title: A low-frequency variant in SMAD7 modulates TGF-β signaling and confers risk for colorectal cancer in Chinese population.
abstract: The TGF-β pathway plays an essential role in regulating cell proliferation and differentiation. GWASs and candidate approaches have identified a battery of genetic variants in the TGF-β pathway contributing to colorectal cancer (CRC). However, most of the significant variants are common variants and their functions remain ambiguous. To identify causal variants with low-frequency in the TGF-β pathway contributing to CRC susceptibility in Chinese population, we performed targeted sequencing of 12 key genes in TGF-β signaling in CRC patients followed by a two-stage case-control study with a total of 5109 cases and 5169 controls. Bioinformatic annotations and biochemical experiments were applied to reveal the potential functions of significant variants. Seven low-frequency genetic variants were captured through targeted sequencing. The two stage association studies showed that missense variant rs3764482 (c. 83C>T; p. S28F) in the gene SMAD7 was consistently and significantly associated with CRC risk. Compared with the wild type, the ORs for variant allele were 1.37 (95%CI: 1.10-1.70, P = 0.005), 1.55 (95%CI: 1.30-1.86, P = 1.15 × 106), and 1.48 (1.29-1.70, P = 2.44 × 10;8) in stage 1, stage 2, and the combined analyses, respectively. Functional annotations revealed that the minor allele T of rs3764482 was more effective than the major allele C in blocking the TGF-β signaling and inhibiting the phosphorylation of receptor-regulated SMADs (R-SMADs). In conclusion, low-frequency coding variant rs3764482 in SMAD7 is associated with CRC risk in Chinese population. The rs3764482 variant may block the TGF-β signaling via impeding the activation of downstream genes, leading to cancer cell proliferation, thus contributing to CRC pathogenesis.
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Jiaoyuan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Health Care, Bao'an Maternal and Child Health Hospital, Shenzhen, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zou
authors.affiliation: Institute of Orthopaedics, the First Affiliated Hospital of Chinese PLA General Hospial, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Lou
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Juntao
authors.initials: J
authors.lastname: Ke
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Danyi
authors.initials: D
authors.lastname: Zou
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Xiating
authors.initials: X
authors.lastname: Peng
authors.affiliation: Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhong
authors.affiliation: Brigham and Women's Hospital, Channing Division of Network Medicine, Boston, Massachusetts.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
authors.forename: Xiaoping
authors.identifier: 0000-0002-9473-7219
authors.initials: X
authors.lastname: Miao
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta
keywords: SMAD7; TGF-β; colorectal cancer; targeted sequencing