Genetic Epidemiology of Diabetic Complications

在目前的项目中，正在利用遗传连锁和关联分析技术寻找糖尿病肾病及其相关特征的遗传决定因素。从有信息的家系中已经建立了淋巴母细胞系。从流行病学研究中获得的血液样本中提取的核小球中，可以从其他家庭获得DNA。使用遗传连锁和关联方法的作图研究正在被用来确定包含变异的基因组区域，这些变异赋予糖尿病肾病和相关特征的易感性。通过与多中心肾病家族调查(FIND)联盟的合作，糖尿病肾病和糖尿病视网膜病变的遗传学也在研究中。FIND最初是作为全基因组连锁研究发起的，目前正在使用全基因组关联策略来确定感兴趣的区域。 FIND联盟的一部分还进行了一项使用1,000,000个单核苷酸多态的糖尿病肾病全基因组关联研究。初步分析显示，有几个地区可能存在肾病易感基因。对其他样本的复制研究发现了CNKSR3和SCAF8之间的一个变异，该变异与全基因组统计意义上的肾病有关，并跨越了多个种族。最近的研究发现，在拉美裔人群中被发现与肾功能测量相关的低频变异在美洲原住民中有类似的频率，但不会复制与肾功能相关。其他后续分析目前正在进行中。 目前的工作重点是在从FIND联盟收集的全部样本中分析全基因组关联；在美洲印第安人研究中正在进行进一步的全基因组关联研究。与合作者一起，在美国印第安人中与肾病和总胆固醇相关联的候选区域正在生成密集的连锁不平衡图。我们发现，在东亚人中观察到的一些外周血DNA甲基化特征也可以预测美洲印第安人；对DNA甲基化特征的进一步分析和对此的复制研究正在进行中。继续招募更多的土著家庭，为糖尿病肾病的相关性研究提供信息。与合作者一起，密克罗尼西亚已经招募了更多对糖尿病肾病遗传学研究有信息的家庭，并正在进行全基因组关联研究的基因分型。计划对更多的个体进行基因分型以进行复制。

In the current project, genetic determinants of diabetic nephropathy and related traits are being sought using techniques of genetic linkage and association analysis. Lymphoblast cell lines have been established from informative pedigrees. DNA is available from other families in nuclear pellets extracted from blood specimens obtained in the epidemiologic studies. Mapping studies, using both genetic linkage and association methods, are being used to identify genomic regions containing variants that confer susceptibility to diabetic kidney disease and related traits. Through collaboration with the multicenter Family Investigation of Nephropathy (FIND) consortium, the genetics of diabetic nephropathy and of diabetic retinopathy are also being studied. FIND was initiated as a genome-wide linkage study and is currently using a genome-wide association strategy to identify regions of interest. A genome-wide association study for diabetic nephropathy using 1,000,000 single nucleotide polymorphisms has also been conducted part of the FIND consortium. Initial analyses showed several regions that potentially harbor nephropathy-susceptibility loci. Replication studies in additional samples identified a variant between CNKSR3 and SCAF8 that was associated with nephropathy at genome-wide statistical significance, and across multiple ethnic groups. Recent studies have found that low-frequency variants identified as associated with renal function measures in Hispanic populations had similar frequencies in Indigenous Americans but did not replicate as associated with kidney function. Additional follow-up analyses are currently underway. Current efforts are focused on analysis of genome-wide association in the full collection of samples from the FIND consortium; further genome-wide association studies are being conducted in American Indian studies. With collaborators, dense linkage disequilibrium maps are being generated in candidate regions for linkage with nephropathy and total cholesterol in American Indian. We found that some DNA methylation profiles from peripheral blood observed in East Asians are also predictive in American Indians; further analyses of DNA methylation profiles and replication studies of this are being pursued. Additional Indigenous families informative for association studies of diabetic nephropathy continue to be recruited. In conjunction with collaborators, additional families informative for study of genetics of diabetic nephropathy have been recruited in Micronesia, and genotyping is underway for a genome-wide association study. Genotyping of additional individuals is planned for replication.