Abstract
RegQTL, a novel concept, indicates that different genotypes of some SNPs have differential effects on the expression patterns of miRNAs and their target mRNAs. We aimed to identify the association between regQTL-SNPs and lung cancer risk and to explore the underlying mechanisms. The two-stage case–control study included the first stage in a Chinese population (626 lung cancer cases and 667 healthy controls) and the second stage in a European population (18,082 lung cancer cases and 13,780 healthy controls). Functional annotations were conducted based on the GTEx and the TCGA databases. Functional experiments were performed to explore the underlying biological mechanisms in vitro and vivo. After strict screening, five candidate regQTL-SNPs (rs7110737, rs273957, rs6593210, rs3768617, and rs6836432) were selected. Among them, the variant T allele of rs3768617 in LAMC1 was found to significantly increase the risk of lung cancer (first stage: P = 0.044; second stage: P = 0.007). The eQTL analysis showed that LAMC1 expression level was significantly higher in subjects with the variant T allele of rs3768617 (P = 1.10 × 10–14). In TCGA paired database, the regQTL annotation indicated the different expression patterns between LAMC1 and miRNA-548b-3p for the distinct genotypes of rs3768617. Additionally, LAMC1 knockdown significantly inhibited malignant phenotypes in lung cancer cell lines and suppressed tumor growth. A novel regQTL-SNP, rs3768617, might affect lung cancer risk by modulating the expression patterns of miRNA-548b-3p and LAMC1. RegQTL-SNPs could provide a new perspective for evaluating the regulatory function of SNPs in lung cancer development.
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The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Acknowledgements
The authors are grateful for the help of Pro. Zuo-Feng Zhang from University of California Los Angeles and Dr. Rayjean Hung from the ILCCO who help in applying for European GWAS data. We also thank the patients and investigators who participated in TCGA and GTEx for providing the data.
Funding
This work was supported by the National Natural Science Foundation of China (81502876, 81703297), Natural Science Foundation of Jiangsu Province (BK20191449), The Jiangsu Association of Science and Technology Youth Science and Technology Talents Enrollment Project in 2019, Jiangsu Government Scholarship for Overseas Studies (JS-2019-256), Science and Technology Program of Nantong City (JC2019119), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX21-3126, KYCX20-2852, KYCX19-2082).
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YY, LM, ZC, XZ, and JC participated in functional experiments, collecting data, analyzing data, and drafting the article. XF, JC, YZ, AQ, and YD participated in data analyses. XZ, YL, and YL participated in revising the article. TT, SW, and MC contributed to the design and coordination of the study. All authors read and approved the final article. All the authors listed have approved the article and contributed significantly.
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Yu, Y., Mao, L., Cheng, Z. et al. A novel regQTL-SNP and the risk of lung cancer: a multi-dimensional study. Arch Toxicol 95, 3815–3827 (2021). https://doi.org/10.1007/s00204-021-03170-5
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DOI: https://doi.org/10.1007/s00204-021-03170-5