Application of the Explicit Test of Epistasis to Colon Cancer

The paper below by Leroy et al. is a nice example of how the explicit test of epistasis by Greene et al. can be used with MDR to identify and confirm interactions that are independent of marginal effects.

Greene CS, Himmelstein DS, Nelson HH, Kelsey KT, Williams SM, Andrew AS, Karagas MR, Moore JH. Enabling personal genomics with an explicit test of epistasis. Pac Symp Biocomput. 2010:327-36. [PubMed]

Leroy EC, Moore JH, Hu C, Martínez ME, Lance P, Duggan D, Thompson PA. Genes in the insulin and insulin-like growth factor pathway and odds of metachronous colorectal neoplasia. Hum Genet. 2011 Jan 11. [Epub ahead of print] PubMed PMID: 21221997. [PubMed]

Abstract

Insulin and insulin-like growth factor (IGF) genes are implicated in colorectal carcinogenesis. Gene-by-gene interactions that influence the insulin/IGF pathways were hypothesized as modifiers of colorectal neoplasia risk. We built a classification tree to detect interactions in 18 IGF and insulin pathway-related genes and metachronous colorectal neoplasia among 1,439 subjects pooled from two chemoprevention trials. The probability of colorectal neoplasia was greatest (71.8%) among carriers of any A allele for rs7166348 (IGF1R) and AA genotype for rs1823023 (PIK3R1). In contrast, carriers of any A at rs7166348 (IGF1R), any G for the PIK3R1 variant, and AA for rs10426094 (INSR) had the lowest probability (14.3%). Logistic regression modeling showed that any A at rs7166348 (IGF1R) with the AA genotype at rs1823023 (PIK3R1) conferred the highest odds of colorectal neoplasia (OR 3.7; 95% CI 2.2-6.5), compared with carriage of GG at rs7166348 (IGF1R). Conversely, any A at rs7166348 (IGFR1), any G allele at rs1823023 (PIK3R1), and the AA genotype at rs10426094 (INSR) conferred the lowest odds (OR 0.22; 95% CI 0.07-0.66). Stratifying the analysis by parent study and intervention arm showed highly consistent trends in direction and magnitude of associations, with preliminary evidence of genotype effects on measured IGF-1 levels in a subgroup of subjects. These results were compared to those from multifactor dimensionality reduction, which identified different single nucleotide polymorphisms in the same genes (INSR and IGF1R) as effect modifiers for colorectal neoplasia. These results support a role for genetic interactions in the insulin/IGF pathway genes in colorectal neoplasia risk.