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.
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ABSTRACT: A number of studies have evaluated the role of gene-diet interaction in the etiology of colorectal cancer (CRC). Historically, these studies focused on established dietary risk factors and genes involved in their metabolism. However, results from these candidate gene studies were inconsistent, possibly due to multiple testing and publication bias. In recent years, genome-wide association studies have identified a number of CRC susceptibility loci, and subsequent meta-analyses have observed limited evidence that diet may modify the risk associated with these susceptibility loci. Statistical techniques have been recently developed to evaluate the presence of interaction across the entire genome; results from these genome-wide studies have demonstrated limited evidence of interaction and have failed to replicate results from candidate gene studies and those using established susceptibility loci. However, larger sample sizes are likely needed to elucidate modest or weak interaction in genome-wide studies of gene-diet interaction.12/2014; 4(1). DOI:10.1007/s13668-014-0114-2
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ABSTRACT: Recent genome-wide association studies (GWASs) designed to detect the main effects of genetic markers have had considerable success with many findings validated by replication studies. However, relatively few findings of gene-gene or gene-environment interactions have been successfully reproduced. Besides the main issues associated with insufficient sample sizes in current studies, a complication is that interactions that rank high based on p-values often correspond to extreme forms of joint effects that are biologically less plausible. To reduce false positives and to increase power, we develop various gene-environment/gene-gene tests based on biologically more plausible constraints using bivariate isotonic regressions for case-control data. We extend our method to exploit gene-environment or gene-gene independence information, integrating the approach proposed by Chatterjee and Carroll. We propose appropriate nonparametric and parametric permutation procedures for evaluating the significance of the tests. Simulations show that our method gains power over traditional unconstrained methods by reducing the sizes of alternative parameter spaces. We apply our method to several real-data examples, including an analysis of bladder cancer data to detect interactions between the NAT2 gene and smoking. We also show that the proposed method is computationally feasible for large-scale problems by applying it to the National Cancer Institute (NCI) lung cancer GWAS data.Journal of the American Statistical Association 12/2012; 107(500). DOI:10.1080/01621459.2012.726892 · 2.11 Impact Factor
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ABSTRACT: Previous research has shown that greater intakes of dietary folate are associated with reduced risk for colorectal cancer (CRC) and that single nucleotide polymorphisms (SNPs) in genes involved in folate-mediated one-carbon metabolism (FOCM) also may be involved in altering CRC risk. The objective of this study was to evaluate the role of folate intake (and intakes of related dietary components such as methionine), 35 SNPs in three FOCM pathway genes (MTHFD1, MTHFR, and TYMS), and their interactions on CRC risk in a population-based case-control study in Pennsylvania (686 cases, 740 controls). Diet and supplement use was assessed for the year before diagnosis or interview for cases and controls, respectively, with a modified Diet History Questionnaire from the National Cancer Institute. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using unconditional logistic regression. Using a dominant model for the variant allele, several SNPs were significantly associated with CRC including MTHFD1 rs8003379 (OR = 1.65; 95% CI = 1.00-2.73) and rs17824591 (OR = 1.98; 95% CI = 1.14-3.41) and the TYMS rs2853533 SNP (OR = 1.38; 95% CI = 1.05-1.80). Using a nondominant model, the AA genotype for MTHFR rs1476413 exhibited a marginally significant (OR = 1.56; 95% CI = 1.00-2.44) association with CRC. Two TYMS SNPs (rs16948305 and rs495139) exhibited significant (P = 0.024 and P = 0.040, respectively) gene-diet interactions with folate intake. One MTHFD1 (P = 0.019) and one MTHFR (P = 0.042) SNP exhibited gene-diet interactions with methionine intake. These findings suggest that allelic variants in genes involved in FOCM interact with dietary factors including folate and methionine to modify risk for CRC. © 2013 Wiley Periodicals, Inc.Genes Chromosomes and Cancer 07/2013; 52(10). DOI:10.1002/gcc.22089 · 3.84 Impact Factor