title: Association of a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene with bone phenotypes depends on plasma folate status.
abstract: A study of a polymorphism in the MTHFR gene, plasma folate, and bone phenotypes in 1632 individuals revealed that the genotype effect on BMD and quantitative ultrasound was dependent on the level of folate. Our findings support the hypothesis that the association between an MTHFR polymorphism and bone phenotypes depends on folate status.
  
  
  BACKGROUND
  Genome-wide screens using quantitative ultrasound (QUS) and BMD phenotypes have shown suggestive linkage on chromosome 1pter-1p36.3, a region containing the methylenetetrahydrofolate reductase (MTHFR) gene. Individuals homozygous (TT) for the MTHFR C677T polymorphism who have low plasma folate concentrations exhibit elevated plasma homocysteine (tHcy) concentrations that may compromise bone quality. We hypothesized that folate status might modify an association between the C677T polymorphism and bone, possibly by influencing homocysteine concentrations.
  
  
  METHODS
  QUS (broadband ultrasound attenuation [BUA], speed of sound, and quantitative ultrasound index) of the heel and BMD of the hip and spine were measured in 1632 male and female members of the Framingham Offspring Study (1996-2001). Participants were assessed for plasma folate concentration and genotyped for the MTHFR C677T polymorphism. TT participants were compared with individuals in the CC + CT group using analysis of covariance.
  
  
  RESULTS
  Adjusted mean QUS and BMD measures did not differ between C677T groups. Although all participants with plasma folate concentrations > or =4 ng/ml had approximately 2% higher QUS and BMD than those with folate <4 ng/ml, the association disappeared after controlling for tHcy. Suggestive interactions between folate status and the C677T group (CC + CT versus TT) were found for hip BMD (p < or = 0.05) and BUA (p = 0.11). Compared with CC + CT participants, TT individuals had lower mean BUA (p = 0.06) and Ward's area BMD (p = 0.08) within the folate <4 ng/ml group and significantly higher hip BMD (p < or = 0.05) within the folate > or =4 ng/ml group. For both folate groups, TT participants had higher age-adjusted mean plasma tHcy versus CC + CT participants. Controlling for tHcy in these models did not affect the statistical significance of the interaction effects.
  
  
  CONCLUSIONS
  Our findings support the hypothesis that the association between the C677T MTHFR polymorphism and bone phenotypes depends on folate status. The mechanism mediating the association, however, remains unclear, but may be partially caused by homocysteine effects on bone.
authors.affiliation: Research and Training Institute, Hebrew Rehabilitation Center for Aged, Boston, Massachusetts 01702, USA. bob@fram.nhlbi.nih.gov
authors.forename: Robert R
authors.initials: RR
authors.lastname: McLean
authors.forename: David
authors.initials: D
authors.lastname: Karasik
authors.forename: Jacob
authors.initials: J
authors.lastname: Selhub
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Tucker
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ordovas
authors.forename: Giuseppina T
authors.initials: GT
authors.lastname: Russo
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.forename: Paul F
authors.initials: PF
authors.lastname: Jacques
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Kiel
mesh_terms: D015415:Biomarkers / Q000097:blood; D015519:Bone Density; D001842:Bone and Bones / Q000000981:diagnostic imaging; D005260:Female; D005492:Folic Acid / Q000097:blood*; D006710:Homocysteine / Q000097:blood; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D014463:Ultrasonography
chemical_list: D015415:Biomarkers; D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)