Genetic and environmental determinants of plasma total homocysteine levels: Impact of population-wide folate fortification

Peter Nagele, Konrad Meissner, Amber Francis, Manuela Födinger, Nancy L. Saccone

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Objectives: Folate metabolism is an important target for drug therapy. Drug-induced inhibition of folate metabolism often causes an elevation of plasma total homocysteine (tHcy). Plasma tHcy levels are influenced by several nongenetic (e.g. folate intake, age, smoking) as well as genetic factors. Over the last decade, several countries have implemented a nationwide folate fortification program of all grain products. This investigation sought to determine the impact of folate fortification on the relative contribution of environmental and genetic factors to the variability of plasma tHcy. Methods: Two cohorts were compared in this study, one from the United States (with folate fortification, n=281) and one from Austria (without folate fortification, n=139). Several environmental factors as well as previously identified gene variants important for tHcy levels (MTHFR C677T, MTHFR A1298C, MTRR A66G) were examined for their ability to predict plasma tHcy in a multiple linear regression model. Results: Nongenetic, environmental factors had a comparable influence on plasma tHcy between the two cohorts (R: approximately 0.19). However, after adjusting for other covariates, the tested gene variants had a substantially smaller impact among patients from the folate-fortified cohort (R=0.021) compared with the nonfolate-fortified cohort (R=0.095). The MTHFR C677T polymorphism was the single most important genetic factor. Male sex, smoking, and folate levels were important predictors for nonfolate-fortified patients; age was for folate-fortified patients. Conclusion: Population wide folate fortification had a significant effect on the variability of plasma tHcy and reduced the influence of genetic factors, most importantly the MTHFR 677TT genotype, and may be an important confounder for a personalized drug therapy.

Original languageEnglish
Pages (from-to)426-431
Number of pages6
JournalPharmacogenetics and Genomics
Issue number7
StatePublished - Jul 2011


  • folate fortification
  • folic acid
  • homocysteine


Dive into the research topics of 'Genetic and environmental determinants of plasma total homocysteine levels: Impact of population-wide folate fortification'. Together they form a unique fingerprint.

Cite this