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Department of Health and Exercise Science
Colorado State University
Fort Collins, CO 80523
E-mail: lcordain{at}cahs.colostate.edu
Dear Sir:
In a recent issue of the Journal, Guéant-Rodriguez et al (1) and Devlin et al (2) confirmed prior observations (3) of a nutrient-gene interaction between methylenetetrahydrofolate reductase (MTHFR) and folate status. Homozygosity for the MTHFR 677TT genotype converts an alanine to a valine at position 222 in the amino acid sequence and reduces the enzyme activity, which causes hyperhomocysteinemia (4), which in turn increases the risk for cardiovascular disease, cognitive dysfunction, Alzheimer disease, and osteoporotic fractures (5), as well as recurrent early pregnancy loss (6, 7). These pathophysiologic sequelae likely materialize only when folate status is compromised (1, 2). Hence, it has been suggested that MTHFR 677TT genotype homozygosity may confer survival value in populations with sufficient dietary folate (8, 9), because this polymorphism is protective against colon cancer (10) and acute lymphatic leukemia (11), perhaps by contributing methylenetetrahydrofolate to DNA synthesis and thereby preventing double-strand DNA ruptures (12).
In addition to reduced dietary folate intake and absorption, it is less well appreciated that other environmental factors, including dermal exposure to ultraviolet (UV) radiation, may adversely influence folate status (13, 14). Exposure of human plasma in vitro to simulated strong sunlight causes a 30–50% loss of folate within 60 min, and light-skinned patients chronically exposed to UV radiation for dermal disorders maintain low plasma folate concentrations, which suggests in vivo dermal photolysis of folate (13). In contrast, dark skin (via its greater concentration of melanin) may prevent UV photolysis of folate (13, 14).
In European populations, a simultaneous south-to-north gradient exists for dermal pigmentation (14) and the presence of MTHFR 677TT (15). The prevalence of MTHFR 677TT decreases in a south-to-north manner: 10–12% of light-skinned Northern Europeans maintain the MTHFR 677TT genotype (2), but the highest frequency of this polymorphism occurs in more dark-skinned Southern Europeans, such as Sicilians (1). A similar, simultaneous and latitudinally dependent gradient in the frequency of the MTHFR 677TT allele (16, 17) and dermal pigmentation (14) has been found in the Americas.
As human populations move into more northern latitudes where they are exposed to less annual UV radiation, the evolutionary selection for less pigmented, lighter skin may represent an asset in that it can improve vitamin D status and lessen the risk for rickets and other vitamin D–related disorders (14). However, because lighter skin contains less protective melanin, it represents a liability with respect to folate metabolism, because lighter skin may be more susceptible than darker skin to photolysis of folate (13). Hence, to counter the increased loss of folate in lighter-skinned populations during seasonal exposure to UV sunlight, genes that lower plasma homocysteine concentrations by favoring increased the synthesis of MTHFR would convey selective advantage, perhaps by reducing recurrent early pregnancy loss (6, 7). The risk of recurrent early pregnancy loss in those who are homozygous for the MTHFR 677TT genotype is 2- to 3-fold that in those who maintain the wild or heterozygous genotype (6). In females of reproductive age, recurrent early pregnancy loss caused by impaired folate status represents the most likely environmental pressure favoring the selection of protective genotypes such as MTHFR 677CC, because cardiovascular disease, cognitive dysfunction, Alzheimer disease, and osteoporotic fractures typically occur in the postreproductive years.
ACKNOWLEDGMENTS
Neither author had a personal or financial conflict of interest with respect to the studies of Guéant-Rodriguez et al and Devlin et al.
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