Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND)

Abstract

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

APOL1 renal-risk genotypes associate with longer hemodialysis survival in prevalent nondiabetic African American patients with end-stage renal disease

“…31 This demonstrates that APOL1 genotypes provide improved discriminatory capability for dialytic survival in this population. The presence of diabetes clearly alters genetic susceptibility to development of ESRD; APOL1 is not associated with classic diabetic kidney disease 32;33 and the survival outcome in patients with diabetes and ESRD was different from those in non-diabetic cases. How hyperglycemia impacts APOL1 genetic risk and why the previously reported lower level of CP in African Americans with diabetes lacking advanced nephropathy differs from the results in this study of prevalent dialysis patients requires further study.…”

APOL1 variants change C-terminal conformational dynamics and binding to SNARE protein VAMP8

“…In this study, we further characterized APOL1 localization and distribution in podocytes to determine if these phenotypes were dependent upon kidney disease diagnosis or APOL1 genotype. First, we compared APOL1 distribution in biopsies of diabetic kidney disease, which is not associated with APOL1 risk variants (5,6), to its distribution in biopsies of APOL1-associated kidney diseases (i.e., hypertension-associated, disease, FSGS and HIVAN) by quantifying APOL1 proximity to the podocyte plasma membrane protein GLEPP1 (Supplemental Table 1 and Supplemental Figure 1, A-J; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.92581DS1). In healthy kidney, APOL1 and GLEPP1 were almost always associated, but APOL1 staining was lost in GLEPP1-positive podocytes in kidney biopsy samples from individuals with kidney disease.…”

“…A landmark discovery associated genetic variation in the APOL1 gene with excess prevalence of advanced, nondiabetic CKD in African Americans (2,3). Although data showed higher rates of CKD progression in African Americans, regardless of diabetes status (4), the kidney disease-risk variants failed to associate with diabetic kidney disease (5,6). CKD subjects with APOL1 risk genotypes benefit less from optimal treatments (4,7,8).…”

Związek polimorfizmu rs 3807337 genu CALD1 z nefropatią cukrzycową w przebiegu cukrzycy typu 1 — wstępne wyniki badania rodzin

“…Peak incidence of diabetic nephropathy appears after 15-20 years of disease duration and declines afterwards, meaning that the cumulative incidence of diabetic nephropathy is not more that 30%. It is therefore obvious that is it not only hyperglycaemia itself that leads patients to end-stage renal disease but also some patients are predisposed to nephropathy development despite glycaemic control [7] DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND).…”