A functional variant in GREM1 confers risk for colorectal cancer by disrupting a hsa-miR-185-3p binding site
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Jiaoyuan Li1, Hui Liu2, Li Zou3, Juntao Ke1, Yi Zhang1, Ying Zhu1, Yang Yang1, Yajie Gong1, Jianbo Tian1, Danyi Zou1, Xiating Peng1, Jing Gong1, Rong Zhong1, Kun Huang4, Jiang Chang5,* and Xiaoping Miao1,*
1Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
2National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan, China
3Department of Health Care, Bao’an Maternal and Child Health Hospital, Shenzhen, China
4Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China
5Key Laboratory of Environment and Health, Ministry of Education & Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
*These authors have contributed equally to this work
Xiaoping Miao, email: [email protected]
Jiang Chang, email: [email protected]
Keywords: TGF-β, GREM1, untranslated region, microRNA, colorectal cancer
Received: February 25, 2017 Accepted: April 26, 2017 Published: May 23, 2017
The transforming growth factor beta (TGF-β) pathway has been implicated in carcinogenesis of intestinal canal. Except for common variants indentified by genome-wide association studies, variants with lower frequency can also explain a part of the disease heritability, especially those in gene regulatory regions. In this study, we searched for colorectal cancer (CRC) related functional low-frequency variants (minor allele frequency 1-5%) in untranslated regions (UTR) involved in the TGF-β signaling using a next-generation sequencing based approach. A case-control study including 1,841 CRC cases and 1,837 controls was performed to identify CRC associated variants and biological experiments were applied to further explore the potential functions of the significant variants. Three low-frequency UTR variants were selected as our candidates and subsequent association analyses showed that a low-frequency variant rs12915554 in the 3’ UTR of GREM1 was significantly associated with CRC risk (Additive model: OR=1.43, 95%CI: 1.04-1.95, P=0.026). Functional annotations suggested that rs12915554 variation increased the expression of GREM1 by perturbing a hsa-miR-185-3p binding site. Moreover, higher expression level of GREM1 was investigated in colon tumor tissues compared with adjacent normal tissues using TCGA data. In conclusion, low-frequency UTR variant rs12915554 in the gene GREM1 was in relation to CRC susceptibility in a Chinese population and this variation might promote CRC development through enhancing GREM1 expression in a miRNA-mediated posttranscriptional manner.
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