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Background <p>Glucagon-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).</p> Methods <p>For the MR analysis, instruments mimicking GLP-1R expression were identified using pancreas-specific cis-expression quantitative trait loci from GTEx (<i>N</i> ≤ 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.</p> Results <p>GLP-1R expression showed robust effects on CKD (odds ratio [OR] 0.96, 95%CI 0.95 to 0.97, q = 1.7 × 10<sup>− 10</sup> ), HF (OR = 0.96, 95%CI 0.94 to 0.97, q = 2.5 × 10<sup>− 8</sup>) and MASLD (OR = 0.96, 95%CI 0.93 to 0.98, q = 1.3 × 10<sup>− 3</sup>) 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 <i>TFPI</i> region.</p> Conclusions <p>This 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>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • 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

摘要

Background

Glucagon-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).

Methods

For 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.

Results

GLP-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.

Conclusions

This 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.