Association of kidney structure-related gene variants with type 2 diabetes-attributed end-stage kidney disease in African Americans

Abstract

African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD) compared to European Americans. Genome-wide association studies have identified variants associated with diabetic and non-diabetic kidney diseases. Nephropathy loci, including SLC7A9, UMOD, and SHROOM3, have been implicated in the maintenance of normal glomerular and renal tubular structure and function. Herein, 47 genes important in podocyte, glomerular basement membrane, mesangial cell, mesangial matrix, renal tubular cell, and renal interstitium structure were examined for association with type 2 diabetes (T2D)-attributed ESKD in AAs. Single-variant association analysis was performed in the discovery stage, including 2041 T2D-ESKD cases and 1140 controls (non-diabetic, non-nephropathy). Discrimination analyses in 667 T2D cases-lacking nephropathy excluded T2D–associated SNPs. Nominal associations were tested in an additional 483 T2D-ESKD cases and 554 controls in the replication stage. Meta-analysis of 4218 discovery and replication samples revealed three significant associations with T2D-ESKD at CD2AP and MMP2 (Pcorr < 0.05 corrected for effective number of SNPs in each locus). Removal of APOL1 renal-risk genotype carriers revealed additional association at five loci, TTC21B, COL4A3, NPHP3-ACAD11, CLDN8, and ARHGAP24 (Pcorr < 0.05). Genetic variants at COL4A3, CLDN8, and ARHGAP24 were potentially pathogenic. Gene-based associations revealed suggestive significant aggregate effects of coding variants at four genes. Our findings suggest that genetic variation in kidney structure-related genes may contribute to T2D–attributed ESKD in the AA population.

Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen

“…The rs55703767 SNP is predicted to alter the third amino acid of the canonical triple-helical domain sequence of Glycine (G)-X-Y (where X and Y are often proline (P) and hydroxyproline (Y), respectively) from G-E-D (D=Aspartic) to G-E-Y 63 , potentially impacting the structure of the collagen complex. In addition, a recent study 64 of candidate genes involved in renal structure reported rs34505188 in COL4A3 (not in linkage disequilibrium with rs55703767, r 2 =0.0006) to be associated with ESRD in African Americans with T2D (MAF=2%, OR=1.55, P=5×10 -4 ). Together with the trend towards association we have seen in SUMMIT and the glycemic interaction we have reported here, these findings suggest variation in COL4A3 may be associated with DKD in T2D as well.…”

COL4A3 Gene Variants and Diabetic Kidney Disease in MODY

“…Therefore, misfolded proteins will be secreted to the GBM or accumulated in podocytes, disturbing the glomerular permselective barrier properties and activating downstream pathologic pathways (29,30). Recently, a genome-wide association study revealed that a rare variant in African populations, R408H (rs34505188), was associated with type 2 diabetes and -ESKD (31). The frequency of R408H is higher (0.1899) in Han Chinese, on the basis of the 1000 Chinese Genomes data, compared with European (0.069) and African populations (0.028) on the basis of 1000 Genomes Project data.…”

Current State and Future Trends to Optimize the Care of African Americans with End-Stage Renal Disease

“…Furthermore, chemicals, drugs, and environmental pollutants can both initiate kidney disease and promote CKD progression [9]. Additionally, gene-gene and gene-environment interactions in AAs contribute to the increased risk of non-diabetic and hypertension-related ESRD [10–12]. This review discusses the factors that contribute to the disparities in care of AAs with ESRD and provides recommendations to reduce these disparities.…”