| Title: | Integrative proteogenomic analyses implicate KLK13 as a glycaemia-linked circulating protein in diabetic kidney disease |
| Journal: | Diabetes Research and Clinical Practice |
| Published: | 19 May 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42155607/ |
| DOI: | https://doi.org/10.1016/j.diabres.2026.113329 |
Publication 19994
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Abstract
BACKGROUND: Diabetic kidney disease (DKD) is a major complication of diabetes, but circulating proteins linking glycaemic stress to kidney injury remain unclear. We aimed to identify glycaemia-linked plasma proteins associated with DKD risk and assess their treatment responsiveness.</p>
METHODS: We integrated Mendelian randomization, cis-protein quantitative trait locus-based summary-data-based Mendelian randomization (cis-pQTL-based SMR), deCODE protein genome-wide association study (GWAS) validation, prospective UK Biobank analysis, and semaglutide-associated proteomic assessment. We screened 2,923 plasma proteins for hemoglobin A1c (HbA1c)-driven effects, and evaluated incident DKD.</p>
RESULTS: Fifty proteins were associated with genetically predicted HbA1c, and 10 were supported by independent HbA1c datasets. Cis-pQTL-based SMR analyses prioritized ITGBL1 and KLK13. In deCODE validation, KLK13 was the only candidate supported across both glycaemic trait-to-protein and protein-to-DKD analyses (OR 1.13, 95% CI 1.02-1.24). Among 9,936 UK Biobank participants without baseline DKD, 107 developed incident DKD. Higher KLK13 was associated with incident DKD (HR 1.52, 95% CI 1.13-2.06), whereas serine peptidase inhibitor Kazal type 6 (SPINK6) showed stronger association (HR 2.02, 95% CI 1.49-2.74). KLK13 decreased with semaglutide, but attenuated after weight and HbA1c adjustment.</p>
CONCLUSIONS: KLK13 was prioritized as a glycaemia-linked circulating protein associated with DKD, implicating protease-inhibitor biology in DKD progression.</p>
5 Authors
- Duanke Liu
- Xinjie Lin
- Junqing Xie
- Li Chen
- Ningli Wang
1 Application
| Application ID | Title |
|---|---|
| 988975 | Multi-omics Dissection of Diabetic Retinopathy: Integrating Genomics, Proteomics, and Metabolomics in UK Biobank |
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