title: Energy restriction at young age, genetic variants in the insulin-like growth factor pathway and colorectal cancer risk in the Netherlands Cohort Study.
abstract: The energy restriction (ER)-colorectal cancer (CRC) association is inconsistent in literature. To strengthen the biological plausibility of the ER-CRC association, we investigated whether genetic variation in the insulin-like growth factor (IGF) pathway, a putative underlying mechanism, modulated this association in the Netherlands Cohort Study. Participants completed a questionnaire (n = 120,852) and provided toenail clippings for DNA (∼75%) at baseline. Individuals living in a Western city during the Hunger Winter (1944-45) or Western rural versus non-Western area were exposed to (severe) ER at young age. Genotyping was performed for 3,768 subcohort members and 2,580 CRC cases (case-cohort with 16.3 years follow-up). Cox hazard ratios for CRC were estimated across combined categories of ER and a genetic sum score of unfavorable alleles based on 18 single nucleotide polymorphisms in IGF-related genes and ER and an IGF1 19-CA repeat polymorphism. The reference included ER exposed individuals, so that increased hazard ratios were expected in higher combined categories for calculating relative excess risks due to interaction (additive interactions). Wald tests for multiplicative interactions were also performed. Multiplicative and additive interactions were nonsignificant. Combined ER-genetic sum score categories showed increasing CRC risks in men, but confidence intervals were wide. Women carrying two variant IGF1 19-CA repeat alleles versus those carrying two wild type IGF1 19-CA repeat alleles were at an ∼50% decreased CRC risk, irrespective of ER exposure. In conclusion, data indicate that the IGF pathway might be involved in the ER-CRC association in men, but not women, although interactions were nonsignificant, hampering definite conclusions.
authors.affiliation: Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
authors.forename: Colinda C J M
authors.initials: CC
authors.lastname: Simons
authors.affiliation: Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Schouten
authors.affiliation: Department of Toxicology, NUTRIM-School for Nutrition and Translational Research on Metabolism, Maastricht University, Maastricht, the Netherlands.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Godschalk
authors.affiliation: Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Manon
authors.initials: M
authors.lastname: van Engeland
authors.affiliation: Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
authors.forename: Piet A
authors.initials: PA
authors.lastname: van den Brandt
authors.affiliation: Department of Toxicology, NUTRIM-School for Nutrition and Translational Research on Metabolism, Maastricht University, Maastricht, the Netherlands.
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: van Schooten
authors.affiliation: Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
authors.forename: Matty P
authors.initials: MP
authors.lastname: Weijenberg
mesh_terms: D000483:Alleles; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics
chemical_list: C583557:IGF1 protein, human; D007334:Insulin-Like Growth Factor I
keywords: colon neoplasms; energy restriction; insulin-like growth factors; polymorphisms; rectal neoplasms