Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses
Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses
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DOI：
10.1053/j.gastro.2019.12.020
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发表时间：
2020-04-01
期刊：
影响因子：
29.4
通讯作者：
Gunter，Marc J.
中科院分区：
文献类型：
--
作者：
Murphy，Neil;Carreras-Torres，Robert;Gunter，Marc J.
研究循环胰岛素样生长因子1 （IGF1）和胰岛素样生长因子结合蛋白3 （IGFBP3）水平与结直肠癌风险之间关系的人类研究报告了不一致的结果。我们进行了补充血清学和孟德尔随机化（MR）分析，以确定IGF1或IGFBP3循环水平的改变是否与结直肠癌的发展有关。方法：从2006年到2010年，从英国生物银行收集了397380名参与者的血液样本，测量了IGF1的血清水平。通过与国家癌症和死亡登记处的联系，确定了癌症事件病例和死亡证明中首先记录的癌症病例。完整的随访一直持续到2016年3月31日。对于MR分析，我们确定了与IGF1和IGFBP3循环水平相关的遗传变异。使用全基因组关联研究联盟数据（52,865例结直肠癌患者和46,287例无[对照]个体），采用双样本MR方法检测这些遗传变异与结直肠癌的相关性。结果中位随访期为7.1年，记录了2665例结直肠癌病例。在多变量调整模型中，循环中IGF1水平与结直肠癌风险相关（IGF1每1个标准差增量的风险比为1.11；95%可信区间[CI] 1.05-1.17）。性别、随访时间和肿瘤亚部位也有类似的关联。在MR分析中，基于遗传因素预测的IGF1水平每增加1个标准差与结直肠癌风险增加相关（优势比1.08;95% CI 1.03-1.12；P= 3.3 × 10-4）。基于遗传因素预测的IGFBP3水平与结直肠癌风险相关（每1个标准差增量的优势比为1.12；95% CI为1.06-1.18；P= 4.2 × 10-5）。结直肠癌风险仅与igfbp3基因区域（rs11977526）的1个变异相关，该变异也与人体测量特征和IGF2循环水平相关。在对英国生物银行近40万参与者的血液样本进行分析后，我们发现循环中IGF1水平与结直肠癌之间存在关联。根据52865例结直肠癌患者和46287例对照者的遗传数据，由遗传因素决定的较高水平的IGF1与结直肠癌有关。需要进一步的研究来确定这种信号通路如何促进结直肠癌的发生。
Background & AimsHuman studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development.MethodsSerum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls])ResultsAfter a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05–1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03–1.12;P= 3.3 × 10–4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06–1.18;P= 4.2 × 10–5). Colorectal cancer risk was associated with only 1 variant in theIGFBP3gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2.ConclusionsIn an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.