title: Maternal MTHFR genotype and haplotype predict deficits in early cognitive development in a lead-exposed birth cohort in Mexico City.
abstract: BACKGROUND
  Maternal folate nutritional status and prenatal lead exposure can influence fetal development and subsequent health. The methylenetetrahydrofolate reductase (MTHFR) gene is important for folate metabolism, and 2 common polymorphisms, C677T and A1298C, reduce enzymatic activity; C677T is present at high penetrance in Mexican populations.
  
  
  OBJECTIVE
  The objective of this study was to examine potential links between maternal and child MTHFR polymorphisms and child neurodevelopment in a lead-exposed population.
  
  
  METHODS
  Data regarding MTHFR polymorphisms C677T and A1298C, peri- and postnatal lead measures, and Bayley Mental Development Index at 24 mo of age (MDI-24) scores were available for 255 mother-child pairs who participated in the ELEMENT (Early Life Exposures in Mexico to Environmental Toxicants) study during 1994-1995.
  
  
  RESULTS
  In covariate-adjusted regression models, maternal MTHFR 677 genotype predicted MDI-24 scores, in which each copy of the maternal MTHFR 677T variant allele was associated with lower MDI-24 scores (beta = -3.52; 95% CI: -6.12, -0.93; P = 0.004). Maternal MTHFR haplotype also predicted MDI-24 scores (mean +/- SE: 93.3 +/- 1.2 for 677C-1298A compared with 89.9 +/- 0.8 for 677T-1298A; P < 0.05). MDI-24 scores were not associated with maternal MTHFR 1298 genotype or child MTHFR genotypes. We did not observe significant MTHFR genotype x lead interactions with respect to any of the subject biomarkers of lead exposure.
  
  
  CONCLUSIONS
  The maternal MTHFR 677T allele is an independent predictor of poorer child neurodevelopment at 24 mo. These results suggest that maternal genetic variations in folate metabolism during pregnancy may program offspring neurodevelopment trajectories. Further research is warranted to determine the generalizability of these results across other populations.
authors.affiliation: Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA. rpils@umich.edu
authors.forename: J Richard
authors.initials: JR
authors.lastname: Pilsner
authors.forename: Howard
authors.initials: H
authors.lastname: Hu
authors.forename: Robert O
authors.initials: RO
authors.lastname: Wright
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kordas
authors.forename: Adrienne S
authors.initials: AS
authors.lastname: Ettinger
authors.forename: Brisa N
authors.initials: BN
authors.lastname: Sánchez
authors.forename: David
authors.initials: D
authors.lastname: Cantonwine
authors.forename: Alicia L
authors.initials: AL
authors.lastname: Lazarus
authors.forename: Alejandra
authors.initials: A
authors.lastname: Cantoral
authors.forename: Lourdes
authors.initials: L
authors.lastname: Schnaas
authors.forename: Martha Maria
authors.initials: MM
authors.lastname: Téllez-Rojo
authors.forename: Mauricio
authors.initials: M
authors.lastname: Hernández-Avila
mesh_terms: D000293:Adolescent; D000328:Adult; D001842:Bone and Bones / Q000378:metabolism; D002675:Child, Preschool; D003072:Cognition Disorders / Q000139:chemically induced* / Q000235:genetics*; D002658:Developmental Disabilities / Q000453:epidemiology / Q000235:genetics*; D019587:Dietary Supplements; D002149:Energy Intake; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007854:Lead / Q000378:metabolism; D007855:Lead Poisoning / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008800:Mexico; D009035:Mothers; D010298:Parity; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D049590:Postpartum Period; D011247:Pregnancy; D012044:Regression Analysis
chemical_list: D007854:Lead; D042965:Methylenetetrahydrofolate Reductase (NADPH2)