Associations between Genes in the One-Carbon Metabolism Pathway and Advanced Colorectal Adenoma Risk in Individuals with Low Folate Intake

Abstract

Folate is essential for one-carbon metabolism, a pathway required by DNA synthesis, methylation, and repair. Low dietary and circulating folate and polymorphic variation in this pathway are associated with increased risk of colorectal adenoma and cancer. We genotyped 882 single nucleotide polymorphisms (SNP) in 82 one-carbon metabolism genes for 1,331 cases of advanced colorectal adenoma, identified by sigmoidoscopy at baseline, and 1,501 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). We evaluated associations between one-carbon genes and adenoma risk in all subjects and stratified by folate intake. We applied the Adaptive Rank Truncated Product (ARTP) method to assess statistical significance at the gene and pathway levels. Folate intake was inversely associated with advanced colorectal adenoma risk [odds ratio (OR) by quartile = 0.85, P = 1.9 × 10(-5)]. We found no statistically significant associations between one-carbon genes and adenoma risk in all subjects. As hypothesized, we observed a statistically significant pathway-level association (P = 0.038) in the lowest quartile of folate; no significant associations were found in higher quartiles. Several genes including adenosine deaminase (ADA) and cysteine dioxygenase (CDO1) contributed to this signal (gene-level P = 0.001 and 0.0073, respectively). The most statistically significant SNP was rs244072 in ADA (P = 2.37 × 10(-5)). Stratification by dietary folate and application of the ARTP method revealed statistically significant pathway- and gene-level associations between one-carbon metabolism genes and risk of advanced colorectal adenoma, which were not apparent in analysis of the entire population. Folate intake may interact with associations between common variants in one-carbon metabolism genes and colorectal adenoma risk.