title: Evidence That Loss-of-FunctionFilaggrinGene Mutations Evolved in Northern Europeans to Favor Intracutaneous Vitamin D3 Production.
abstract: Skin pigmentation lightened progressively to a variable extent, as modern humans emigrated out of Africa, but extreme lightening occurred only in northern Europeans. Yet, loss of pigmentation alone cannot suffice to sustain cutaneous vitamin D3 (VD3) formation at the high latitudes of northern Europe. We hypothesized that loss-of-function mutations in the epidermal structural protein, filaggrin (FLG), could have evolved to sustain adequate VD3 status. Loss of FLG results in reduced generation of trans-urocanic acid, the principal endogenous ultraviolet-B (UV-B) filter in lightly-pigmented individuals. Accordingly, we identified a higher prevalence ofFLGmutations in northern European populations when compared to more southern European, Asian and African populations that correlates significantly with differences in circulating 25-OH-VD3 levels in these same populations. By allowing additional UV-B penetration and intracutaneous VD3 formation, the latitude-dependent gradient inFLGmutations, likely together with other concurrent mutations in VD3 metabolic pathways, provide a non-pigment-based mechanism that sustains higher levels of circulating VD3 in northern Europeans. At the time thatFLGmutations evolved, xerosis due to FLG deficiency was a lesser price to pay for enhanced VD3 production. Yet, the increase inFLGmutations has inadvertently contributed to an epidemic of atopic diseases that has emerged in recent decades.
authors.affiliation: Department of Dermato-Allergology, National Allergy Research Centre, Gentofte University Hospital, University of Copenhagen, Hellerup, Denmark.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Thyssen
authors.affiliation: Endocrinology Service, Veterans Affairs Medical Center, and Department of Medicine, UC San Francisco, San Francisco, CA, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
authors.affiliation: Dermatology Service, Veterans Affairs Medical Center, and Department of Dermatology, UC San Francisco, San Francisco, CA, USA eliasp@derm.ucsf.edu.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
keywords: Filaggrin; Human evolution; Pigmentation; Skin color; Vitamin D3