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Archived Comments for: Human genetic selection on the MTHFR 677C>T polymorphism

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  1. Human genetic selection for the MTHFR 677>T polymorphism: A leap in the dark

    María Luisa Martínez-Frías, Centro de Investigación Anomalías Congéntias (CIAC)

    19 February 2009

    Letter to the Editor

    Human genetic selection for the MTHFR 677>T polymorphism: A leap in the dark

    Martínez-Frías ML1-3& Bermejo E1,2,4 Rodríguez-Pinilla E1,2, and ECEMC Working Group5

    1ECEMC, Centro de Investigación de Anomalías Congénitas, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Madrid, Spain.
    2 CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Madrid, Spain.
    3 Dpto. Farmacología, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
    4 Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III. Ministerio de Ciencia e Innovación, Madrid, Spain.

    & Corresponding author: (

    We read with great interest the recent article by Mayor-Olea and co-workers [1], and wish to express our concern about their conclusions, which are based in an incorrect interpretation of the results of two studies published by our group as monographs in Spanish in 1989 and 1993 [2-3]. Therefore, we feel compelled to clarify our data, which does not support their contention that FA may have an effect on embryo selection, which has generated great concern [4].
    In 1998, Reyes-Engel’s group published a Letter to the Editor [5] reporting an increase in the frequency of the T allele at position 677 of the methylenetetrahydrofolate reductase (MTHFR) gene in Spain. They hypothesized that early folic acid (FA) supplementation during pregnancy could be responsible for the increasing prevalence of this mutant allele. Their conclusion was based on data on the use of medicines during pregnancy published by our group as the first of the above mentioned monographs [2]. This publication analyzed the use of all types of medicines at any time during pregnancy in Spain during the period April 1976-December 1986 [2]. Our second monograph [3], which analyzed the drugs most frequently taken during pregnancy over the period April 1976 to 1990, was later used by the same group to support the results of subsequent studies, also concluding that FA supplementation caused human genetic selection [1,6].
    However, it must be clarified that the information included in our two monographs [2,3] did not refer to the periconceptional use of drugs, as assumed by Reyes-Engel’s group in their first publication [5]. Our first analysis [2] covered a period (1976-1986) when FA supplementation for the prevention of birth defects had yet to become established. Moreover, in this first monograph, we did not analyze FA consumption, but only multivitamins and minerals, without considering whether or not they contained FA. Hence, the data interpreted by Muñoz-Morán et al. [5] as equivalent to the consumption of FA only referred to the use of multivitamins, which might or might not have included FA.
    In our second study [3], we did analyze the consumption of FA in any type of commercial preparation, with or without vitamins/minerals/others (FA±VM), and separate from multivitamins that did not include FA. The period included, however, was from 1976 to 1990. Therefore, since the results of the MRC Vitamin Study Research Group [7] confirming the effectiveness of FA supplementation in the prevention of neural tube defects recurrence were published in 1991, it is highly unlikely that during this study period, as well as during the initial one (1976-1986), Spanish women would have consumed FA±VM preconceptionally. Indeed, in a recent study we found that the preconceptional use of FA±VM in our population commenced during the years 1996-1997 [8].
    To better document this information [3], we have summarized the proportion of mothers who consumed FA±VM at any time during gestation in four time periods between 1976 and 1990, being 0.15% (1976-1882), 1.37% (1983-1985), 5.71% (1986-1988) and 7.53% (1989-1990). A progressive increase in the use of FA±VM at any time during pregnancy is evident. However, the proportion of mothers exposed to this supplement remains rather small and it does not reach 8% of pregnant women in the most recent study period.
    Therefore, in light of the actual data from our studies [2,3] it is difficult to accept that the small proportion of mothers that ingest FA±VM at any time during pregnancy could cause a population effect or genetic selection in only one generation, as alleged by these investigators [1,5-6]. As suggested by Whitehead [9] in response to the first publication by Muñoz-Morán et al. [5], sampling biases due to stratification in the study population are most probably the explanation for their observations.

    Acknowledgments: CIBER de Enfermedades Raras, is an initiative of the Instituto de Salud Carlos III. We would like to thanks the Fundación 1000, sobre Defectos Congénitos, for their support.


    1. Mayor-Olea A, Callejon G, Palomares AR, Jimenez AJ, Gaitan MJ, Rodriguez A, Ruiz M, Reyes-Engel A. Human genetic selection on the MTHFR 677C>T polymorphism. BMC Med Genet. 2008;9:104.
    2. Salvador J, Martínez-Frías ML, Rodríguez-Pinilla E. Consumo de medicamentos por la mujer embarazada en España: perfil de una muestra de la población de los años 1976-1986. Ed. Ministerio de Sanidad y Consumo. Madrid. 1989.
    3. Rodríguez-Pinilla E, Bermejo Sánchez E, Martínez-Frías ML. Medicamentos de uso más frecuente durante la gestación. Ed. Ministerio de Sanidad y Consumo. Madrid. 1993.
    4. Haggarty P, Campbell DM, Duthie S, Andrews K, Hoad G, Piyathilake C, Fraser I, McNeill G. Folic acid use in pregnancy and embryo selection. BJOG. 2008 Jun;115(7):851-856.
    5. Muñoz-Moran E, Dieguez-Lucena JL, Fernandez-Arcas N, Peran-Mesa S, Reyes-Engel A. Genetic selection and folate intake during pregnancy. Lancet. 1998;352:1120-1121. Comment in: Lancet. 1998;352:1784-1785.
    6. Callejón G, Mayor-Olea A, Jiménez AJ, Gaitán MJ, Palomares AR, Martínez F, Ruiz M, Reyes-Engel A. Genotypes of the C677T and A1298C polymorphisms of the MTHFR gene as a cause of human spontaneous embryo loss. Hum Reprod. 2007;22:3249-3254.
    7. Medical Research Council (MRC) Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet. 1991;338:131-137.
    8. Martínez-Frías ML; Grupo de trabajo del ECEMC. Folic acid dose in the prevention of congenital defects. Med Clin (Barc). 2007;128:609-616.
    9. Whitehead AS. Changes in MTHFR genotype frequencies over time. The Lancet 1998;352:1784

    Competing interests

    We have not competing interest