| Title: | The association between GLP-1R expression and cardiovascular-kidney-metabolic-related diseases in non-diabetic and non-obese population: evidence triangulation using Mendelian randomization, observational and polygenic score association analysis |
| Journal: | BMC Medicine |
| Published: | 26 May 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42192387/ |
| DOI: | https://doi.org/10.1186/s12916-026-04888-8 |
Publication 19910
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Abstract
BackgroundGlucagon-like peptide-1 receptor (GLP-1R) agonists are emerging as promising therapies for cardiovascular-kidney-metabolic (CKM) related diseases in individuals with type 2 diabetes mellitus (T2DM) or obesity. But their effects in non-obese and non-diabetic individuals are unclear. This study triangulates evidence using Mendelian randomization (MR), polygenic scores (PGS) and observational analyses to estimate the associations of GLP-1R expression with chronic kidney disease (CKD), heart failure (HF) and metabolic dysfunction-associated steatotic liver disease (MASLD).MethodsFor the MR analysis, instruments mimicking GLP-1R expression were identified using pancreas-specific cis-expression quantitative trait loci from GTEx (N ≤ 305). MR-Robust method was used as the primary MR approach. PGS and observational analyses were performed both in non-diabetic and non-obese individuals separately. A genome-wide association study (GWAS) for MASLD (14,231 cases and 348,091 controls) was performed in the general population using data from UK Biobank.ResultsGLP-1R expression showed robust effects on CKD (odds ratio [OR] 0.96, 95%CI 0.95 to 0.97, q = 1.7 × 10− 10 ), HF (OR = 0.96, 95%CI 0.94 to 0.97, q = 2.5 × 10− 8) and MASLD (OR = 0.96, 95%CI 0.93 to 0.98, q = 1.3 × 10− 3) in the general population. Consistent results were observed in validation analyses. Furthermore, PGS and observational analyses among non-T2DM and non-obese individuals found little evidence to support its association with CKD, HF or MASLD. GWAS analysis identified eight conditionally independent variants associated with MASLD, in which rs563199662 was a new signal located at TFPI region.ConclusionsThis study provides multilayered evidence for GLP-1R expression in mitigating CKD, HF and MASLD risks in the general population, while de-prioritized its effect on CKM-related diseases in non-obese and non-diabetic individuals. Further clinical trials are needed to validate the effects of GLP-1R agonists in relative health population.</p>
23 Authors
- Zhihe Chen
- Qian Yang
- Jiajia Liu
- Huiling Zhao
- Hui Ying
- Haoyu Liu
- Lanhui Huang
- Hong Lin
- Shuangyuan Wang
- Mian Li
- Yangbo Sun
- Tiange Wang
- Zhiyun Zhao
- Min Xu
- Yuhong Chen
- Yu Xu
- Jieli Lu
- Guang Ning
- Yanyun Gu
- Weiqing Wang
- Jing Li
- Yufang Bi
- Jie Zheng
1 Application
| Application ID | Title |
|---|---|
| 104086 | Omics Harbour: a multi-ancestry causal atlas of plasma proteome on human phoneme |
Enabling scientific discoveries that improve human health