FLG (filaggrin) null mutations and sunlight exposure: Evidence of a correlation

Cascella, Raffaella; Strafella, Claudia; Germani, Chiara; Manzo, L; Marsella, Lt; Borgiani, Paola; Sobhy, Nagat; R, Abdelmaksood; Gerou, Spyridon; Ioannides, Demetrios; Sangiuolo, Federica; Novelli, Giuseppe; Hashad, Doaa; Vakirlis, Efstratios; Giardina, Emiliano

doi:10.1016/j.jaad.2015.06.022

Cited by 16 publications

(24 citation statements)

References 5 publications

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“…Most of the patients experienced the beginning of the disease at early infancy, after the 3rd month of life. In the group of patients with very early onset (0–3 years), we had 72% of patients; early onset (3–5 years), 9% of patients; childhood (5–18 years), 15% of patients; and adult‐onset, 4% patients. There were no patients with late onset of the disease (>40 years; Table ).…”

Section: Resultsmentioning

confidence: 99%

“…Another study that included Greek and Egyptian 162 AD patients reported the absence of known null mutations (501X and 2282del4 mutations) and the sequence analysis revealed 2 unknown null mutations only in 2 Egyptian patients, suggesting a low frequency of FLG null mutations in Greek and Egyptian populations …”

Section: Discussionmentioning

confidence: 99%

“…37 Another study that included Greek and Egyptian 162 AD patients reported the absence of known null mutations (501X and 2282del4 mutations) and the sequence analysis revealed 2 unknown null mutations only in 2 Egyptian patients, suggesting a low frequency of FLG null mutations in Greek and Egyptian populations. 38 The reason for such a large variability of the prevalence of FLG mutations is still under debate. Thyssen et al suggested that the latitude-dependent gradient of FLG mutations could have provided an evolutionary advantage for heterozygous FLG mutation carriers residing at northern latitudes.…”

Section: Discussionmentioning

confidence: 99%

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Filaggrin loss‐of‐function mutations and levels of filaggrin degradation products in adult patients with atopic dermatitis in Croatia

Tončić

Kežić

Jakaša

et al. 2020

Acad Dermatol Venereol

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Background FLG loss-of-function mutations (FLG LOF) represent the strongest genetic risk factor for atopic dermatitis (AD) and are associated with early-onset and more severe disease. The prevalence of FLG mutations varies greatly across Europe. At present, there are no data on FLG mutation prevalence in Croatian AD patients. Objectives To investigate the prevalence of FLG LOF mutations in adult patients with AD and healthy controls. Next to measure the stratum corneum (SC) levels of filaggrin degradation products (NMF), transepidermal water loss (TEWL) and pH in lesional and non-lesional skin. Methods We recruited 100 AD patients with moderate to severe disease and 50 healthy controls. They were screened for three FLG mutations (R501X, 2282del4 and R2447X). Samples of the SC for NMF analysis were collected by adhesive tapes. TEWL and skin surface pH levels were determined on the lesional and non-lesional skin. Results The combined mutation frequency was 4% in the AD group, and all patients with FLG mutations were homozygous carriers. In the control group, no mutations were found. The most common FLG mutation in AD patients was 2282del4 (3%), followed by R501X (1%). As compared to healthy controls, NMF values were strongly reduced in lesional skin; however, no significant difference was found for non-lesional skin. AD patients had elevated TEWL in both lesional and non-lesional skin. The same pattern was observed for pH. Conclusions Our study expands understanding of the landscape of FLG mutations in the European population. The low frequency of FLG mutations and similar levels of filaggrin degradation products in healthy controls and in non-lesional skin of AD patients suggest that filaggrin deficiency does not confer a major risk for AD in the Croatian population.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Filaggrin loss‐of‐function mutations and levels of filaggrin degradation products in adult patients with atopic dermatitis in Croatia

Tončić

Kežić

Jakaša

et al. 2020

Acad Dermatol Venereol

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“…We were unable to investigate whether differences in the distribution of important genetic risk factors may be confounding our associations, because it was not feasible to collect genetic data. It is known that the prevalence and profiles of mutations in the FLG gene vary geographically, and it has been suggested that certain mutations may correlate with UVR exposure (Cascella et al, 2015). Furthermore, areas of the skin more exposed to climatic and physical stressors have been shown to be affected more often in FLG mutation carriers, suggesting that filaggrindeficient individuals may have a reduced ability to adapt to environmental exposures (Carson et al, 2012).…”

Section: Possible Mechanismsmentioning

confidence: 99%

Global Associations between UVR Exposure and Current Eczema Prevalence in Children from ISAAC Phase Three

Fuertes

Flohr

Silverberg

et al. 2017

Journal of Investigative Dermatology

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We sought to examine the relationship globally between UVR dose exposure and current eczema prevalences. ISAAC Phase Three provided data on eczema prevalence for 13- to 14-year-olds in 214 centers in 87 countries and for 6- to 7-year-olds in 132 centers in 57 countries. Linear and nonlinear associations between (natural log transformed) eczema prevalence and the mean, maximum, minimum, standard deviation, and range of monthly UV dose exposures were assessed using linear mixed-effects regression models. For the 13- to 14-year-olds, the country-level eczema prevalence was positively and linearly associated with country-level monthly mean (prevalence ratio = 1.31 [95% confidence interval = 1.05-1.63] per kJ/m) and minimum (1.25 [1.06-1.47] per kJ/m) UVR dose exposure. Linear and nonlinear associations were also observed for other metrics of UV. Results were similar in trend, but nonsignificant, for the fewer centers with 6- to 7-year-olds (e.g., 1.24 [0.96-1.59] per kJ/m for country-level monthly mean UVR). No consistent within-country associations were observed (e.g., 1.05 [0.89-1.23] and 0.92 [0.71-1.18] per kJ/m for center-level monthly mean UVR for the 13- to 14- and 6- to 7-year-olds, respectively). These ecological results support a role for UVR exposure in explaining some of the variation in global childhood eczema prevalence.

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“…Further work showed that ∼8–10% of normal Northern Europeans are heterozygous carriers of common FLG mutations, while only 1–4% of southern Europeans (i.e., Italy, France and Greece) displayed these mutations, and only very rarely could mutations be detected in African populations, i.e., Ethiopians, Moroccans, and South Africans (Cascella et al. 2011, 2015; Winge et al. 2011; Thyssen et al.…”

mentioning

confidence: 99%

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

Thyssen

Elias

2017

Genome Biology and Evolution

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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.

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FLG (filaggrin) null mutations and sunlight exposure: Evidence of a correlation

Cited by 16 publications

References 5 publications

Filaggrin loss‐of‐function mutations and levels of filaggrin degradation products in adult patients with atopic dermatitis in Croatia

Filaggrin loss‐of‐function mutations and levels of filaggrin degradation products in adult patients with atopic dermatitis in Croatia

Global Associations between UVR Exposure and Current Eczema Prevalence in Children from ISAAC Phase Three

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

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