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

May 27, 2026BMC medicine

Links between GLP-1 receptor levels and heart, kidney, and metabolism diseases in people without diabetes or obesity using genetic and observational data

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Abstract

GLP-1R expression is associated with a 0.96 odds ratio for chronic kidney disease, heart failure, and metabolic dysfunction-associated liver disease in the general population.

Higher GLP-1R expression correlates with reduced odds of chronic kidney disease, heart failure, and metabolic dysfunction-associated liver disease.
No significant association was found between GLP-1R expression and these conditions in non-diabetic and non-obese individuals.
Eight independent genetic variants linked to metabolic dysfunction-associated liver disease were identified, including a new signal at the TFPI region.
Mendelian randomization and polygenic scores were used to triangulate these associations, supporting the findings from observational analyses.

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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), HF (OR = 0.96, 95%CI 0.94 to 0.97, q = 2.5 × 10) and MASLD (OR = 0.96, 95%CI 0.93 to 0.98, q = 1.3 × 10) 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. - 10 - 8 - 3

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.

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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

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