title: Assessing the association between the methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism and blood folate concentrations: a systematic review and meta-analysis of trials and observational studies.
abstract: BACKGROUND
  The methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism is a risk factor for neural tube defects. The T allele produces an enzyme with reduced folate-processing capacity, which has been associated with lower blood folate concentrations.
  
  
  OBJECTIVE
  We assessed the association between MTHFR C677T genotypes and blood folate concentrations among healthy women aged 12-49 y.
  
  
  METHODS
  We conducted a systematic review of the literature published from January 1992 to March 2014 to identify trials and observational studies that reported serum, plasma, or red blood cell (RBC) folate concentrations and MTHFR C677T genotype. We conducted a meta-analysis for estimates of percentage differences in blood folate concentrations between genotypes.
  
  
  RESULTS
  Forty studies met the inclusion criteria. Of the 6 studies that used the microbiologic assay (MA) to measure serum or plasma (S/P) and RBC folate concentrations, the percentage difference between genotypes showed a clear pattern of CC > CT > TT. The percentage difference was greatest for CC > TT [S/P: 13%; 95% credible interval (CrI): 7%, 18%; RBC: 16%; 95% CrI: 12%, 20%] followed by CC > CT (S/P: 7%; 95% CrI: 1%, 12%; RBC: 8%; 95% CrI: 4%, 12%) and CT > TT (S/P: 6%; 95% CrI: 1%, 11%; RBC: 9%; 95% CrI: 5%, 13%). S/P folate concentrations measured by using protein-binding assays (PBAs) also showed this pattern but to a greater extent (e.g., CC > TT: 20%; 95% CrI: 17%, 22%). In contrast, RBC folate concentrations measured by using PBAs did not show the same pattern and are presented in the Supplemental Material only.
  
  
  CONCLUSIONS
  Meta-analysis results (limited to the MA, the recommended population assessment method) indicated a consistent percentage difference in S/P and RBC folate concentrations across MTHFR C677T genotypes. Lower blood folate concentrations associated with this polymorphism could have implications for a population-level risk of neural tube defects.
authors: From the Division of Birth Defects and Developmental Disabilities, National Center for Birth Defects and Developmental Disabilities (NCBDDD), CDC, Atlanta, GA (AMC, RJB, JR, and KSC); the Division of Nutrition, Physical Activity, and Obesity, National Center on Chronic Disease Prevention and Health Promotion, CDC, Atlanta, GA (HCH); Acentia (contractor for CDC, NCBDDD), Falls Church, VA (JG); Carter Consulting Inc. (contractor for CDC, NCBDDD), Atlanta, GA (OJD, JM, and YPQ); the Oak Ridge Institute for Science and Education, Oak Ridge, TN (BLT, CMM, and YPQ); SciMetrika LLC (contractor for CDC, NCBDDD), Atlanta, GA (PM).
authors: Becky L
authors: BL
authors: Tsang
authors: From the Division of Birth Defects and Developmental Disabilities, National Center for Birth Defects and Developmental Disabilities (NCBDDD), CDC, Atlanta, GA (AMC, RJB, JR, and KSC); the Division of Nutrition, Physical Activity, and Obesity, National Center on Chronic Disease Prevention and Health Promotion, CDC, Atlanta, GA (HCH); Acentia (contractor for CDC, NCBDDD), Falls Church, VA (JG); Carter Consulting Inc. (contractor for CDC, NCBDDD), Atlanta, GA (OJD, JM, and YPQ); the Oak Ridge Institute for Science and Education, Oak Ridge, TN (BLT, CMM, and YPQ); SciMetrika LLC (contractor for CDC, NCBDDD), Atlanta, GA (PM).
authors: Owen J
authors: OJ
authors: Devine
authors: From the Division of Birth Defects and Developmental Disabilities, National Center for Birth Defects and Developmental Disabilities (NCBDDD), CDC, Atlanta, GA (AMC, RJB, JR, and KSC); the Division of Nutrition, Physical Activity, and Obesity, National Center on Chronic Disease Prevention and Health Promotion, CDC, Atlanta, GA (HCH); Acentia (contractor for CDC, NCBDDD), Falls Church, VA (JG); Carter Consulting Inc. (contractor for CDC, NCBDDD), Atlanta, GA (OJD, JM, and YPQ); the Oak Ridge Institute for Science and Education, Oak Ridge, TN (BLT, CMM, and YPQ); SciMetrika LLC (contractor for CDC, NCBDDD), Atlanta, GA (PM).
