Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, China.
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Int J Epidemiol. 2020 Feb 1;49(1):259-269. doi: 10.1093/ije/dyz096.
Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown.
Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis.
During 18-20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584).
Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC.
越来越多的证据表明，传统腺瘤（CAs）和锯齿状息肉（SPs）代表结直肠癌（CRC）的两种不同的前体病变。常见遗传变异对 CAs 和 SPs 风险的影响在很大程度上仍不清楚。
在三个前瞻性队列研究的 27426 名参与者中，我们基于先前全基因组关联研究中确定的 40 个 CRC 相关单核苷酸多态性（SNPs）创建了一个加权遗传风险评分（GRS）；并通过多变量逻辑回归检查 GRS（每增加一个标准差）与 CAs、SPs 和同步 CAs 和 SPs 的风险之间的关联。我们还在二次分析中分析了个别变体。
在 18-20 年的随访中，我们记录了 2952 例 CAs、1585 例 SPs 和 794 例同步 CAs 和 SPs。较高的 GRS 与 CAs（比值比 [OR] = 1.17，95%置信区间 [CI]：1.12-1.21）和 SPs（OR = 1.09，95% CI：1.03-1.14）的风险增加相关，CAs 的相关性强于 SPs（P异质性= 0.01）。在同时患有 CAs 和 SPs、进展期 CAs（OR = 1.22）和多发性 CAs（OR = 1.25）的患者中，相关性更强。与两种病变相关的 40 个 SNPs 的 OR 之间的斯皮尔曼相关系数为 0.02，这表明不同的变体集与 CAs 和 SPs 相关。在进行多重检验校正后，有 3 个变体与 CAs 相关（rs3802842、rs6983267 和 rs7136702），2 个变体与 SPs 相关（rs16892766 和 rs4779584）。
常见遗传变异在 CRC 的传统和锯齿状途径中发挥潜在作用。两种途径中鉴定出了不同的变体集，进一步支持 CRC 的病因异质性。
