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Inserm U-724
Cellular and Molecular Pathology in Nutrition
Faculté de Médecine
Université Henry Poincaré de Nancy
54500 Vandoeuvre lés Nancy
France
E-mail: jl.gueant{at}chu-nancy.fr
Dear Sir:
The 677CT polymorphism of methylenetetrahydrofolate reductase (MTHFR) is a good model in which to study nutrigenetic and nutrigenomic mechanisms related to folate in populations with a contrasting status. Indeed, this polymorphism reduces by 75% the catalytic rate of the enzyme and therefore is a key genetic determinant of the folate imbalance between DNA synthesis and methylation. Despite a north-to-south increasing gradient of 677T allele frequency in Western Europe, this polymorphism may correspond to a single ancestral mutation because it is associated with a common haplotype of the gene (1). Folate has a strong influence on the phenotypic consequences of this polymorphism by neutralizing its effect on homocysteine plasma concentration (2). We have observed an association between T allele frequency and the contrasting folate status of populations that suggests an influence of folate status on the worldwide distribution of T alleles. In our opinion, one of the major factors that may explain the north-to-south increasing gradient of T allele frequency in Europe is, therefore, the superimposed north-to-south decreasing gradient of dietary folate intake (2).
Such a gradient of T alleles also exists in China, but no complementary data on dietary folate intake are available from that country (3). The populations of tropical regions of Africa have the lowest and Mexicans (a population with a diet rich in folate) the highest frequency of T alleles. However, despite this association between folate status and T alleles, it seems reasonable to propose that, worldwide, other factors influence the genetic pressure on T alleles. Cordain and Hickey suggested that the sun exposure of whites exerts an evolutionary pressure on MTHFR that is counterbalanced by skin pigmentation (4). Indeed, ultraviolet (UV) exposure increases the requirement for dietary folates by degrading folates in the skin, and this mechanism could increase the folate dietary allowance in Northern European, light-skinned populations in the summer. However, this hypothesis does not explain why T alleles are more frequent in southern China than in northern China, when only a small difference exists in the skin pigmentation of those 2 areas' populations. If this genetic pressure is effective, it should, given the low storage capacity of folate in humans, produce a seasonal influence of MTHFR on the one-carbon metabolism and on early pathological events of life. In Europe, such a seasonal influence of UV exposure should have been limited in past generations by the difference in dietary intakes of folate between the winter and the summer—the latter being the season in which fruit and vegetables were more accessible.
As previously discussed by us (2), the association of folate with T allele frequency could reflect an effect of folate and MTHFR on very early pathological events of life rather than on cardiovascular and degenerative diseases. These early events include several developmental abnormalities, particularly neural tube defects and trisomies, and pregnancy complications, such as recurrent pregnancy loss, pre-eclampsia, abruptio placentae, intrauterine growth retardation, and intrauterine fetal death. In Spain, the prevalence of MTHFR 677T alleles doubled with the development of folic acid–supplementation programs for pregnant women in recent decades (5).
Thus, systematic supplementation could have rescued mutated fetuses whose viability may otherwise be reduced by MTHFR polymorphisms. However, it seems unlikely that this shift in allele frequency occurred in a few generations and that folate was the single limiting factor that influenced T allele frequency. For example, contrary to what has been reported in population studies, one would expect a dramatic difference in T allele frequency between Africans and African Americans, given the better folate status in the United States than in West Africa (2). Consequently, other nutritional determinants of one-carbon metabolism—such as vitamin B-12 and vitamin B-6, polymorphisms of other genes encoding for enzymes of this metabolism, and gene-gene interactions—may also contribute to the distribution of T alleles worldwide. For example, the influence of a common epigenetic pathway on neural tube defects and trisomies, possibly related to impaired one-carbon metabolism, has been suggested (6). The same genetic determinants of one-carbon metabolism are associated with neural tube defect and Down syndrome in the geographical area where the 2 types of case-control studies were conducted. For both diseases, MTHFR polymorphisms are at risk in countries with a low dietary intake of folate, such as those in Northern Europe, and they are neutral in France and Sicily (6). In contrast, genetic determinants related to vitamin B-12 metabolism, such as MTR, MTRR, and TCN2 polymorphisms, are at risk in Sicily, where vitamin B-12 is a determinant of the plasma concentration of homocysteine (2). By comparison, folate, but not vitamin B-12, is a determinant of homocysteine in the population we studied in northeastern France (2).
The influence of MTHFR and folate status on fertility may also be involved in the distribution of T alleles worldwide. Several authors have investigated the prevalence of MTHFR 677CT genotypes in infertile male patients. The association between infertility and MTHFR 677TT genotype was neutral in studies from the Netherlands (7) and Italy (8) and significant in studies from India (9) and Korea (10), both of which have a low T allele frequency. This association may be under the influence of folate status. One would also expect higher pigmentation and higher skin exposure to UV radiation in the latter 2 countries than in the population of the Netherlands.
In conclusion, it is reasonable to hypothesize that folate status may influence the frequency of T alleles worldwide. As suggested by Cordain and Hickey, UV exposure has to be considered as one of the determinants of folate status, besides dietary intake, that could exert a selective pressure on MTHFR T allele frequency via a mechanism counterbalanced by pigmentation. A worldwide survey of T allele distribution and of its influence on early events of life and infertility suggests that folate status is only one of the interacting determinants of one-carbon metabolism that may influence the 677T allele frequency of MTHR.
ACKNOWLEDGMENTS
The authors had no personal or financial conflict of interest.
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