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Diabetic kidney disease, also known as diabetic nephropathy (DN), is a complex, heterogeneous complication of diabetes. Genetic factors are known to contribute to DN susceptibility; however, despite intense effort, the identification of variants that underlie its risk has been challenging. As such, novel approaches are needed to advance our understanding of the heritable factors associated with DN. Despite this bottleneck, longitudinal studies conducted over the past 20 years have improved our understanding of the course of deteriorating renal function in diabetic patients with kidney disease, establishing progressive renal decline as the predominant clinical feature of DN. Here, we propose a novel study to examine the role of epigenetics in rapid renal decline in type 1 diabetes (T1D) participants of the Joslin Kidney Study (JKS). Specifically, we hypothesize that integrative analysis of co-measured DNAme (methylome), gene expression (transcriptome), and genetic variation (genome) taken during follow-up of JKS participants will aid in identifying DNAme changes that persist during renal function decline and the associated genes that drive progressive renal decline in DN. The goals of this Pilot and Feasibility project are i) to perform DNAme profiling in a subset of JKS participants in our preliminary studies, ii) to perform RNA-sequencing in co-ascertained whole-blood RNA specimens from these participants, and iii) to integrate these data with genetic data to identify ‘omics’ signatures of rapid renal decline. To accomplish these goals, we will i) establish persistent DNAme profiles and gene expression profiles in well-phenotyped participants of the JKS (Specific Aim 1) and ii) identify persistent DNAme signatures, methylation quantitative trait loci (mQTLs), and expression QTLs (eQTLs) associated with rapid renal decline (Specific Aim 2). We will perform DNAme profiling in follow-up whole-blood DNA specimens from 25 slow decliners and 25 rapid decliners with T1D from the JKS and conduct high-depth RNA-sequencing (RNA-Seq) on co-ascertained whole-blood RNA specimens from these 25 slow decliners and 25 rapid decliners from the JKS. We will then examine associations between persistent DNAme and gene expression in rapid renal function decline and map genetic regulators of DNAme (mQTLs) and gene expression (eQTLs) that are associated with rapid renal decline. Importantly, our proposed research is poised to generate critical new knowledge on the role of DNAme in the progression of renal decline in T1D. Our approach is highly innovative, leveraging a unique, well-characterized collection of patients and an integrative ‘omics’ approach, and involves a multidisciplinary team of investigators with expertise in all aspects of the proposed research. Our implementation of the proposed studies will define currently unknown factors in DN and serve as a springboard for future studies aimed at establishing the biological and mechanistic significance of the identified DNAme sites. Together, these efforts may lay the foundation for novel therapeutic strategies to prevent progression of renal decline in T1D.
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