The impact of GDF-15, a biomarker for metformin, on the risk of coronary artery disease, breast and colorectal cancer, and type 2 diabetes and metabolic traits: a Mendelian randomisation study

Aims/hypothesis: Growth differentiation factor 15 (GDF-15), a suggested biomarker for metformin use, may explain the potential cardioprotective and anti-cancer properties of metformin. We conducted a Mendelian randomisation study to examine the role of GDF-15 in risk of coronary artery disease (CAD) and breast and colorectal cancer. Secondary analyses included examination of the association of GDF-15 with type 2 diabetes, glycaemic traits, BP, lipids and BMI. Methods: We obtained SNPs strongly (p value <5 × 10⁻⁸) predicting GDF-15 from a genome-wide association study (GWAS) (n = 5440) and applied them to genetic studies of CAD (CARDIoGRAMplusC4D 1000 Genomes-based GWAS [n = 184,305]), type 2 diabetes (DIAGRAM [DIAbetes Genetics Replication And Meta-analysis; n = 898,130]), glycaemic traits (MAGIC [the Meta-Analyses of Glucose and Insulin-related traits Consortium; HbA_1c: n = 123,665; fasting glucose: n = 46,186]), BP, breast cancer and colorectal cancer (UK Biobank [n ≤ 401,447]), lipids (GLGC [Global Lipids Genetic Consortium; n ≤ 92,820]) and adiposity (GIANT [Genetic Investigation of ANthropometric Traits Consortium; n = 681,275]). Causal estimates were obtained using inverse variance weighting, taking into account correlations between SNPs. Sensitivity analyses included focusing on the lead SNP (rs888663) and validation for CAD in the UK Biobank and for breast cancer in the Breast Cancer Association Consortium. Results: Using 5 SNPs, increased GDF-15 was associated with lower CAD (OR 0.93 per SD increase, 95% CI 0.87, 0.99) and breast cancer (OR 0.89 per SD increase, 95% CI 0.82, 0.96), with similar results from lead SNP analysis. However, the associations with CAD (OR 0.99 per SD increase, 95% CI 0.93, 1.04) and breast cancer (OR 0.97 per SD increase, 95% CI 0.94, 1.01) in the validation studies were not as apparent. GDF-15 was not associated with type 2 diabetes, glycaemic traits, CAD risk factors or colorectal cancer. Conclusions/interpretation: There is no convincing evidence that GDF-15 reduces risk of CAD or breast or colorectal cancer. Whether the observed inverse association of metformin use with cancer risk is via other unexplored mechanistic pathways warrants further investigation.