title: Insulin pathway related genes and risk of colorectal cancer: INSR promoter polymorphism shows a protective effect.
abstract: Western lifestyle leading to obesity and type 2 diabetes has been associated with increased risk of colorectal cancer (CRC). Diet and related factors may affect the risk by modifying plasma insulin levels. Thus, the inter-individual variation in insulin signaling may play a plausible role in the development of CRC. We hypothesized that functional polymorphisms in the insulin pathway genes INS, INSR, IGFBPI, insulin receptor substrate 1 (IRS1), and IRS2 may be associated with CRC. We studied the association of five single nucleotide polymorphisms (SNPs) with the risk of CRC using a hospital-based case-control design with 712 cases and 748 controls from the Czech Republic. The INSR A-603G promoter SNP, which is located within a known Sp1-binding site, was associated with the risk of CRC, with carriers of the G allele having a decreased risk (odds ratios (OR) 0.71, 95% confidence interval (CI) 0.54-0.93). Carrying the variant allele of the IRS1 Gly972Arg SNP further decreased the risk among the INSR-603G allele carriers (OR 0.28, 95% CI 0.11-0.70). SNPs in the INS, IGFBPI, and IRS2 genes did not affect the risk of CRC. In conclusion, genetic variation in the insulin signaling pathway genes may affect the risk of CRC.
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors.forename: Sonali
authors.initials: S
authors.lastname: Pechlivanis
authors.forename: Barbara
authors.initials: B
authors.lastname: Pardini
authors.forename: Justo Lorenzo
authors.initials: JL
authors.lastname: Bermejo
authors.forename: Kerstin
authors.initials: K
authors.lastname: Wagner
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
authors.forename: Ludmila
authors.initials: L
authors.lastname: Vodickova
authors.forename: Jan
authors.initials: J
authors.lastname: Novotny
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D015703:Antigens, CD; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; C435941:INSR protein, human; D011972:Receptor, Insulin