title: A Candidate-Pathway Approach to Identify Gene-Environment Interactions: Analyses of Colon Cancer Risk and Survival.
abstract: BACKGROUND
  Genetic association studies have traditionally focused on associations between individual single nucleotide polymorphisms (SNPs) and disease. Standard analysis ignores interactions between multiple SNPs and environmental exposures explaining a small portion of disease heritability: the often-cited issue of "missing heritability."
  
  
  METHODS
  We present a novel three-step analytic framework for modeling gene-environment interactions (GEIs) between an angiogenesis candidate-gene pathway and three lifestyle exposures (dietary protein, smoking, and alcohol consumption) on colon cancer risk and survival. Logic regression was used to summarize the gene-pathway effects, and GEIs were modeled using logistic regression and Cox proportional hazards models. We analyzed data from 1541 colon cancer case patients and 1934 control subjects in the Diet, Activity and Lifestyle as a Risk Factor for Colon Cancer Study.
  
  
  RESULTS
  We identified five statistically significant GEIs for colon cancer risk. For risk interaction, odds ratios (ORINT) and 95% confidence intervals (CIs) were FLT1(rs678714) and BMP4(rs17563) and smoking (ORINT = 1.64, 95% CI = 1.11 to 2.41 and ORINT = 1.60, 95% CI = 1.10 to 2.32, respectively); FLT1(rs2387632 OR rs9513070) and protein intake (ORINT = 1.69, 95% CI = 1.03 to 2.77); KDR(rs6838752) and TLR2(rs3804099) and alcohol (ORINT = 1.53, 95% CI = 1.10 to 2.13 and ORINT = 1.59, 95% CI = 1.05 to 2.38, respectively). Three GEIs between TNF, BMP1, and BMPR2 genes and the three exposures were statistically significant at the 5% level in relation to colon cancer survival but not after multiple-testing adjustment.
  
  
  CONCLUSIONS
  Adopting a comprehensive biologically informed candidate-pathway approach identified GEI effects on colon cancer. Findings may have important implications for public health and personalized medicine targeting prevention and therapeutic strategies. Findings from this study need to be validated in other studies.
authors.affiliation: School of Public Health, University of Alberta, Edmonton, Alberta, Canada (NS, QL, CFV, YY); Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT (MLS); Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA (BJC); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (JDP); Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA (JDP); Centre for Public Health Research, Massey University, Wellington, New Zealand (JDP).
authors.forename: Noha
authors.initials: N
authors.lastname: Sharafeldin
authors.affiliation: School of Public Health, University of Alberta, Edmonton, Alberta, Canada (NS, QL, CFV, YY); Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT (MLS); Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA (BJC); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (JDP); Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA (JDP); Centre for Public Health Research, Massey University, Wellington, New Zealand (JDP).
authors.forename: Martha L
authors.initials: ML
authors.lastname: Slattery
authors.affiliation: School of Public Health, University of Alberta, Edmonton, Alberta, Canada (NS, QL, CFV, YY); Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT (MLS); Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA (BJC); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (JDP); Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA (JDP); Centre for Public Health Research, Massey University, Wellington, New Zealand (JDP).
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: School of Public Health, University of Alberta, Edmonton, Alberta, Canada (NS, QL, CFV, YY); Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT (MLS); Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA (BJC); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (JDP); Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA (JDP); Centre for Public Health Research, Massey University, Wellington, New Zealand (JDP).
authors.forename: Conrado
authors.initials: C
authors.lastname: Franco-Villalobos
authors.affiliation: School of Public Health, University of Alberta, Edmonton, Alberta, Canada (NS, QL, CFV, YY); Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT (MLS); Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA (BJC); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (JDP); Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA (JDP); Centre for Public Health Research, Massey University, Wellington, New Zealand (JDP).
authors.forename: Bette J
authors.initials: BJ
authors.lastname: Caan
authors.affiliation: School of Public Health, University of Alberta, Edmonton, Alberta, Canada (NS, QL, CFV, YY); Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT (MLS); Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA (BJC); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (JDP); Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA (JDP); Centre for Public Health Research, Massey University, Wellington, New Zealand (JDP).
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.affiliation: School of Public Health, University of Alberta, Edmonton, Alberta, Canada (NS, QL, CFV, YY); Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT (MLS); Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA (BJC); Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA (JDP); Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA (JDP); Centre for Public Health Research, Massey University, Wellington, New Zealand (JDP). yyasui@ualberta.ca sharafeldin.n@ualberta.ca.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yasui
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000009:adverse effects*; D055395:Bone Morphogenetic Protein 1 / Q000235:genetics*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D003110:Colonic Neoplasms / Q000098:blood supply / Q000209:etiology* / Q000235:genetics; D004044:Dietary Proteins / Q000009:adverse effects*; D005260:Female; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D004044:Dietary Proteins; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II; C525705:BMP1 protein, human; D055395:Bone Morphogenetic Protein 1