Changes in MTHFR genotype frequencies over time
Authors: E Muñoz-Moran, JL Dieguez-Lucena, N Femandez-Arcas, S Peran-Mesa, A Reyes-Engel
Journal: The Lancet (1998)

Authors' reply Sir—The absence of counterselection, as A S Whitehead proposes, would not greatly reduce the frequency of the V allele, since the full viability of AV individuals and the differences in folate dietary intake would maintain allele frequency and therefore Hardy-Weinberg equilibrium would not be distorted. The only valid explanation for a striking reduction in the V allele would be folate deficiency in the diet. In fact in those populations in which this could happen for social or dietary reasons, such as in Africans1Franco RF Araujo AG Guerreiro JF Elion J Zago MA Analysis of the 677 C-T mutation of the methylenetetrahydrofolate reductase gene in different ethnic groups.Thromb Haemost. 1998; 79: 119-121PubMed Google Scholar or Inuits,2Mandelcorn R Connelly PW Boright A Young TK Hegele RA F5 Q506 mutation and the low prevalence of cardiovascular disease in Canadian Inuit.J Invest Med. 1998; 46: 232-235PubMed Google Scholar the frequency of the VV genotype is only around 1%. Therefore, the variability of dietary folate intake can lead to a fluctuation in the number of VV individuals in the world population.3Wilcken DEL MTHFR 677 C-T mutation, folate intake, neural-tube defect, and risk of cardiovascular disease.Lancet. 1997; 350: 603-604Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 4Rizzari C Valsecchi MG Conter V MTHFR 677 C-T mutation and neural-tube defects.Lanceet. 1997; 350: 1479-1480Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar This effect might be even more remarkable if 5 mg of folic acid per day are given to all pregnant women. We do not agree with Whitehead that pregnancies with a VV fetus are twice as likely to result in a live birth than pregnancies carrying fetuses with other genotypes since VV individuals do not have increased fertility in relation to the other two genotypes. VV fetuses have a double probability of being born alive when mothers are taking folic acid, but viability remains unaltered in fetuses with the other two genotypes. More clearly, these VV fetuses belonged to those judged clinical miscarriages or early loss of pregnancy (44% of all pregnancies).5Miller JF Williamson E Glue J Gordon YB Grudzinskas JG Sykes A Fetal loss after implantation.Lancet. 1980; ii: 554-556Summary Scopus (329) Google Scholar With respect to a possible bias in our study, the population was very carefully selected to avoid this kind of difficulty. Depending on age, the population studied was randomly selected as follows: dried blood spots from neonatal screening papers, and students from primary and high schools and university. Older individuals were recruited with the Andalusian health service identity card. Individuals in each group were representative of the whole population at that age. Individuals were also carefully considered and selected from different areas of our province (Malãga) and various social groups. All the selected individuals were genotyped for different gene polymorphisms to establish whether our adult and young populations were genetically homogeneous. No significant differences were recorded for the allele or genotype frequencies of this gene when young people were compared with the total adult population. We also studied the parental and grandparental birthplaces and those did not cluster in any region of Spain. Therefore we can conclude that there is no genetic founder effect. In any case, there is unlikely to be a genetic drift in Spain for historical reasons—ie, a large population without isolation. Although it is difficult to accept that a genetic selection can be produced in two generations, the human capacity to establish rapid therapeutic actions could even lead to a genetic selection as fast as an epidemic. Furthermore, folate intake influences fetal development, so this hypothesis should not be refuted because of its immediateness or repercussions on the population. Changes in MTHFR genotype frequencies over timeE Muñoz-Moran and colleagues (Oct 3, p 1120)1 report that in a healthy Spanish population the proportion of individuals who are homozygous for the mildly dysfunctional methylenetetrahydrofolate reductase (MTHFR) 225V (ie, 677T) variant has recently doubled—from 13% in 21–40 year olds to 26% in 0–20 year olds. The VV genotype has been associated with conditions such as cardiovascular disease that cause premature mortality; however, these workers state it is unlikely that their young population has been subject to substantial genotype-specific attrition from such diseases. Full-Text PDF