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The Capital Region of Denmark - a part of Copenhagen University Hospital
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Evidence That Loss-of-Function Filaggrin Gene Mutations Evolved in Northern Europeans to Favor Intracutaneous Vitamin D3 Production

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  1. Mice with epidermal filaggrin deficiency show increased immune reactivity to nickel

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  2. Temporal changes in chromium allergy in Denmark between 2002 and 2017

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  3. Temporal changes in chromium allergy in Denmark between 2002 and 2017

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  4. Increase in Vitamin D but not Regulatory T Cells following Ultraviolet B Phototherapy of Patients with Atopic Dermatitis

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  5. A systematic review and meta-analysis of the regional and age-related differences in atopic dermatitis clinical characteristics

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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 of FLG mutations 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 in FLG mutations, 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 that FLG mutations evolved, xerosis due to FLG deficiency was a lesser price to pay for enhanced VD3 production. Yet, the increase in FLG mutations has inadvertently contributed to an epidemic of atopic diseases that has emerged in recent decades.

Original languageEnglish
Book seriesEvolutionary Biology
Volume41
Issue number3
Pages (from-to)388-396
Number of pages9
ISSN0071-3260
DOIs
Publication statusPublished - 1 Sep 2014

ID: 44855447