Insulin-like growth factors (IGF) play important roles in carcinogenesis. The associations of circulating IGF-1 and insulin-like growth factor-binding protein-3 (IGFBP-3) with the risks of bladder cancer remain unclear. In this large case control study of 2011 bladder cancer cases and 2369 heathy controls, we assessed the associations of circulating IGF-1 and IGFBP-3 with bladder cancer risks using a Mendelian randomization approach, which uses genetic variants as instruments to study causal relationship between risk factors and diseases. We first constructed a weighted genetic risk score (GRS) predictive of circulating IGF-1 and IGFBP-3 using 413 genome-wide association study-identified single nucleotide polymorphisms (SNPs) associated with IGF-1 and four SNPs with IGFBP-3, respectively. We found that higher GRS for IGF-1 was associated with a significantly reduced bladder cancer risk (odds ratio [OR] = 0.66 per SD increase, 95% confidence interval [CI], 0.54–0.82, p < 0.001). We then used a summary statistics-based MR method, inverse-variance weighting (IVW), and found a similar risk estimate (OR = 0.67 per SD increase, 95% CI = 0.54–0.83, p < 0.001). When we categorized individuals into high and low IGF-1 groups using the median GRS value in the controls, the high GRS group had a 21% reduced bladder cancer risk (OR = 0.79, 95% CI = 0.70–0.89) compared to the low GRS group. Genetically predicted circulating IGFBP-3 was not associated with bladder cancer risk. In conclusion, our data demonstrated for the first time a strong inverse relationship between circulating IGF-1 level and bladder cancer risk.

中文翻译：

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遗传预测的循环胰岛素样生长因子-1 和胰岛素样生长因子结合蛋白-3 与膀胱癌风险的关联

胰岛素样生长因子 (IGF) 在致癌作用中起重要作用。循环 IGF-1 和胰岛素样生长因子结合蛋白 3 (IGFBP-3) 与膀胱癌风险的关联仍不清楚。在这项针对 2011 名膀胱癌病例和 2369 名健康对照的大型病例对照研究中，我们使用孟德尔随机化方法评估了循环 IGF-1 和 IGFBP-3 与膀胱癌风险的关联，该方法使用遗传变异作为工具来研究两者之间的因果关系危险因素和疾病。我们首先使用 413 个全基因组关联研究确定的与 IGF-1 相关的单核苷酸多态性 (SNP) 和四个与 IGFBP-3 相关的 SNP，构建了一个加权遗传风险评分 (GRS)，预测循环 IGF-1 和 IGFBP-3。 .SD增加，95% 置信区间 [CI]，0.54–0.82，p  < 0.001）。然后，我们使用了基于汇总统计的 MR 方法、逆方差加权 (IVW)，并发现了类似的风险估计（每个 SD 增加 OR = 0.67，95% CI = 0.54–0.83，p  < 0.001）。当我们使用对照组的 GRS 中值将个体分为高和低 IGF-1 组时，与低 GRS 组相比，高 GRS 组膀胱癌风险降低了 21%（OR = 0.79，95% CI = 0.70–0.89） GRS 组。遗传预测的循环 IGFBP-3 与膀胱癌风险无关。总之，我们的数据首次证明了循环 IGF-1 水平与膀胱癌风险之间存在强烈的负相关关系。