Multimodal analysis stratifies genetic susceptibility and reveals the pathogenic mechanism of kidney injury in diabetic nephropathy
The genetic etiology of diabetic nephropathy (DN) is masked by inaccurate phenotyping and ethnic disparities. Here, we conduct a stepwise genome-wide association study (GWAS) in the Chinese Han population, using a precise phenotype of biopsy-proven DN as cases, patients with type 2 diabetes without microvascular complications as controls, and healthy individuals for comparison. Our analysis reveals that the genetic etiology of DN is primarily attributed to an inherent susceptibility to kidney injury. We identify 10 suggestive loci, 5 of which have a high probability of being causal, with 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 biopsy-proven DN and provides a mechanistic rationale for its pathogenesis.
Authors
- Weiping Jia (ORCID: https://orcid.org/0000-0002-6244-2168)
- Tianjun Guan (ORCID: https://orcid.org/0000-0001-9425-1641)
- Chengyu Hu (ORCID: https://orcid.org/0000-0001-8226-5747)
- Qing Hou (ORCID: https://orcid.org/0000-0001-9372-0354)
- Dandan Yan (ORCID: https://orcid.org/0000-0001-9799-3325)
- Guisen Li (ORCID: https://orcid.org/0000-0003-1970-9979)
- Song Jiang (ORCID: https://orcid.org/0000-0002-7656-9434)
- R. Zhang (ORCID: https://orcid.org/0009-0006-1641-5026)
- Jingyuan Xie (ORCID: https://orcid.org/0000-0002-5508-0664)
- Md. Asif Ahsan (ORCID: https://orcid.org/0000-0002-0043-6184)
- Zhaohui Ni (ORCID: https://orcid.org/0000-0002-1334-7658)
- Chuan‐Ming Hao (ORCID: https://orcid.org/0000-0002-4307-0987)
- Niansong Wang (ORCID: https://orcid.org/0000-0002-5265-5792)
- Jianxin Wan (ORCID: https://orcid.org/0000-0002-6733-0472)
- Jingsong Shi (ORCID: https://orcid.org/0000-0001-7250-8813)
- Hong Cheng (ORCID: https://orcid.org/0000-0002-7908-3333)
- Zhi-hong Liu (ORCID: https://orcid.org/0000-0002-2857-5231)
- Jing Li (ORCID: https://orcid.org/0000-0001-9392-6600)
- Hongli Chen (ORCID: https://orcid.org/0000-0002-9002-2603)
- Pengfei Zheng (ORCID: https://orcid.org/0009-0008-3433-2878)
- Ning Shen (ORCID: https://orcid.org/0000-0001-8686-5459)
- Zhangsuo Liu (ORCID: https://orcid.org/0000-0002-8120-9767)
- Hanying Jia (ORCID: https://orcid.org/0009-0005-0260-8305)
Institutions
- Fujian Medical University (CN)
- Army Medical University (CN)
- Shanghai Jiao Tong University (CN)
- Capital Medical University (CN)
- Fudan University (CN)
- Renji Hospital (CN)
- Ruijin Hospital (CN)
- Xinqiao Hospital (CN)
- Beijing Anzhen Hospital (CN)
- First Affiliated Hospital of Fujian Medical University (CN)
- Zhongshan Hospital of Xiamen University (CN)
- Shanghai Sixth People's Hospital (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- Huashan Hospital (CN)
- Zhejiang University (CN)
- Nanjing University (CN)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-07-24
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102249
- Citations
- 6
- Primary Topic
- Chronic Kidney Disease and Diabetes
- Type
- article
- Field-Weighted Citation Impact
- 8.58