Division of Data Science, Data Coordinating Center, Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan.
Department of Public Health, Aichi Medical University School of Medicine, Nagakute, Japan.
PLoS One. 2018 Sep 7;13(9):e0203386. doi: 10.1371/journal.pone.0203386. eCollection 2018.
Genome-wide association studies (GWASs) have identified many single nucleotide polymorphisms (SNPs) that are significantly associated with pancreatic cancer susceptibility. We sought to replicate the associations of 61 GWAS-identified SNPs at 42 loci with pancreatic cancer in Japanese and to develop a risk model for the identification of individuals at high risk for pancreatic cancer development in the general Japanese population. The model was based on data including directly determined or imputed SNP genotypes for 664 pancreatic cancer case and 664 age- and sex-matched control subjects. Stepwise logistic regression uncovered five GWAS-identified SNPs at five loci that also showed significant associations in our case-control cohort. These five SNPs were included in the risk model and also applied to calculation of the polygenic risk score (PRS). The area under the curve determined with the leave-one-out cross-validation method was 0.63 (95% confidence interval, 0.60-0.66) or 0.61 (0.58-0.64) for versions of the model that did or did not include cigarette smoking and family history of pancreatic cancer in addition to the five SNPs, respectively. Individuals in the lowest and highest quintiles for the PRS had odds ratios of 0.62 (0.42-0.91) and 1.98 (1.42-2.76), respectively, for pancreatic cancer development compared with those in the middle quintile. We have thus developed a risk model for pancreatic cancer that showed moderately good discriminatory ability with regard to differentiation of pancreatic cancer patients from control individuals. Our findings suggest the potential utility of a risk model that incorporates replicated GWAS-identified SNPs and established demographic or environmental factors for the identification of individuals at increased risk for pancreatic cancer development.
全基因组关联研究（GWAS）已经确定了许多与胰腺癌易感性显著相关的单核苷酸多态性（SNP）。我们试图在日本人群中复制 61 个 GWAS 确定的 42 个位点与胰腺癌的关联，并为日本普通人群中胰腺癌高危个体的识别开发风险模型。该模型基于包括 664 例胰腺癌病例和 664 例年龄和性别匹配对照的直接确定或推断的 SNP 基因型数据。逐步逻辑回归揭示了五个 GWAS 确定的位于五个位点的 SNP 与我们的病例对照队列中也存在显著关联。这五个 SNP 被纳入风险模型，并应用于多基因风险评分（PRS）的计算。通过留一法交叉验证方法确定的曲线下面积分别为 0.63（95%置信区间，0.60-0.66）或 0.61（0.58-0.64），这两种模型版本分别在包括五个 SNP 之外还包括吸烟和胰腺癌家族史，或不包括这些因素。PRS 最低和最高五分位数的个体患胰腺癌的比值比分别为 0.62（0.42-0.91）和 1.98（1.42-2.76），与五分位数中间的个体相比。因此，我们开发了一种胰腺癌风险模型，该模型在区分胰腺癌患者和对照个体方面具有中等良好的区分能力。我们的研究结果表明，一种风险模型具有潜在的应用价值，该模型可以将经过复制的 GWAS 确定的 SNP 与已确立的人口统计学或环境因素相结合，用于识别胰腺癌发病风险增加的个体。
