转录物具有明显的双峰频率分布;其中绝大多数是由转录物编码区域附近的遗传多态性的影响引起的。使用来自密集基因型数据的血统估计的经验同一性的分析表明，基因表达中的大量遗传性是由于转录本编码区域内或附近的变体的作用。与德克萨斯大学里奥格兰德谷分校的研究人员合作，还在外周血样本中测量了大规模的全基因组转录谱。糖尿病并发症也正在研究中-最近我们发现周围神经病变的危险因素在糖尿病和非糖尿病个体中是不同的。最近不同祖先群体之间基因型和表型差异的比较表明，差异自然选择是没有必要解释糖尿病风险和肥胖的祖先群体之间的差异。对特定转录组模式的进一步分析正在进行中，以确定可能影响疾病风险和可能受到自然选择的特定途径。 目前正在分析外周血样本中的转录与糖尿病、肥胖症和相关因素的关系，评估遗传性和父母的影响。招募更多的个人和家庭以及纵向跟踪也在进行中。

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 transcript. Large scale genome-wide transcription profiles are also being measured in peripheral blood samples in collaboration with investigators from University of Texas-Rio Grande Valley. Diabetic complications are also being studied- recently we found that risk factors for peripheral neuropathy are different in diabetic and nondiabetic individuals. Recent comparisons of genotypic and phenotypic divergence among diverse ancestry groups suggest that differential natural selection is not necessary to explain differences in diabetes risk and obesity among ancestry groups. Further analyses of specific transcriptomic patterns is underway to identify specific pathways that may influence disease risk and that may be subject to natural selection. 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.