title: Transcobalamin-II variants, decreased vitamin B12 availability and increased risk of frailty.
abstract: OBJECTIVE
  This project was designed to follow-up prior evidence that demonstrated a significant association between vitamin B12 transport and metabolism and the frailty syndrome in community-dwelling older women. The cross-sectional relationship between genetic variants within six candidate genes along this pathway with serum methylmalonic acid (MMA) levels and frailty was evaluated in this same population of older women.
  
  
  METHODS
  Baseline measures were collected prior to folate fortification from 326 women in the Women's Health and Aging Studies I and II. Odds ratios and statistical tests were estimated for single SNP and haplotype via linear regression models for serum MMA, a marker for available vitamin B12, and in logistic regression models for frailty.
  
  
  RESULTS
  Fifty-six SNPs from CBS, MTHFR, MTR, MTRR, TCN1 and TCN2 genes were genotyped. Several SNPs in MTHFR, MTR and MTRR demonstrated a modest association to elevated MMA, while SNPs in TCN2 showed significant association to the frailty syndrome. TCN2 polymorphisms, particularly one SNP reported to be in perfect LD with functional variant Pro259Arg, were significantly associated with increased odds of frailty, after adjustment for age, presence of cardiovascular disease and elevated MMA (OR = 2.25, p-value = 0.009).
  
  
  CONCLUSIONS
  Using MMA as a marker for vitamin B12, these results suggest that TCN2 gene variants may lead to decreased vitamin B12 availability, leading to reduced energy metabolism, ultimately contributing to frailty pathology. Further studies to determine the biological role of functional TCN2 polymorphisms in frailty are needed.
authors.affiliation: Johns Hopkins University, Baltimore, MD 21205, USA. amatteini@jhmi.edu
authors.forename: A M
authors.initials: AM
authors.lastname: Matteini
authors.forename: J D
authors.initials: JD
authors.lastname: Walston
authors.forename: K
authors.initials: K
authors.lastname: Bandeen-Roche
authors.forename: D E
authors.initials: DE
authors.lastname: Arking
authors.forename: R H
authors.initials: RH
authors.lastname: Allen
authors.forename: L P
authors.initials: LP
authors.lastname: Fried
authors.forename: A
authors.initials: A
authors.lastname: Chakravarti
authors.forename: S P
authors.initials: SP
authors.lastname: Stabler
authors.forename: M D
authors.initials: MD
authors.lastname: Fallin
mesh_terms: D000368:Aged; D001682:Biological Availability; D015415:Biomarkers / Q000097:blood; D002244:Carbon / Q000378:metabolism; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics / Q000378:metabolism; D005492:Folic Acid / Q000008:administration & dosage / Q000378:metabolism; D005527:Food, Fortified; D016330:Frail Elderly; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D016014:Linear Models; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D008764:Methylmalonic Acid / Q000097:blood*; D020641:Polymorphism, Single Nucleotide; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014155:Transcobalamins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014805:Vitamin B 12 / Q000097:blood / Q000378:metabolism*; D016387:Women's Health
chemical_list: D015415:Biomarkers; C109868:CRZ1 protein, S cerevisiae; D004268:DNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D014155:Transcobalamins; D014157:Transcription Factors; D002244:Carbon; D008764:Methylmalonic Acid; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12