title: Single nucleotide polymorphisms in the matrix metalloproteinase gene family and the frequency and duration of gastroesophageal reflux disease influence the risk of esophageal adenocarcinoma.
abstract: The matrix metalloproteinase (MMP) family of proteins mediates various cellular pathways, including apoptosis and angiogenesis. Polymorphisms of MMP genes are associated with increased esophageal adenocarcinoma (EAC) risk. Gastroesophageal reflux disease (GERD) is an established EAC risk factor. We examined whether MMP polymorphism-EAC risk is modified by GERD. In total, 309 EAC patients and 279 frequency-matched healthy controls underwent MMP1 1G/2G, MMP3 6A/5A, MMP12 -82A/G and MMP12 1082A/G genotyping. Questionnaires collected GERD history. EAC risk was analyzed using logistic regression, adjusted for key covariates and stratified by GERD. Joint effects models explored GERD severity and duration, whereas additional models explored genotype-GERD interactions in EAC risk. We determined that each MMP1 and MMP3 minor (variant) allele was independently associated with increased EAC risk (adjusted odds ratio (AOR) 3.2, 95% confidence interval (CI) 2.0-5.1, p < 0.001 and AOR 1.8, 95% CI 1.1-2.7, p = 0.01, respectively) only among those with GERD but not in GERD-free individuals (all p = nonsignificant). There were significant interactions between the MMP1 variants and the presence of GERD (p = 0.002) and between MMP3 variants and GERD (p = 0.04). There was an equally strong interaction between cumulative GERD severity and MMP1 (p = 0.002). The AOR of each variant allele was 14.9 (95% CI 1.6-136) for individuals with severe GERD, 1.7 (95% CI 1.0-2.7) for mild-moderate GERD and 0.98 (95% CI 0.7-1.4) for those without GERD. This was further reflected in separate analyses of frequency and duration of GERD. In conclusion, MMP1 1G/2G (and possibly MMP3 6A/5A) polymorphisms alter EAC risk differentially for GERD and GERD-free individuals.
authors.affiliation: Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors.forename: Winson Y
authors.initials: WY
authors.lastname: Cheung
authors.forename: Rihong
authors.initials: R
authors.lastname: Zhai
authors.forename: Penny
authors.initials: P
authors.lastname: Bradbury
authors.forename: Jessica
authors.initials: J
authors.lastname: Hopkins
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Kulke
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Heist
authors.forename: Kofi
authors.initials: K
authors.lastname: Asomaning
authors.forename: Clement
authors.initials: C
authors.lastname: Ma
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Zhaoxi
authors.initials: Z
authors.lastname: Wang
authors.forename: Suzanne
authors.initials: S
authors.lastname: Hooshmand
authors.forename: Li
authors.initials: L
authors.lastname: Su
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics*; D000368:Aged; D000483:Alleles; D016001:Confidence Intervals; D004938:Esophageal Neoplasms / Q000201:enzymology* / Q000235:genetics*; D005260:Female; D005764:Gastroesophageal Reflux / Q000201:enzymology* / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics*; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D020782:Matrix Metalloproteinases