在亚洲进行欧洲人肺癌易感性的大规模全基因组基因

A large-scale genome-wide gene-gene interaction study of lung cancer susceptibility in Europeans with a trans-ethnic validation in Asians

(Journal of Thoracic Oncology; IF:15.609)

Introduction 引言

Although genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G×G) interactions that may influence the risk of non-small cell lung cancer (NSCLC).

虽然已经进行了全基因组相关的研究来调查肺肿瘤发生的遗传变异，但对可能影响非小细胞肺癌(NSCLC)风险的基因-基因相互作用知之甚少(G×G)。

Methods 方法

Leveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G×G interaction study on European NSCLC risk via a series of analyses. First, we used BiForce to evaluate and rank over 58 billion G×G interactions from 340,958 SNPs. Then, the top interactions were further tested by demographically adjusted logistic regression models. Finally, we used the selected interactions to build lung cancer screening models of NSCLC, separately, for never and ever smokers. 

利用来自国际肺癌联盟(International Lung Cancer Consortium) OncoArray项目、肺癌跨学科研究和英国生物银行(UK Biobank)的445,221名欧洲后裔参与者，通过一系列分析，我们对欧洲NSCLC风险进行了大规模的全基因组G×G交互研究。首先，我们使用BiForce对340,958个SNPs中超过580亿个G×G交互进行评估和排名。然后，通过人口统计学调整logistic回归模型进一步检验交互作用。最后，我们使用选定的交互作用分别为从不吸烟和曾吸烟的人建立了NSCLC的肺癌筛查模型。

Results 结果

With the Bonferroni correction, we identified eight statistically significant pairs of SNPs, which predominantly appeared in the 6p21.32 and 5p15.33 regions (e.g., rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.17, P = 6.57×10-13; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.17, P = 2.43×10-13; rs2858859HLA-DQA1 and rs9275572HLA-DQA2, ORinteraction = 1.15, P = 2.84×10-13; rs2853668TERT and rs62329694CLPTM1L, ORinteraction = 0.73, P = 2.70×10-13). Notably, even with much genetic heterogeneity across ethnicities, three pairs of SNPs in the 6p21.32 region identified from the European-ancestry population remained significant among an Asian population from the Nanjing Medical University Global Screening Array project (rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.13, P = 0.008; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.11, P = 5.23×10-4; rs3135369BTNL2 and rs9271300HLA-DQA1, ORinteraction = 0.89, P = 0.006). The interaction empowered polygenetic risk score (iPRS) that integrated classical polygenetic risk score and G×G information score was remarkable in lung cancer risk stratification 

通过Bonferroni校正，我们发现了8对具有统计学意义的SNPs，它们主要出现在6p21.32和5p15.33区域(例如rs521828C6orf10和rs204999PRRT1, ORinteraction = 1.17, P = 6.57×10-13;rs3135369BTNL2 和 rs2858859HLA-DQA1, ORinteraction = 1.17, P = 2.43×10-13;rs2858859HLA-DQA1和rs9275572HLA-DQA2, ORinteraction = 1.15, P = 2.84×10-13;rs2853668TERT和rs62329694CLPTM1L, ORinteraction = 0.73, P = 2.70×10-13)。值得注意的是，即使存在种族间的遗传异质性，来自欧洲血统人群的6p21.32区域的3对snp在南京医科大学全球筛选阵列项目的亚洲人群中仍然具有显著性(rs521828C6orf10和rs204999PRRT1, ORinteraction = 1.13, P = 0.008;rs3135369BTNL2 和 rs2858859HLA-DQA1, ORinteraction = 1.11, P = 5.23×10-4;rs3135369BTNL2和rs9271300HLA-DQA1, ORinteraction = 0.89, P = 0.006)。这种增强的多基因风险评分交互作用整合了经典的多基因风险评分和G×G信息评分，在肺癌风险分层中具有重要意义。

Conclusions 结果

Significant G×G interactions were identified and enriched in the 5p15.33 and 6p21.32 regions, which may enhance lung cancer screening models.

我们发现了显著的G×G相互作用，并在5p15.33和6p21.32区域富集，这可能会增强肺癌筛查模型。

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