Background Insulin-like Growth Factor (IGF)-1 has been proposed to mediate the obesity-related carcinogenic effects of 'western lifestyle'. While genetic factors explain at least half of inter-individual IGF1 variation, the IGF1 polymorphisms hypothesized to underlie the variation in cancer incidence rates remain ill-defined.
Methods We used a comparative genomics approach to identify putative regulatory polymorphisms in the IGF1 promoter region within a rapidly westernizing population, the Singapore Chinese. Association of IGF1 genotype with colorectal cancer risk was assessed among 298 colorectal cancer cases and 1142 controls nested within the Singapore Chinese Health Study.
Results We identified a common (minor allele frequency = 0.36) single nucleotide polymorphism (SNP), IGF1-2995 C/A, within a consensus domain for an octamer binding factor (Oct1/Oct2) transcription factor binding site. Possession of one or two copies of the minor allele (genotypes AA and CA) conferred an approximate 40 per cent decrease in risk in comparison to genotype CC (odds ratio: 0.59; 95 percent confidence interval: 0.45, 0.77). This association was stronger for colon than for rectal cancer (Ρheterogeneity< 0.001) and for those who were physically active vs. inactive (Ρinteraction=0.05). Models including other previously identified promoter polymorphisms did not provide a better prediction of colorectal cancer risk.
Conclusions Our results support the hypotheses that IGF1 plays a role in colonic carcinogenesis and that genetically inherited variation in IGF1 expression influences risk of colorectal cancer.