It Remains Unknown Whether Filaggrin Gene Mutations Evolved to Increase Cutaneous Synthesis of Vitamin D

About 8-10% of normal Northern Europeans are heterozygous carriers of common FLG mutations, while only 1-4% of southern Europeans display these mutations, and only very rarely are mutations detected in African populations. Although mutations are found in Asians, they are different from those encountered in Northern Europeans. Importantly, FLG mutation carriers have 10% increased serum vitamin D concentrations compared to controls. Based on these observations, we have proposed that this latitude-dependent gradient of FLG mutations across Europe, Asia and Africa could have provided an evolutionary advantage for heterozygous FLG mutation carriers, residing at northern latitudes, depletion of the FLG downstream product, trans-urocanic acid, would facilitate the intracutaneous synthesis of vitamin D3 by allowing increased transcutaneous absorption of UVB photons. Such loss-of-function FLG mutations would have provided an evolutionary advantage for modern humans, living in the far North of Europe, where little UV-B penetrates the atomosphere. In a recent article, it was concluded not only that the UVB-Vitamin D3 hypothesis is invalid, but also that FLG genetic variations, including loss-of-function variants, provide little or no impact on the fitness of modern humans. While we welcome studies that reassess our hypothesis, their conclusions are not valid for reasons explained in this letter.