基于多基因风险评分和生活方式暴露的结直肠癌风险评估：东亚和欧洲人群的大规模关联研究。

Risk assessment for colorectal cancer via polygenic risk score and lifestyle exposure: a large-scale association study of East Asian and European populations.

机构信息

Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China.

Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

出版信息

Genome Med. 2023 Jan 24;15(1):4. doi: 10.1186/s13073-023-01156-9.

DOI:10.1186/s13073-023-01156-9

PMID:36694225

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9875451/

Abstract

BACKGROUND

The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations.

METHODS

A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle.

RESULTS

In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRS) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRS on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRS than in the low score subgroup (P = 8.15 × 10). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk.

CONCLUSIONS

In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.

摘要

背景

结直肠癌的遗传结构在不同人群中存在差异。迄今为止，大多数多基因风险评分（PRS）是从欧洲人群（EUR）中得出的，这限制了它们在其他人群中的准确推断。在这里，我们旨在通过纳入东亚（EAS）和 EUR 血统群体来生成 PRS，并验证其在不同人群中用于结直肠癌风险评估的效用。

方法

利用包含东亚（EAS）和 EUR 人群的 35145 例病例和 288934 例对照的大规模结直肠癌全基因组关联研究（GWAS），进行 EAS-EUR GWAS 荟萃分析，并通过不同方法构建候选 EAS-EUR PRS。然后，分别在 EAS（727 例病例和 1452 例对照）和 EUR（1289 例病例和 1284 例对照）血统的外部 GWAS 数据集验证每个 PRS 的性能。然后，使用英国生物银行的 355543 名个体的纵向队列进一步测试最佳 PRS，并最终应用于分层健康生活方式所带来的个体风险。

结果

在 EAS 和 EUR 人群的荟萃分析中，我们在先前报道的基因座之外发现了 48 个独立的具有全基因组意义的变异（P < 5×10）。在 26 种候选的 EAS-EUR PRS 中，PRS-CSx 方法衍生的 PRS（定义为 PRS），包含全基因组变异，在两个验证数据集中均具有最佳的判别能力，并且在 EAS 人群中的表现优于源自已知变异的 PRS。使用英国生物库队列，我们进一步验证了 PRS 对结直肠癌发病的显著剂量反应效应，在中间和高 PRS 个体中，风险分别比低评分亚组高 2.11 倍和 3.88 倍（P = 8.15×10）。值得注意的是，通过遵循有利的生活方式，高遗传风险的不利影响可以在很大程度上得到缓解，5 年内绝对风险降低 0.53%。