title: Intronic and promoter polymorphisms of hMLH1/hMSH2 and colorectal cancer risk in Heilongjiang Province of China.
abstract: OBJECTIVE
  Given that mismatch repair (MMR) system plays an important role in recognizing and removing insertion/deletion mutations which occur during DNA replication, common variants associated with impaired MMR system may thus increase risk of colorectal cancer (CRC). Therefore, we aimed to demonstrate the associations between common variants in two MMR genes (hMLH1 and hMSH2) and CRC risk.
  
  
  METHODS
  We genotyped 10 intronic/promoter single-nucleotide polymorphisms (SNPs) of hMLH1 and hMSH2 in 451 CRC patients and 630 controls. Associations between genotypes and CRC risk were estimated using odds ratios and 95 % confidence intervals. Gene-gene interactions, as well as gene-environment interactions on CRC risk were also investigated.
  
  
  RESULTS
  We found that IVS15-214T>C and IVS11 + 107A>G of hMSH2 were significantly associated with CRC risk. In dominant model, variant carriers of the two SNPs could decrease risk of CRC by 31 % (ORadj = 0.69, 95 % CI 0.53-0.91, p < 0.01) and 33 % (ORadj = 0.67, 95 % CI 0.47-0.95, p = 0.02), respectively. In addition, IVS7-212T>A, IVS11+183A>G and IVS8+719T>C of hMSH2 were associated with the susceptibility to colon cancer rather than rectal cancer. ATTTGGGT and TCTTAGAC haplotypes were associated with 44 and 45 % decreased risk of CRC, respectively, while ATTTGAGT and TTTCAGAC haplotypes were associated with 1.37-fold and 2.49-fold increased risk of CRC, respectively. There was a significant three-way gene-gene interaction among hMSH2 IVS11+107A>G, IVS11+183A>G and IVS8+719T>C (p < 0.01). Significant gene-environment interactions were observed between hMSH2 IVS15-214T>C and IVS11+107A>G and cereals consumption (both with p < 0.01).
  
  
  CONCLUSIONS
  Our findings suggested that intronic SNPs, gene-gene and gene-environment interactions in hMSH2 might be associated with susceptibility to CRC.
authors.affiliation: Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, Heilongjiang Province, People's Republic of China.
authors.forename: Guangxiao
authors.initials: G
authors.lastname: Li
authors.forename: Fulan
authors.initials: F
authors.lastname: Hu
authors.forename: Fengshun
authors.initials: F
authors.lastname: Yuan
authors.forename: Jialong
authors.initials: J
authors.lastname: Fan
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Yu
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wu
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Zhao
authors.forename: Ye
authors.initials: Y
authors.lastname: Li
authors.forename: Shuying
authors.initials: S
authors.lastname: Li
authors.forename: Jiesheng
authors.initials: J
authors.lastname: Rong
authors.forename: Binbin
authors.initials: B
authors.lastname: Cui
authors.forename: Xinshu
authors.initials: X
authors.lastname: Dong
authors.forename: Huiping
authors.initials: H
authors.lastname: Yuan
authors.forename: Yashuang
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein