title: Folate-mediated one-carbon metabolism genes and interactions with nutritional factors on colorectal cancer risk: Women's Health Initiative Observational Study.
abstract: BACKGROUND
  Investigations of folate-mediated one-carbon metabolism (FOCM) genes and gene-nutrient interactions with respect to colorectal cancer (CRC) risk are limited to candidate polymorphisms and dietary folate. This study comprehensively investigated associations between genetic variants in FOCM and CRC risk and whether the FOCM nutrient status modified these associations.
  
  
  METHODS
  Two hundred eighty-eight candidate and tagging single-nucleotide polymorphisms (SNPs) in 30 FOCM genes were genotyped for 821 incident CRC case-control matched pairs in the Women's Health Initiative Observational Study cohort. FOCM biomarkers (red blood cell [RBC] folate, plasma folate, pyridoxal-5'-phosphate [PLP], vitamin B12, and homocysteine) and self-reported alcohol consumption were measured at the baseline. Conditional logistic regression was implemented; effect modification was examined on the basis of known enzyme-nutrient relations.
  
  
  RESULTS
  Statistically significant associations were observed between CRC risk and functionally defined candidate SNPs of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1; K134R), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR; P450R), and PR domain containing 2 with ZNF domain (PRDM2; S450N) and a literature candidate SNP of thymidylate synthase (TYMS; g.676789A>T; nominal P < .05). In addition, suggestive associations were noted for tagging SNPs in cystathionine-β-synthase (CBS), dihydrofolate reductase (DHFR), DNA (cytosine-5-)-methyltransferase 3β (DNMT3B), methionine adenosyltransferase I α (MAT1A), MTHFD1, and MTRR (nominal P < .05; adjusted P, not significant). Significant interactions between nutrient biomarkers and candidate polymorphisms were observed for 1) plasma/RBC folate and folate hydrolase 1 (FOLH1), paraoxonase 1 (PON1), transcobalamin II (TCN2), DNMT1, and DNMT3B; 2) plasma PLP and TYMS TS3; 3) plasma B12 and betaine-homocysteine S-methyltransferase 2 (BHMT2); and 4) homocysteine and methylenetetrahydrofolate reductase (MTHFR) and alanyl-transfer RNA synthetase (AARS).
  
  
  CONCLUSIONS
  Genetic variants in FOCM genes are associated with CRC risk among postmenopausal women. FOCM nutrients continue to emerge as effect modifiers of genetic influences on CRC risk.
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Ting-Yuan David
authors.initials: TY
authors.lastname: Cheng
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Makar
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Marian L
authors.initials: ML
authors.lastname: Neuhouser
authors.affiliation: Department of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey.|Department of Pathology and Laboratory Medicine, University of California Davis, Davis, California.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Miller
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Song
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Elissa C
authors.initials: EC
authors.lastname: Brown
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Shirley A A
authors.initials: SA
authors.lastname: Beresford
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Yingye
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Medicine, Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Poole
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Galbraith
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: David J
authors.initials: DJ
authors.lastname: Duggan
authors.affiliation: Department of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Habermann
authors.affiliation: Department of Foods and Nutrition, University of Georgia, Athens, Georgia.
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Bailey
authors.affiliation: Department of Food Science and Human Nutrition, University of Florida, Gainesville, Florida.
authors.forename: David R
authors.initials: DR
authors.lastname: Maneval
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Caudill
authors.affiliation: Department of Surgery, Division of Public Health Sciences and Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Adetunji T
authors.initials: AT
authors.lastname: Toriola
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Davis, Davis, California.
authors.forename: Ralph
authors.initials: R
authors.lastname: Green
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Department of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.|Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics; D005492:Folic Acid / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D018570:Risk Assessment; D014157:Transcription Factors / Q000235:genetics; D014803:Vitamin B Complex / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D014157:Transcription Factors; D014803:Vitamin B Complex; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D011495:Histone-Lysine N-Methyltransferase; C093563:PRDM2 protein, human
keywords: biomarker; colorectal cancer; gene-nutrient interaction; one-carbon metabolism; postmenopausal women