Wang Nan, Lu Yingchang, Khankari Nikhil K, Long Jirong, Li Hong-Lan, Gao Jing, Gao Yu-Tang, Xiang Yong-Bing, Shu Xiao-Ou, Zheng Wei
Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN.
Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
Int J Cancer. 2017 Sep 15;141(6):1130-1139. doi: 10.1002/ijc.30812. Epub 2017 Jun 21.
Genome-wide association studies (GWAS) have identified over 40 genetic loci associated with colorectal cancer (CRC) risk. The association of single nucleotide polymorphisms (SNPs) at these loci with CRC risk and survival has not been adequately evaluated in East Asians. GWAS-identified CRC risk variants were used to construct weighted genetic risk scores (GRSs). We evaluated these GRSs in association with CRC risk in 3,303 CRC cases and 3,553 controls using logistic regression models. Associations with overall and CRC-specific survival were assessed in 731 CRC patients using Cox regression models. The association between the GRSs (overall and Asian-specific) and CRC risk was approximately twofold (highest vs. lowest quintile), and the shape of the dose-response was linear (p = 1.24 × 10 and 3.02 × 10 for overall GRS and Asian-specific GRS, respectively). The association of the GRS with CRC risk was stronger among those with a family history of CRC (p = 0.007). Asian-specific GRS using previously reported survival SNPs increased risk for mortality and the shape of the dose-response was linear for CRC-specific and all-cause mortality (p = 0.01 and 0.006, respectively). Furthermore, the minor alleles of rs6983267 and rs1957636 were associated with worse CRC-specific and overall survival. We show that GRSs constructed using GWAS-identified common variants are strongly associated with CRC risk in Asians. We confirm previous findings for the possible association between some SNPs with survival, and provide evidence for two additional CRC risk variants that may be related to CRC survival.
全基因组关联研究（GWAS）已鉴定出40多个与结直肠癌（CRC）风险相关的基因位点。在东亚人群中，这些位点的单核苷酸多态性（SNP）与CRC风险及生存的关联尚未得到充分评估。利用GWAS鉴定出的CRC风险变异构建加权遗传风险评分（GRS）。我们使用逻辑回归模型在3303例CRC病例和3553例对照中评估了这些GRS与CRC风险的关联。使用Cox回归模型在731例CRC患者中评估了与总生存和CRC特异性生存的关联。GRS（总体和亚洲特异性）与CRC风险之间的关联约为两倍（最高五分位数与最低五分位数相比），剂量反应呈线性（总体GRS和亚洲特异性GRS的p值分别为1.24×10和3.02×10）。在有CRC家族史的人群中，GRS与CRC风险的关联更强（p = 0.007）。使用先前报道的生存SNP构建的亚洲特异性GRS增加了死亡风险，对于CRC特异性和全因死亡率，剂量反应呈线性（p值分别为0.01和0.006）。此外，rs6983267和rs1957636的次要等位基因与更差的CRC特异性生存和总生存相关。我们表明，使用GWAS鉴定的常见变异构建的GRS与亚洲人群的CRC风险密切相关。我们证实了先前关于某些SNP与生存可能关联的发现，并为另外两个可能与CRC生存相关的CRC风险变异提供了证据。
