title: Folate-genetics and colorectal neoplasia: what we know and need to know next.
abstract: METHODS
  The metabolism of folate involves a complex network of polymorphic enzymes that may explain a proportion of the risk associated with colorectal neoplasia. Over 60 observational studies primarily in non-Hispanic White populations have been conducted on selected genetic variants in specific genes, MTHFR, MTR, MTRR, CBS, TCNII, RFC, GCPII, SHMT, TYMS, and MTHFD1, including five meta-analyses on MTHFR 677C>T (rs1801133) and MTHFR 1298C>T (rs1801131); two meta-analyses on MTR-2756A>C (rs1805087); and one for MTRR 66A>G (rs1801394).
  
  
  RESULTS
  This systematic review synthesizes these data, highlighting the consistent inverse association between MTHFR 677TT genotype and risk of colorectal cancer (CRC) and its null association with adenoma risk. Results for other variants varied across individual studies; in our meta-analyses we observed some evidence for SHMT 1420C>T (rs1979277) ((odds ratio) OR = 0.85; 95% confidence interval (CI) = 0.73-1.00 for TT v. CC) and TYMS 5' 28 bp repeat (rs34743033) and CRC risk (OR = 0.84; 95% CI = 0.75-0.94 for 2R/3R v. 3R/3R and OR = 0.82; 95% CI = 0.69-0.98 for 2R/2R v. 3R/3R).
  
  
  CONCLUSIONS
  To gain further insight into the role of folate variants in colorectal neoplasia will require incorporating measures of the metabolites, including B-vitamin cofactors, homocysteine and S-adenosylmethionine, and innovative statistical methods to better approximate the folate one-carbon metabolism pathway.
authors: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. janefigu@usc.edu
authors: Jane C
authors: JC
authors: Figueiredo
authors: A Joan
authors: AJ
authors: Levine
authors: Jimmy W
authors: JW
authors: Crott
authors: James
authors: J
authors: Baurley
authors: Robert W
authors: RW
authors: Haile
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D005287:Ferredoxin-NADP Reductase / Q000235:genetics; D005492:Folic Acid / Q000008:administration & dosage* / Q000097:blood; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006710:Homocysteine / Q000235:genetics; D006801:Humans; D015201:Meta-Analysis as Topic; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D012436:S-Adenosylmethionine / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D006710:Homocysteine; D012436:S-Adenosylmethionine; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D013940:Thymidylate Synthase