title: Mismatch repair polymorphisms and colorectal polyps: hMLH1-93G>A variant modifies risk associated with smoking.
abstract: OBJECTIVE
  Mutations in the mismatch repair (MMR) enzymes hMLH1 and hMSH6 are known causes of hereditary nonpolyposis colorectal cancer and act by inducing a mutator phenotype characterized by microsatellite instability. The aim of our study was to determine if polymorphisms in the DNA MMR genes hMLH1 and hMSH6 are associated with an increased risk of colorectal polyps, and to evaluate interactions with exposures known to cause DNA damage.
  
  
  METHODS
  In a Minnesota-based case-control study of individuals with adenomas (N=401), hyperplastic polyps (N=195), or both adenomas and hyperplastic polyps (N=123) versus polyp-free controls (N=624), we investigated the role of hMLH1-93G>A, hMLH1 I219V, and hMSH6 G39E polymorphisms in increasing the risk of colorectal polyps. Polytomous multivariate logistic regression analysis was used, adjusting for age, sex, body mass index, postmenopausal hormone use, aspirin use, and NSAID use.
  
  
  RESULTS
  Overall, no evidence of an association between any of the three polymorphisms or hMLH1 haplotypes and colorectal polyps was observed. However, risk associated with the hMLH1-93A variant differed by smoking: smoking-associated risks were stronger among those with variant -93AA or -93AG genotypes, showing a twofold greater risk of adenoma with >25 pack-years of smoking compared with nonsmokers, and a corresponding eightfold greater risk of hyperplastic polyps (genotype smoking: p-interaction=0.02 for hyperplastic polyps and p-interaction=0.08 for adenomas).
  
  
  CONCLUSIONS
  These data are consistent with the observation that smoking is associated with MMR in colorectal neoplasia and suggest that the risk increase with smoking may differ by hMLH1-93G>A genotype.
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington 98109-1024, USA.
authors.forename: Joon-Ho
authors.initials: JH
authors.lastname: Yu
authors.forename: Jeannette
authors.initials: J
authors.lastname: Bigler
authors.forename: John
authors.initials: J
authors.lastname: Whitton
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D020137:Base Pair Mismatch; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016009:Chi-Square Distribution; D003111:Colonic Polyps / Q000201:enzymology / Q000235:genetics*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D011795:Surveys and Questionnaires
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1