Original Article

European Journal of Clinical Nutrition (2008) 62, 1010–1021; doi:10.1038/sj.ejcn.1602810; published online 23 May 2007

Association between decreased vitamin levels and MTHFR, MTR and MTRR gene polymorphisms as determinants for elevated total homocysteine concentrations in pregnant women

Contributors: PRB was a Master Degree student at the Faculty of Pharmaceutical Science, University of Sao Paulo and she determined the clinical chemistry and the gene polymorphism genotypes at the Hematology laboratory of the Clinical and Toxicology Analysis Department of the University of São Paulo. ALKM and RB provided technical assistance and were recipients of fellowships from Projeto 4 of University of São Paulo and PIBIC-CNPq, Brazil, respectively. MHH and RDCH contributed with the strategies and interpretation of results from genotyping analysis as well as in preparation of the manuscript. LFSN is the obstetrician who participated in planning and executing this study at the Hospital Regional of Conjunto Hospitalar and at the Hospital Santa Lucinda. The Brazilian authors have no conflicts of interest. SPS and RHA were responsible for the assays of the amino acids, SAM and SAH in their laboratories. They also provided interpretation of the values and participated in the preparation of the manuscript. The University of Colorado and SPS and RHA hold patents on various aspects of the use of homocysteine and methylmalonic acid in the diagnosis of cobalamin or folate deficiency. A company (called Metabolite Laboratories Inc.) has been formed at the University of Colorado to perform the assays. EMG-S was the coordinator of this study in Brazil, responsible for all of its phases (planning, collecting the samples, interviews, analysis of the data, interpretation of the values and preparation of the manuscript).

P R Barbosa1, S P Stabler2, A L K Machado1, R C Braga1, R D C Hirata1, M H Hirata1, L F Sampaio-Neto3, R H Allen2 and E M Guerra-Shinohara1

  1. 1Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas da Universidade de São Paulo, São Paulo, SP, Brazil
  2. 2Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA
  3. 3Faculdade de Medicina, Pontificia Universidade Católica de São Paulo, São Paulo, SP, Brazil

Correspondence: Professor EM Guerra-Shinohara, Department of Clinical Chemistry and Toxicology, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 580 Bloco 17, Sao Paulo, SP CEP 05508-900, Brazil. E-mail: emguerra@usp.br

Received 17 October 2006; Revised 19 March 2007; Accepted 18 April 2007; Published online 23 May 2007.

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Abstract

Objectives:

 

To examine the association between methylenetetrahydrofolate reductase (MTHFR) (C677T and A1298C), methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G gene polymorphisms and total homocysteine (tHcy), methylmalonic acid (MMA) and S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) levels; and to evaluate the potential interactions with folate or cobalamin (Cbl) status.

Subjects/Methods:

 

Two hundred seventy-five healthy women at labor who delivered full-term normal babies. Cbl, folate, tHcy, MMA, SAM and SAH were measured in serum specimens. The genotypes for polymorphisms were determined by PCR-restriction fragment length polymorphism (RFLP).

Results:

 

Serum folate, MTHFR 677T allele and MTR 2756AA genotypes were the predictors of tHcy levels in pregnant women. Serum Cbl and creatinine were the predictors of SAM/SAH ratio and MMA levels, respectively. The gene polymorphisms were not determinants for MMA levels and SAM/SAH ratios. Low levels of serum folate were associated with elevated tHcy in pregnant women, independently of the gene polymorphisms. In pregnant women carrying MTHFR 677T allele, or MTHFR 1298AA or MTRR 66AA genotypes, lower Cbl levels were associated with higher levels of tHcy. Lower SAM/SAH ratio was found in MTHFR 677CC or MTRR A2756AA genotypes carriers when Cbl levels were lower than 142 pmol/l.

Conclusions:

 

Serum folate and MTHFR C677T and MTR A2576G gene polymorphisms were the determinants for tHcy levels. The interaction between low levels of serum Cbl and MTHFR (C677T or A1298C) or MTRR A66G gene polymorphisms was associated with increased tHcy.

Keywords:

cobalamin, folate, polymorphisms, homocysteine, methylmalonic acid, pregnant women

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