title: MAD1L1 Arg558His and MAD2L1 Leu84Met interaction with smoking increase the risk of colorectal cancer.
abstract: The spindle assembly checkpoint (SAC) has been established as an important mechanism of driving aneuploidy, which occurs at a high frequency in the colorectal tumorigenesis. Two important components of SAC are MAD1L1 and MAD2L1, which function together in an interactive manner to initiate the checkpoint signal. We hypothesize that genetic variants in the binding domains of MAD1L1 and MAD2L1 may modulate protein structures and eventually contribute to CRC susceptibility. A case-control study including 710 CRC cases and 735 controls was performed to examine MAD1L1 Arg558His and MAD2L1 Leu84Met's conferring susceptibility to CRC. Cytokinesis-block micronucleus cytome assays were applied to assess the effect of two functional variants on chromosomal instability (CIN). Significant associations with CRC risk were observed for MAD1L1 Arg558His (OR = 1.38,95% CI: 1.09-1.75) and MAD2L1 Leu84Met in a dominant model (OR = 1.48,95% CI: 1.09-2.01). Moreover, significant multiplicative gene-smoking interactions were found in MAD1L1 Arg558His (P = 0.019) and MAD2L184 Leu/Met (P = 0.016) to enhance CRC risk. Additionally, the frequencies of lymphocytic micro-nucleated binucleated cells for MAD1L1 Arg558His polymorphism were significantly different in the exposed group (P = 0.013), but not in the control group. The study emphasized that MAD1L1 Arg558His and MAD2L1 Leu84Met can significantly interact with smoking to enhance CRC risk, and the genetic effects of MAD1L1Arg558His on CIN need to be further clarified in follow-up studies.
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 430030, Hubei, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhong
authors.affiliation: 1] Department of Laboratory Medicine, No 161 Hospital of PLA, Wuhan 430010, China [2] Department of Medical Genetics, school of Basic Medical Science, Wuhan University, Wuhan 430071, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Chen
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 430030, Hubei, China.
authors.forename: Xueqin
authors.initials: X
authors.lastname: Chen
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 430030, Hubei, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Zhu
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 430030, Hubei, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Lou
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 430030, Hubei, China.
authors.forename: Jiaoyuan
authors.initials: J
authors.lastname: Li
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 430030, Hubei, China.
authors.forename: Na
authors.initials: N
authors.lastname: Shen
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 430030, Hubei, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
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 430030, Hubei, China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Gong
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 430030, Hubei, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Clinical Laboratory of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Xia
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 430030, Hubei, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Miao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D003062:Codon; D015179:Colorectal Neoplasms / Q000209:etiology*; D005260:Female; D005787:Gene Frequency; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D064246:Mad2 Proteins / Q000235:genetics*; D008297:Male; D048629:Micronuclei, Chromosome-Defective; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000009:adverse effects*
chemical_list: D018797:Cell Cycle Proteins; D003062:Codon; C501384:MAD1L1 protein, human; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D009687:Nuclear Proteins