Gene-specific DNA methylation of DNMT3B and MTHFR and colorectal adenoma risk.
DNA methyltransferase 3B (DNMT3B) and methylenetetrahydrofolate reductase (MTHFR) are genes which encode enzymes critical to one-carbon metabolism. Polymorphisms in these genes have been implicated in colorectal cancer etiology; however, epigenetic modifications such as gene-specific DNA methylation also affect gene expression. DNA methylation of DNMT3B and MTHFR was quantified in blood leukocytes using Sequenom EpiTYPER® among 272 participants undergoing a screening colonoscopy. DNA methylation was quantified in 66 and 28CpG sites of DNMT3B and MTHFR respectively, and conceptualized using two approaches. First, measures representing average methylation across all CpG sites were created. Second, unsupervised principal component (PC) analysis was used to identify summary variables representing methylation around the transcription start site and in the gene-coding area for both DNMT3B and MTHFR. Logistic regression was used to compare methylation levels between participants diagnosed with colorectal adenoma(s) versus those with a normal colonoscopy via the estimation of odds ratios (ORs) and 95% confidence intervals (95% CIs) for the risk of colorectal adenomas. No association was observed between average DNA methylation of either DNMT3B or MTHFR and colorectal adenoma risk. For DNMT3B, increasing DNA methylation of CpG sites in the gene-coding area was associated with a higher risk of colorectal adenomas (OR=1.34; 95% CI: 1.01-1.79 per SD). This research provides preliminary evidence that methylation of DNMT3B may have functional significance with respect to colorectal adenomas, precursors to the vast majority of colorectal cancers.
Department of Public Health Sciences, Queen's University, Kingston, Ontario K7L3N6, Canada. Electronic address: vikki.epid@gmail.com.
Vikki
V
Ho
Department of Public Health Sciences, Queen's University, Kingston, Ontario K7L3N6, Canada.
Janet E
JE
Ashbury
Department of Medical Genetics, University of Alberta, Edmonton, Alberta T6G 2R3, Canada.
Sherryl
S
Taylor
Gastrointestinal Diseases Research Unit (GIDRU), Queen's University, Kingston, Ontario K7L3N6, Canada.
Stephen
S
Vanner
Department of Public Health Sciences, Queen's University, Kingston, Ontario K7L3N6, Canada.
Will D
WD
King
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D003113:Colonoscopy; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D003430:Cross-Sectional Studies; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D012306:Risk; D000097584:DNA Methyltransferase 3B
D004248:DNA (Cytosine-5-)-Methyltransferases; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000097584:DNA Methyltransferase 3B; C573423:MTHFR protein, human
Colorectal neoplasms; DNA methylation; DNA methyltransferase 3B; Epigenomics; Methylenetetrahydrofolate reductase; One-carbon metabolism