Whole-Exome Sequencing Study of Diabetic Nephropathy

To identify rare variants of diabetic kidney disease (DKD), we conducted a whole-exome sequencing (WES) study. This study employed an extreme case–control design, which included a selection of the 593 most rapidly progressing DKD cases from the Chronic Renal Insufficiency Cohort (CRIC) Study (phs000524). In this two-stage WES study of DKD, participants with DKD from the CRIC were compared with control groups of participants without DKD from another cohort in the first stage. Suggestive signals identified in the first stage were confirmed in the second stage analysis among a diverse population with existing whole-genome sequencing (WGS) data. Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test implemented within our mixed model framework. As a result, we identified four novel gene loci, DIS3L2, KRT6B, ERAP2 and NPEPPS, that achieved exome-wide significance and may play an important role in the DKD disease course. This large WES study provides novel insights into DKD's molecular mechanisms.]]>
Linking CRIC Study SUBJECT ID in dbGaP with other data sourcesTo identify variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts for chronic kidney disease and diabetes. This WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies. DNA samples were prepared and sequenced by Illumina HiSeq platforms in pair-end mode. This study employed an extreme case-control design, which included the selection of the 593 most rapidly progressing DKD cases from the CRIC study. Cases were compared with three sets of controls selected from the ARIC study, including 2066 healthy controls in our primary analysis, as well as 652 diabetes controls and 1061 diabetes-free CKD controls in secondary analyses.To identify variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts for chronic kidney disease and diabetes. This WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies. DNA samples were prepared and sequenced by Illumina HiSeq platforms in pair-end mode. This study employed an extreme case-control design, which included the selection of the 593 most rapidly progressing DKD cases from the CRIC study. Cases were compared with three sets of controls selected from the ARIC study, including 2066 healthy controls in our primary analysis, as well as 652 diabetes controls and 1061 diabetes-free CKD controls in secondary analyses. To identify variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts for chronic kidney disease and diabetes. This WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies. DNA samples were prepared and sequenced by Illumina HiSeq platforms in pair-end mode. This study employed an extreme case-control design, which included the selection of the 593 most rapidly progressing DKD cases from the CRIC study. Cases were compared with three sets of controls selected from the ARIC study, including 2066 healthy controls in our primary analysis, as well as 652 diabetes controls and 1061 diabetes-free CKD controls in secondary analyses.This study selected 593 DKD cases with the most rapidly progressing from the CRIC study (phs000524). DKD was defined as: (1) a history of diabetes at baseline, (2) 24-h urinary albumin excretion ≥30 mg/day, and (3) eGFR < 60 mL/min/1.73m2 . Among CRIC participants with DKD, we selected 297 African ancestry and 296 European ancestry participants with the most rapid decline in kidney function based on eGFR measured annually in up to 12 years of follow-up.]]>