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// 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.

// Yi Zhang 1, 2 , Yan Li 2 , Shaojie Jiang 3 , Wei Chen 1, 4 , Jiao Lou 1 , Juntao Ke 1 , Jiaoyuan Li 1 , Ying Zhu 1 , Yajie Gong 1 , Yang Yang 1 , Jianbo Tian 1 , Xiating Peng 1 , Danyi Zou 1 , Jing Gong 1 , Jiang Chang 1 , Xiaoping Miao 1 , Rong Zhong 1 1 Department of Epidemiology and Biostatistics and State Key Laboratory of Environment Health (Incubation), Ministry of Education Key Laboratory of Environment & Health, Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China 2 Department of Preventive Medicine, School of Public Health, Zunyi Medical University, Zunyi, Guizhou, China 3 Department of Gastroenterology, Jing Zhou Central Hospital, Jingzhou, China 4 Zhuhai Center for Chronic Disease Control, Zhuhai, China Correspondence to: Rong Zhong, email: rongzhong91@gmail.com Xiaoping Miao, email: miaoxp@mail.hust.edu.cn Keywords: breast cancer, FOXA1, genetic variants, susceptibility, case-control study Received: August 20, 2016 Accepted: October 19, 2016 Published: November 07, 2016 ABSTRACT The DNA-binding protein FOXA1 has been shown to regulate nearly all estrogen receptor-chromatin interactions, thereby influencing target gene expression levels in breast cancer (BC) cells. Recently, the rs4442975 T-allele, which disrupts the recruitment of FOXA1 and interacts with the IGFBP5 promoter, was associated to BC susceptibility in a European population. We conducted a hospital-based case-control study that included 1227 cases and 1285 controls to explore the potential association between rs4442975 and BC risk in Chinese Han population, and the effect of this SNP on BC progression was also observed in cases. No significant associations between rs4442975 and BC risk were observed under any genetic models, with an odds ratio of 0.96 (95% confidence interval = 0.81-1.15) under the additive model. When stratified based on estrogen or progesterone receptor expression, smoking or drinking habits, or menopausal status, similar negative associations were observed for all subgroups. No significant associations were observed between rs4442975 and traditional progression factors such as tumor size, nodal status, distant metastasis, or TNM staging. These results reveal that rs4442975 may not confer a risk of BC occurrence or progression in the Chinese Han population, which indicates a distinct association related to genetic heterogeneity across ethnic populations.