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Genetic variants in circTUBB interacting with smoking can enhance colorectal cancer risk

  • Ke Zhang
  • Shuwei Li
  • Dongying Gu
  • Kaili Xu
  • Rui Zheng
  • Junyi Xin
  • Yixuan Meng
  • Shuai Ben
  • Haiyan Chu
  • Zhengdong Zhang
  • Yongqian Shu
  • Mulong DuEmail author
  • Lingxiang LiuEmail author
  • Meilin WangEmail author
Genotoxicity and Carcinogenicity

Abstract

Circular RNAs (circRNAs) are an intriguing class of regulatory RNAs involved in the tumorigenesis of many cancers, including colorectal cancer. Mechanistically, circRNAs sponge microRNAs (miRNAs) with specific miRNA response elements (MREs) and compete for regulatory target genes downstream. However, the genetic effects of MREs on colorectal cancer susceptibility remain unclear. The MREs of colorectal cancer-associated circRNAs (CRC-circRNAs) and corresponding single nucleotide polymorphisms (SNPs) were identified by the transcriptome of cancer cells and the 1000 Genomes Project. The association between candidate SNPs and colorectal cancer risk was evaluated in a Chinese population (1150 cases and 1342 controls) and two European populations (9023 cases and 386,896 controls) using logistic regression analysis. Among the 197 candidate SNPs within MREs of 186 CRC-circRNAs, rs25497 in circTUBB was significantly associated with colorectal cancer risk in a Chinese population after false discovery rate (FDR) correction [odds ratio (OR) = 1.78, 95% confidence interval (CI) = 1.44–2.21, P = 1.42 × 10–7, PFDR = 2.80 × 10–5] and even reached significance in a genome-wide association study (GWAS) under the dominant model (P = 1.28 × 10–8). Similar results were found in the European populations (ORmeta = 1.30, 95% CI = 1.10–1.53). Both stratification and interaction analyses revealed that rs25497 interacting with smoking affected the colorectal cancer risk (Pinteraction = 1.48 × 10–2). Here, we first comprehensively identified genetic variants in MREs of CRC-circRNAs and evaluated their effects on colorectal cancer risk in both Chinese and European populations. These findings provide basis for a comprehensive understanding of colorectal cancer etiology.

Keywords

Colorectal cancer circTUBB Genetic variants Interaction 

Notes

Funding

This study was partly supported by National Natural Science Foundation of China (81703307) and the Natural Science Foundation of Jiangsu Province (BK20181371) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

204_2019_2624_MOESM1_ESM.docx (1.8 mb)
Supplementary file1 (DOCX 1846 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of OncologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingPeople’s Republic of China
  2. 2.Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized MedicineNanjing Medical UniversityNanjingPeople’s Republic of China
  3. 3.Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public HealthNanjing Medical UniversityNanjingPeople’s Republic of China
  4. 4.Department of Oncology, Nanjing First HospitalNanjing Medical UniversityNanjingPeople’s Republic of China
  5. 5.Department of Biostatistics, Center for Global Health, School of Public HealthNanjing Medical UniversityNanjingPeople’s Republic of China

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