Filaggrin gene polymorphisms in Indian children with atopic dermatitis: A cross-sectional multicentre study.

Background Filaggrin (FLG) gene encoding the protein filaggrin plays an important role in barrier function of the skin and its alteration is a predisposing factor for atopic dermatitis. FLG gene variants result in absent or decreased filaggrin protein. Worldwide, the prevalence of FLG variants ranges from 14 to 56%. FLG null variants are distinct in each population. Objectives To study the FLG gene polymorphisms in Indian children and attempt a genotype-phenotype correlation in atopic dermatitis. Methods This was a cross-sectional, multicentre study conducted on 75 Indian children. Demographic details, clinical features and identified FLG null variants were recorded. We performed a whole gene sequencing of the entire FLG coding region using next-generation sequencing technology. Results The prevalence of FLG null variants was 34.7%. A total of 20 different FLG loss of function variants in 26 children were documented. Sixteen (80%) variants were novel and four (20%) were previously reported in Asian and European populations. We found a statistically significant association between FLG variants with early age of onset of atopic dermatitis (P = 0.016) and elevated serum IgE levels (P = 0.051). There was no significant difference between atopic dermatitis phenotypes in children having one variant as compared to children harbouring two or more null variants. Limitation Small sample size. Conclusion Our study reports a unique set of FLG variants different from Asian and European populations, with these variants being significantly associated with an early age of onset of atopic dermatitis and elevated serum IgE levels.

Massively Parallel Sequencingof the Filaggrin Gene Reveals an Association Between FLG Loss-of-function Mutations and Leprosy.

Filaggrin, encoded by the FLG gene, plays a crucial role in the barrier function of epidermis, but the association between FLG loss-of-function mutations and infectious skin diseases has not been systematically studied. FLG coding sequences from 945 patients with leprosy and 916 healthy controls were captured and enriched using an array-based high-throughput system, and subjected to next-generation sequencing. The loss-of-function mutations found were further validated by Sanger sequencing. A total of 21 loss-of-function mutations were found in 945 patients with leprosy, with a carrier rate of 17.53%, while the prevalence of these mutations in 916 healthy controls was 14.77%, which was significantly lower than in patients. Two individual FLG loss-of-function mutations (K4022X and Q1790X) were found to be significantly associated with leprosy. These results suggest a possible role for filaggrin in defending against leprosy pathogens.

Genome-Wide Analysis of Protein-Coding Variants in Leprosy.

Although genome-wide association studies have greatly advanced our understanding of the contribution of common noncoding variants to leprosy susceptibility, protein-coding variants have not been systematically investigated. We carried out a three-stage genome-wide association study of protein-coding variants in Han Chinese, of whom were 7,048 leprosy patients and 14,398 were healthy control subjects. Seven coding variants of exome-wide significance were discovered, including two rare variants: rs145562243 in NCKIPSD (P = 1.71 × 10-9, odds ratio [OR] = 4.35) and rs149308743 in CARD9 (P = 2.09 × 10-8, OR = 4.75); three low-frequency variants: rs76418789 in IL23R (P = 1.03 × 10-10, OR = 1.36), rs146466242 in FLG (P = 3.39 × 10-12, OR = 1.45), and rs55882956 in TYK2 (P = 1.04 × 10-6, OR = 1.30); and two common variants: rs780668 in SLC29A3 (P = 2.17 × 10-9, OR = 1.14) and rs181206 in IL27 (P = 1.08 × 10-7, OR = 0.83). Discovered protein-coding variants, particularly low-frequency and rare ones, showed involvement of skin barrier and endocytosis/phagocytosis/autophagy, in addition to known innate and adaptive immunity, in the pathogenesis of leprosy, highlighting the merits of protein-coding variant studies for complex diseases.

Filaggrin mutations and the skin.

Filaggrin is very important in the terminal differentiation of the skin and the formation of cornified envelope in the stratum corneum. Several mutations in the filaggrin gene have been identified in the last decade, mostly from the European countries. Loss of function mutations in the filaggrin gene results in reduced production of filaggrin, depending on the type and site of mutation. Such mutations in the filaggrin gene have been shown to be the most significant genetic risk factor for development of atopic dermatitis and undoubtedly has a role in the pathogenesis of ichthyosis vulgaris. Though there is theoretical possibility of association with hand eczema and allergic contact dermatitis; in clinical studies, the strength of these associations was not significantly strong. In this review, we have discussed the structure and function of filaggrin, basic genetics, type of mutations in filaggrin gene, and association of such mutations with different dermatoses.

GM-CSF activates regenerative epidermal growth and stimulates keratinocyte proliferation in human skin in vivo.

Granulocyte/macrophage-colony-stimulating factor (GM-CSF), an immunomodulator of hematopoietic cells, has also been shown to stimulate human keratinocyte proliferation in vitro and speed healing of wounds in the skin of lepromatous leprosy patients. In this study we have examined the in vivo effects of recombinant human GM-CSF on epidermal keratinocyte proliferation and on expression of proteins marking regenerative epidermal growth. Skin biopsies from GM-CSF injected cutaneous sites were obtained between 1 and 6 d following administration of 7.5 or 15 micrograms of the growth factor. Activation of keratinocyte proliferation, quantified as the expression of the Ki67+ nuclear antigen, was noted 1 d following GM-CSF administration. A regenerative epidermal phenotype, demonstrated by immunohistochemical staining of cellular proteins involucrin, filaggrin, and keratin 16, was similarly noted as early as 1 d following GM-CSF injection. This phenotype persisted as late as 6 d post-injection. These results suggest that GM-CSF injection into human skin induces keratinocyte proliferation as well as regenerative differentiation of the epidermis. To date no other cytokine has been shown to be mitogenic for human keratinocytes both in vivo and in vitro or to alter keratinocyte differentiation along the "alternate" or regenerative pathway.