title: Genetic Variants in the Insulin-like Growth Factor Pathway and Colorectal Cancer Risk in the Netherlands Cohort Study.
abstract: Interrelationships between insulin-like growth factors (IGFs), hyperinsulinaemia, diabetes, and colorectal cancer (CRC) indicate involvement of IGFs in colorectal tumorigenesis. We investigated the CRC risk associated with 24 single nucleotide polymorphisms (SNPs) in 9 genes related to the IGF pathway and an IGF1 19-CA repeat polymorphism. Variants were selected from literature and genotyped in toenail DNA from 3,768 subcohort members and 2,580 CRC cases from the Netherlands Cohort Study, which has a case-cohort design (n = 120,852). We used the follow-up period 1986-2002. Eighteen SNPs were unequivocally associated with selected endpoints in the literature and unfavorable alleles were aggregated into a genetic sum score. Cox regression showed that a higher genetic sum score significantly increased CRC risk at all subsites, except the rectum, in men (highest vs. lowest tertile: HR for CRC = 1.36, 95% CI: 1.11, 1.65; P-trend = 0.002). Single SNPs (except the IGF1 SNP rs5742694) were not associated with risk. Models including the total number of IGF1 19-CA repeats showed CRC risk was halved at all subsites in women carrying < 38 repeats but not > 38 repeats (≤ 36 versus 38 repeats: HR for CRC = 0.44; 95% CI: 0.33, 0.58; P-trend < 0.001). These findings support a role for variants in IGF-related genes in colorectal tumorigenesis.
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 of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.
authors.forename: Roger W L
authors.initials: RW
authors.lastname: Godschalk
authors.affiliation: Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, 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 of Nutrition and Translational Research in 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: D000368:Aged; D000483:Alleles; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012306:Risk; D015398:Signal Transduction; D013002:Somatomedins / Q000235:genetics* / Q000378:metabolism
chemical_list: D013002:Somatomedins