authors: Amy M
authors: AM
authors: Cordero
authors: From the Division of Birth Defects and Developmental Disabilities, National Center for Birth Defects and Developmental Disabilities (NCBDDD), CDC, Atlanta, GA (AMC, RJB, JR, and KSC); the Division of Nutrition, Physical Activity, and Obesity, National Center on Chronic Disease Prevention and Health Promotion, CDC, Atlanta, GA (HCH); Acentia (contractor for CDC, NCBDDD), Falls Church, VA (JG); Carter Consulting Inc. (contractor for CDC, NCBDDD), Atlanta, GA (OJD, JM, and YPQ); the Oak Ridge Institute for Science and Education, Oak Ridge, TN (BLT, CMM, and YPQ); SciMetrika LLC (contractor for CDC, NCBDDD), Atlanta, GA (PM).
authors: Claire M
authors: CM
authors: Marchetta
authors: From the Division of Birth Defects and Developmental Disabilities, National Center for Birth Defects and Developmental Disabilities (NCBDDD), CDC, Atlanta, GA (AMC, RJB, JR, and KSC); the Division of Nutrition, Physical Activity, and Obesity, National Center on Chronic Disease Prevention and Health Promotion, CDC, Atlanta, GA (HCH); Acentia (contractor for CDC, NCBDDD), Falls Church, VA (JG); Carter Consulting Inc. (contractor for CDC, NCBDDD), Atlanta, GA (OJD, JM, and YPQ); the Oak Ridge Institute for Science and Education, Oak Ridge, TN (BLT, CMM, and YPQ); SciMetrika LLC (contractor for CDC, NCBDDD), Atlanta, GA (PM).
authors: Joseph
authors: J
authors: Mulinare
authors: From the Division of Birth Defects and Developmental Disabilities, National Center for Birth Defects and Developmental Disabilities (NCBDDD), CDC, Atlanta, GA (AMC, RJB, JR, and KSC); the Division of Nutrition, Physical Activity, and Obesity, National Center on Chronic Disease Prevention and Health Promotion, CDC, Atlanta, GA (HCH); Acentia (contractor for CDC, NCBDDD), Falls Church, VA (JG); Carter Consulting Inc. (contractor for CDC, NCBDDD), Atlanta, GA (OJD, JM, and YPQ); the Oak Ridge Institute for Science and Education, Oak Ridge, TN (BLT, CMM, and YPQ); SciMetrika LLC (contractor for CDC, NCBDDD), Atlanta, GA (PM).
authors: Patricia
authors: P
authors: Mersereau
authors: From the Division of Birth Defects and Developmental Disabilities, National Center for Birth Defects and Developmental Disabilities (NCBDDD), CDC, Atlanta, GA (AMC, RJB, JR, and KSC); the Division of Nutrition, Physical Activity, and Obesity, National Center on Chronic Disease Prevention and Health Promotion, CDC, Atlanta, GA (HCH); Acentia (contractor for CDC, NCBDDD), Falls Church, VA (JG); Carter Consulting Inc. (contractor for CDC, NCBDDD), Atlanta, GA (OJD, JM, and YPQ); the Oak Ridge Institute for Science and Education, Oak Ridge, TN (BLT, CMM, and YPQ); SciMetrika LLC (contractor for CDC, NCBDDD), Atlanta, GA (PM).
authors: Jing
authors: J
authors: Guo
authors: From the Division of Birth Defects and Developmental Disabilities, National Center for Birth Defects and Developmental Disabilities (NCBDDD), CDC, Atlanta, GA (AMC, RJB, JR, and KSC); the Division of Nutrition, Physical Activity, and Obesity, National Center on Chronic Disease Prevention and Health Promotion, CDC, Atlanta, GA (HCH); Acentia (contractor for CDC, NCBDDD), Falls Church, VA (JG); Carter Consulting Inc. (contractor for CDC, NCBDDD), Atlanta, GA (OJD, JM, and YPQ); the Oak Ridge Institute for Science and Education, Oak Ridge, TN (BLT, CMM, and YPQ); SciMetrika LLC (contractor for CDC, NCBDDD), Atlanta, GA (PM).
