Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
University of Washington, Seattle, Washington.
Cancer Epidemiol Biomarkers Prev. 2021 Jul;30(7):1349-1358. doi: 10.1158/1055-9965.EPI-20-1848. Epub 2021 May 10.
A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer-specific survival.
We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer-specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components.
Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer-specific survival (HD, -1.15; 95% CI, -2.76 to 0.47 per 100,000 person-years; = 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location.
Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer-specific survival.
Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed.
观察性研究报告称，循环 C 反应蛋白（CRP）与结直肠癌生存之间呈正相关，但这些研究易受未测量的混杂因素和反向因果关系的影响。我们使用孟德尔随机化方法来评估遗传预测的 CRP 浓度与结直肠癌特异性生存之间的关联。
我们使用了来自国际结直肠癌生存分析联盟内 15 项研究的 16918 例符合条件的欧洲血统结直肠癌病例的个体水平数据。我们基于从全基因组关联研究中确定的 52 个 CRP 相关遗传变异，计算了一个遗传风险评分。由于 Cox 比例风险模型的危险比不可 collapsible，我们使用加性危险模型来计算遗传预测的 CRP 浓度与结直肠癌特异性生存之间的关联的危险差异（HD）和 95%置信区间（CI），总体以及按诊断时的阶段和肿瘤位置进行分析。调整了年龄、性别、体重指数、基因分型平台、研究和主成分。
在长达 10 年的随访期间，5395 例（32%）死亡中，3808 例（23%）死于结直肠癌。遗传预测的 CRP 浓度与结直肠癌特异性生存无关（HD，-1.15；95%CI，-2.76 至 0.47/10 万人年； = 0.16）。同样，在按诊断时的阶段或肿瘤位置进行的亚组分析中也未观察到关联。
尽管有足够的检测中等关联的能力，但我们的结果不支持循环 CRP 浓度对结直肠癌特异性生存的因果影响。
需要进一步研究评估其他循环炎症生物标志物（即 IL6）的遗传决定水平与结直肠癌生存结果的关系。
