Speakers - DEWC2025

Abstract

The genetic etiology of diabetic nephropathy (DN) is masked by inaccurate phenotyping and ethnic disparity. Here, using a precise phenotype of biopsy-proven DN as cases, type 2 diabetes without microvascular complications and healthy individuals as controls, we conduct a stepwise genome-wide association study (GWAS) in the Chinese Han population. We dissect genetic etiology of DN is primarily attributed to an inherent susceptibility to kidney injury, and identify 10 suggestive loci, 5 of which with a high probability of being causal, featuring a missense variant in TCN2 (p.K77M) as the top candidate. Subsequent multidimensional analyses reveal that genetic variants associated with tubulointerstitial injury are key contributors to the DN predisposition. Furthermore, in vitro and in vivo experiments confirm that TCN2 p.K77M induces mitochondrial dysfunction, exacerbating renal tubular cell damage under high-glucose conditions. Our study elucidates the genetic architecture of renal biopsy-proven DN and provides rationale for novel molecular mechanism for DN.