authors: Yan Ping
authors: YP
authors: Qi
authors: From the Division of Birth Defects and Developmental Disabilities, National Center for Birth Defects and Developmental Disabilities (NCBDDD), CDC, Atlanta, GA (AMC, RJB, JR, and KSC); the Division of Nutrition, Physical Activity, and Obesity, National Center on Chronic Disease Prevention and Health Promotion, CDC, Atlanta, GA (HCH); Acentia (contractor for CDC, NCBDDD), Falls Church, VA (JG); Carter Consulting Inc. (contractor for CDC, NCBDDD), Atlanta, GA (OJD, JM, and YPQ); the Oak Ridge Institute for Science and Education, Oak Ridge, TN (BLT, CMM, and YPQ); SciMetrika LLC (contractor for CDC, NCBDDD), Atlanta, GA (PM).
authors: Robert J
authors: RJ
authors: Berry
authors: From the Division of Birth Defects and Developmental Disabilities, National Center for Birth Defects and Developmental Disabilities (NCBDDD), CDC, Atlanta, GA (AMC, RJB, JR, and KSC); the Division of Nutrition, Physical Activity, and Obesity, National Center on Chronic Disease Prevention and Health Promotion, CDC, Atlanta, GA (HCH); Acentia (contractor for CDC, NCBDDD), Falls Church, VA (JG); Carter Consulting Inc. (contractor for CDC, NCBDDD), Atlanta, GA (OJD, JM, and YPQ); the Oak Ridge Institute for Science and Education, Oak Ridge, TN (BLT, CMM, and YPQ); SciMetrika LLC (contractor for CDC, NCBDDD), Atlanta, GA (PM).
authors: Jorge
authors: J
authors: Rosenthal
authors: From the Division of Birth Defects and Developmental Disabilities, National Center for Birth Defects and Developmental Disabilities (NCBDDD), CDC, Atlanta, GA (AMC, RJB, JR, and KSC); the Division of Nutrition, Physical Activity, and Obesity, National Center on Chronic Disease Prevention and Health Promotion, CDC, Atlanta, GA (HCH); Acentia (contractor for CDC, NCBDDD), Falls Church, VA (JG); Carter Consulting Inc. (contractor for CDC, NCBDDD), Atlanta, GA (OJD, JM, and YPQ); the Oak Ridge Institute for Science and Education, Oak Ridge, TN (BLT, CMM, and YPQ); SciMetrika LLC (contractor for CDC, NCBDDD), Atlanta, GA (PM).
authors: Krista S
authors: KS
authors: Crider
authors: From the Division of Birth Defects and Developmental Disabilities, National Center for Birth Defects and Developmental Disabilities (NCBDDD), CDC, Atlanta, GA (AMC, RJB, JR, and KSC); the Division of Nutrition, Physical Activity, and Obesity, National Center on Chronic Disease Prevention and Health Promotion, CDC, Atlanta, GA (HCH); Acentia (contractor for CDC, NCBDDD), Falls Church, VA (JG); Carter Consulting Inc. (contractor for CDC, NCBDDD), Atlanta, GA (OJD, JM, and YPQ); the Oak Ridge Institute for Science and Education, Oak Ridge, TN (BLT, CMM, and YPQ); SciMetrika LLC (contractor for CDC, NCBDDD), Atlanta, GA (PM). hfc2@cdc.gov.
authors: Heather C
authors: HC
authors: Hamner
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D016208:Databases, Factual; D005260:Female; D005492:Folic Acid / Q000097:blood*; D005838:Genotype; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009436:Neural Tube Defects / Q000235:genetics / Q000517:prevention & control; D064887:Observational Studies as Topic; D011110:Polymorphism, Genetic; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
keywords: MTHFR; neural tube defects; plasma folate; red blood cell folate; serum folate