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

Lili Yu; Yajing Zhou; Lijuan Wang; Xuan Zhou; Jing Sun; Jiarui Xiao; Xiaolin Xu; Susanna C Larsson; Shuai Yuan; Xue Li

doi:10.3389/fgene.2022.814457

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

Front Genet. 2022 Jun 13:13:814457. doi: 10.3389/fgene.2022.814457. eCollection 2022.

Authors

Lili Yu¹, Yajing Zhou¹, Lijuan Wang¹, Xuan Zhou¹, Jing Sun¹, Jiarui Xiao¹, Xiaolin Xu¹, Susanna C Larsson^{2

3}, Shuai Yuan^{1

2}, Xue Li^{1

4}

Affiliations

¹ Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
³ Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
⁴ Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.

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.

Keywords: Mendelian randomization; diabetic complication; gallstones; growth differentiation factor 15; metformin.

Abstract

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