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

• Published in: Archives of toxicology Vol. 94; no. 1; pp. 325 - 333
• Main Authors: Zhang, Ke, Li, Shuwei, Gu, Dongying, Xu, Kaili, Zheng, Rui, Xin, Junyi, Meng, Yixuan, Ben, Shuai, Chu, Haiyan, Zhang, Zhengdong, Shu, Yongqian, Du, Mulong, Liu, Lingxiang, Wang, Meilin
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 2020; Springer Nature B.V
• Subjects: Aged; Asian Continental Ancestry Group - genetics; Biomedical and Life Sciences; Biomedicine; Cancer; Case-Control Studies; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Confidence intervals; Environmental Health; Etiology; European Continental Ancestry Group - genetics; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genetic diversity; Genetic effects; Genetic Predisposition to Disease; Genetic variance; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genotoxicity and Carcinogenicity; Health risk assessment; Health risks; HT29 Cells; Humans; Male; MicroRNAs; Middle Aged; miRNA; Nucleotides; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Polymorphism, Single Nucleotide; Populations; Regression analysis; Regulatory sequences; Response Elements; Risk; RNA, Circular - genetics; Single-nucleotide polymorphism; Smoking; Smoking - adverse effects; Smoking - genetics; Statistical analysis; Tumorigenesis; Genetic variants; circTUBB; Interaction; Colorectal cancer
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-019-02624-1

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 , P FDR  = 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 (OR meta  = 1.30, 95% CI = 1.10–1.53). Both stratification and interaction analyses revealed that rs25497 interacting with smoking affected the colorectal cancer risk ( P interaction  = 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.