Construction and evaluation of the functional polygenic risk score for gastric cancer in a prospective cohort of the European population.
Construction and evaluation of the functional polygenic risk score for gastric cancer in a prospective cohort of the European population.
复制标题
DOI：
10.1097/cm9.0000000000002716
复制
发表时间：
2023-07-20
影响因子：
6.1
通讯作者：
中科院分区：
文献类型：
--
作者：
在中国人群中，已经报道了来自112个单核苷酸多态性（SNP）的胃癌多基因风险评分（PRS-112）。然而，其在其他人群中的表现尚不清楚。使用功能性SNP（fSNP）的功能性PRS（fPRS）可以提高PRS在具有不同种族的人群中的通用性。我们进行功能注释的SNPs在强连锁不平衡（LD）与112个以前报道的SNPs，以确定fSNPs影响蛋白质编码或转录调控。随后，我们通过使用LDpred 2-无穷小模型构建了基于fSNP的fPRS，然后分析了PRS-112和fPRS在英国生物银行队列的457，521名欧洲参与者中胃癌风险预测中的性能。最后，评估fPRS与生活方式因素结合预测胃癌风险的性能。在4，582，045人-年的随访期间，共623例胃癌病例，我们发现PRS-112与欧洲人群中的胃癌风险之间无显著相关性（风险比[HR] = 1.00 [95%置信区间（CI）0.93-1.09]，P = 0.846）。我们鉴定了125个fSNP，包括7个有害的蛋白质编码SNP和118个调节性非编码SNP，并使用它们构建fPRS-125。结果显示fPRS-125与胃癌风险显著相关（HR = 1.11 [95%CI，1.03-1.20]，P = 0.009）。与低fPRS-125（底部五分位数）的参与者相比，高fPRS-125（顶部五分位数）的参与者发生胃癌的风险更高（HR = 1.43 [95%CI，1.12-1.84]，P = 0.005）。此外，我们观察到，与生活方式良好和遗传风险低的参与者相比，生活方式不良和遗传风险高的参与者发生胃癌的风险最高（HR = 4.99 [95%CI，1.55-16.10]，P = 0.007）。这些结果表明，来自fSNPs的fPRS-125可以作为衡量欧洲人群胃癌遗传风险的指标。
A polygenic risk score (PRS) derived from 112 single-nucleotide polymorphisms (SNPs) for gastric cancer has been reported in Chinese populations (PRS-112). However, its performance in other populations is unknown. A functional PRS (fPRS) using functional SNPs (fSNPs) may improve the generalizability of the PRS across populations with distinct ethnicities. We performed functional annotations on SNPs in strong linkage disequilibrium (LD) with the 112 previously reported SNPs to identify fSNPs that affect protein-coding or transcriptional regulation. Subsequently, we constructed an fPRS based on the fSNPs by using the LDpred2-infinitesimal model and then analyzed the performance of the PRS-112 and fPRS in the risk prediction of gastric cancer in 457,521 European participants of the UK Biobank cohort. Finally, the performance of the fPRS in combination with lifestyle factors were evaluated in predicting the risk of gastric cancer. During 4,582,045 person-years of follow-up with a total of 623 incident gastric cancer cases, we found no significant association between the PRS-112 and gastric cancer risk in the European population (hazard ratio [HR] = 1.00 [95% confidence interval (CI) 0.93–1.09], P = 0.846). We identified 125 fSNPs, including seven deleterious protein-coding SNPs and 118 regulatory non-coding SNPs, and used them to construct the fPRS-125. Our result showed that the fPRS-125 was significantly associated with gastric cancer risk (HR = 1.11 [95% CI, 1.03–1.20], P = 0.009). Compared to participants with a low fPRS-125 (bottom quintile), those with a high fPRS-125 (top quintile) had a higher risk of incident gastric cancer (HR = 1.43 [95% CI, 1.12–1.84], P = 0.005). Moreover, we observed that participants with both an unfavorable lifestyle and a high genetic risk had the highest risk of incident gastric cancer (HR = 4.99 [95% CI, 1.55–16.10], P = 0.007) compared to those with both a favorable lifestyle and a low genetic risk. These results indicate that the fPRS-125 derived from fSNPs may act as an indicator to measure the genetic risk of gastric cancer in the European population.