title: Genetic variations in the TGFβ signaling pathway, smoking and risk of colorectal cancer in a Chinese population.
abstract: Recent genome-wide association studies (GWAS) have reported multiple risk loci associated with risk of colorectal cancer (CRC), some of which are involved in the transforming growth factor beta (TGFβ) signaling pathway. We systematically examined associations of common genetic variations in the TGFβ signaling pathway and environmental factors with CRC risk using a two-staged case-control study in a Chinese population. A set of 77 single-nucleotide polymorphisms (SNPs) in 10 candidate genes involved in the TGFβ signaling pathway and several environmental factors including sex, age, smoking and drinking were examined by random forest (RF) to capture the potential gene-gene and gene-environment interactions in stage 1 of the study with 443 CRC patients and 480 controls. Three promising SNPs (SMAD7 rs11874392, TGFBR1 rs10988706 and rs6478972) selected by the RF method were genotyped in stage 2 comprising 351 cases and 360 controls for validation. SMAD7 rs11874392 presented consistently significant associations with a risk of CRC at both stages, with odds ratio = 1.41 (95% confidence interval = 1.21-1.63) using additive modes in combined analyses. Moreover, the potential interactions between SMAD7 rs11874392, TGFBR1 rs10988706 and rs6478972 were indicated consistently in both stages of the study by using pair-wise interaction and multilocus genotype pattern analysis. Additionally, gene-smoking interactions for rs11874392, rs10988706 and rs6478972 were also found to enhance the risk of CRC at both stages, with P for multiplicative interaction equal to 1.162×10(-6), 8.574×10(-8) and 9.410×10(-8) in combined analyses, respectively. This study emphasized the substantial role of the TGFβ signaling pathway in CRC, especially in interaction with smoking.
authors.affiliation: Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhong
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Zou
authors.forename: Wei
authors.initials: W
authors.lastname: Sheng
authors.forename: Beibei
authors.initials: B
authors.lastname: Zhu
authors.forename: Hao
authors.initials: H
authors.lastname: Xiang
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Jigui
authors.initials: J
authors.lastname: Chen
authors.forename: Rui
authors.initials: R
authors.lastname: Rui
authors.forename: Xiawen
authors.initials: X
authors.lastname: Zheng
authors.forename: Jieyun
authors.initials: J
authors.lastname: Yin
authors.forename: Shengyu
authors.initials: S
authors.lastname: Duan
authors.forename: Beifang
authors.initials: B
authors.lastname: Yang
authors.forename: Jingwen
authors.initials: J
authors.lastname: Sun
authors.forename: Jiao
authors.initials: J
authors.lastname: Lou
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Duoshuang
authors.initials: D
authors.lastname: Xie
authors.forename: Yihua
authors.initials: Y
authors.lastname: Xu
authors.forename: Shaofa
authors.initials: S
authors.lastname: Nie
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Miao
mesh_terms: D016022:Case-Control Studies; D002681:China; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D012306:Risk; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects*; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
chemical_list: D018125:Receptors, Transforming Growth Factor beta; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human