Insulin and insulin-like growth factors play important roles in carcinogenesis. Circulating insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) have been linked to cancer susceptibility. The associations of circulating IGF-1 and IGFBP-3 with the risk of renal cell carcinoma (RCC) are inconsistent. Recent large genome-wide association studies (GWAS) have identified 413 single nucleotide polymorphisms (SNPs) associated with IGF-1 and 4 SNPs associated with IGFBP-3. In this large case control study consisting of 2,069 RCC patients and 2,052 healthy controls of European ancestry, we used a two-sample Mendelian randomization (MR) approach to investigate the associations of genetically predicted circulating IGF-1 and IGFBP-3 with RCC risk. We used an individual level data-based genetic risk score (GRS) and a summary statistics-based inverse-variance weighting (IVW) method in MR analyses. We found that genetically predicted IGF-1 was significantly associated with RCC risk in both the GRS analysis (OR =0.43 per SD increase, 95% CI, 0.34-0.53) and the IVW analysis (OR = 0.46 per SD increase, 95% CI, 0.37-0.57). Dichotomized at the median GRS value of IGF-1 in controls, individuals with high GRS had a 45% reduced RCC risk (OR=0.55, 95% CI, 0.48-0.62) compared to those with low GRS. Genetically predicted circulating IGFBP-3 was not associated with RCC risk. This is the largest RCC study of circulating IGF-1 and IGFBP-3 to date and our data suggest a strong inverse relationship between circulating IGF-1 level and RCC risk.
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