GDF-15 as a Therapeutic Target of Diabetic Complications Increases the Risk of Gallstone Disease: Mendelian Randomization and Polygenic Risk Score Analysis

Abstract

Growth differentiation factor 15 (GDF-15) levels have been revealed as a robust biomarker for metformin use. We conducted Mendelian randomization (MR) analysis to explore the association between GDF-15 and gallstone disease to inform potential therapeutic effects targeting GDF-15. Four genetic variants associated with GDF-15 levels at p < 5 × 10–8 were selected as instrumental variables from a genome-wide association meta-analysis including 21,758 individuals. Two-sample MR analysis was conducted using summary-level data from UK Biobank (10,520 gallstone cases and 350,674 controls) and FinnGen consortium (19,023 gallstone cases and 195,144 controls). Polygenic risk score analysis using individual-level data in UK biobank was performed to complement the MR findings by examining the non-linearity of the association. Diabetic complications were taken as positive controls to validate the therapeutic effect of targeting GDF-15. Linear and nonlinear associations between genetically predicted GDF-15 levels and gallstones were estimated with stratification by the diabetic status. In the two-sample MR analysis, the odds ratio (OR) of gallstones was 1.09 (95% confidence interval (CI), 1.03–1.15; p = 0.001) for one standard deviation increase in genetically predicted GDF-15 levels in the meta-analysis of two datasets. Polygenic risk score analysis found this association to be U-shaped (p = 0.037). The observed association was predominantly seen in nondiabetic population (OR = 1.11, 95% CI: 1.01–1.21; p = 0.003). An inverse association between genetically predicted GDF-15 levels and diabetic complications (OR = 0.77, 95% CI: 0.62–0.96; p = 0.023) was observed, validating the potential therapeutic effects of targeting GDF-15 levels. This MR study indicates that the increased risk of gallstone disease should be taken into account when considering GDF-15 as a therapeutic target for diabetic complications.

Genetic effect of metformin use on risk of cancers: Evidence from Mendelian randomization analysis

“…Zhang et al reported the protective causal relationship between metformin targets and osteoarthritis, pointing out AMPK and GDF-15 as promising targets for osteoarthritis treatment [29]. Additionally, GDF-15 as a therapeutic target of metformin might increase the risk of gallstone disorders [30]. However, metformin has multiple drug targets which could not be simpli ed into one or two certain targets, limiting the accuracy of drug target MR analysis for explaining its therapeutic effect.…”

Interplay between Senescence and Macrophages in Diabetic Cardiomyopathy: A Review of the Potential Role of GDF-15 and Klotho

“…renal tubular cells induced by GDF-15 suggest additional DCM-specific protective mechanisms [88]. In a recent study by Donate-Correa et al, in adults with T2DM and preserved kidney function, reduced Klotho levels were observed.…”

“…In a mouse model of T2DM, Klotho overexpression alleviated insulin sensitivity and metabolic disruption, ultimately attenuating DCM [87]. Furthermore, increased Klotho protein expression and function in renal tubular cells induced by GDF-15 suggest additional DCM-specific protective mecha-nisms [88]. In a recent study by Donate-Correa et al, in adults with T2DM and preserved kidney function, reduced Klotho levels were observed.…”

“…GDF-15, a member of the TGF-β family, acts as a stress-responsive cytokine and is expressed by macrophages, epithelial cells, and adipocytes. It exerts anti-inflammatory effects by inhibiting macrophage activation, enhancing insulin sensitivity, and preventing diabetic complications [88]. Under normal conditions, human serum GDF-15 levels are low but are significantly elevated in various diseases, including malignancies, CVDs, renal disorders, and diabetes [92].…”