A functional variant in GREM1 confers risk for colorectal cancer by disrupting a hsa-miR-185-3p binding site

// Jiaoyuan Li 1 , Hui Liu 2 , Li Zou 3 , Juntao Ke 1 , Yi Zhang 1 , Ying Zhu 1 , Yang Yang 1 , Yajie Gong 1 , Jianbo Tian 1 , Danyi Zou 1 , Xiating Peng 1 , Jing Gong 1 , Rong Zhong 1 , Kun Huang 4 , Jiang Chang 5, * and Xiaoping Miao 1, * 1 Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 2 National Key Laboratory of Crop Genetic Improvement, Huazhong Agricultural University, Wuhan, China 3 Department of Health Care, Bao’an Maternal and Child Health Hospital, Shenzhen, China 4 Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China 5 Key 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 Correspondence to: Xiaoping Miao, email: miaoxp@mail.hust.edu.cn Jiang Chang, email: changjiang815@hust.edu.cn Keywords: TGF-β, GREM1, untranslated region, microRNA, colorectal cancer Received: February 25, 2017 Accepted: April 26, 2017 Published: May 23, 2017 ABSTRACT 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.