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

Figures

• 

  Fig. 1. Study design and overview. This study included three major sections. First, instruments proxying GLP-1R expression were selected using pancreas-specific eQTLs from Genotype-Tissue Expression v8. As a positive control analysis, we validated our genetic variants by estimating its associations with T2DM and BMI. Then the casual estimates of GLP-1R expressionon CKD, CVD and MASLD outcomes were calculated. MR-Robust was applied as the primary method in the MR analysis with other five methods (MR-RAPS, dIVW, PC-GMM, weighted median and IVW) as validation methods. Second, to determine whether the causal effects are independent of metabolic benefit, MVMR adjusting for HbA1c and BMI was performed. PGS analyses were performed to test the association of polygenic score of GLP-1R on CKM outcomes in non-diabetic and non-obese populations of UK Biobank. Observational analysis of plasma protein levels of GLP1R on CKM outcomes in non-diabetic and non-obese individuals were conducted in UK Biobank to validate the PGS analysis findings. Lastly, a new GWAS was conducted for MASLD using upadated definition to expand the genetic landscape of MASLD. Abbreviations: GLP-1R, Glucagon-like peptide-1…

• 

  Fig. 2. Casual effect of pancreas-specific GLP-1R expression on CKM-related outcomes. (a) Forest plot (left) and heatmap (right) showing the causal estimates for binary disease outcomes, expressed as Odds Ratios (OR) with 95% confidence intervals (CI). (b) Forest plot (left) and heatmap (right) showing the causal estimates for continuous outcomes, expressed as Beta coefficients with 95% CI. In the forest plots, the MR-Robust method results are presented; dots represent point estimates and error bars represent 95% CIs. Red dots indicate a positive association, while blue dots indicate a negative association. The heatmaps display the results across other five analysis methods (MR-RAPS, dIVW, PC-GMM, Weighted median, and IVW). The color reflects the direction of the OR or Beta (red for positive, blue for negative). An asterisk indicates p < 0.05. Abbreviations: CKD, chronic kidney disease; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; CAD, coronary artery disease; MASLD, metabolic dysfunction-associated steatotic liver disease; eGFR, estimated glomerular filtration rate; BUN, blood urea nitrogen; UACR, urine…

• 

  Fig. 3. Associations of polygenic score of GLP-1R and plasma protein levels of GLP-1R with CKM-related diseases.(a) Associations of polygenic risk scores of GLP-1R with CKD, HF, CAD and MASLD in UK Biobank Europeans. (b) Associations of GLP-1R protein levels with CKD, HF, CAD and MASLD in UKB-PPP Europeans. Hazard ratios (HRs) were calculated across tertiles (T1–T3) of the respective PGS and protein levels within the general population, as well as in non-diabetic and non-obese subgroups. The color of the circles represents the HR, with blue indicating a reduced risk (HR < 1.0) and red indicating an increased risk (HR > 1.0) relative to the reference group (T1). Fully adjusted models were presented for both analyses. Abbreviations: UKB-PPP, UK Biobank Pharma Proteomics Project; CKD, chronic kidney disease; HF, heart failure; CAD, coronary artery disease; MASLD, metabolic dysfunction-associated steatotic liver disease; PGS, polygenic score