FLG mutations in the East Asian atopic dermatitis patients: genetic and clinical implication

Abstract

BackgroundSince the report on the association between FLG mutations and atopic dermatitis (AD) (1), genetic diversity of FLG mutations has been intensively investigated across ethnicities. However, except for well-established racial difference between European and Asian (2), detailed analysis of the genetic diversity and clinical implications of FLG mutations for East Asian ancestry was not performed yet. Questions addressedThe purpose of this study was, first, to overview genetic landscape of FLG mutations across East Asia and to analyse geographic distribution from genealogic point of view, especially prehistoric human migration in East Asia. Second, we investigated the association of FLG mutations with clinical features of AD to evaluate the clinical significance of FLG mutations. Experimental designWe collected data reporting FLG mutations among East Asian populations, including recently completed full sequencing of FLG for Koreans in our laboratory. In total, 1384 AD cases and 1031 normal controls were identified for three East Asian populations at six locations: Chinese Han/Singapore, Chinese Han/Shanghai, Chinese Han/Shanxi, Korean, Japanese/Kyushu and Japanese/ mainland (Table S1). From mutational diversity, genetic distances were calculated and visualized as phylogenetic trees. Ancestryrelated population structures were inferred by clustering software, STRUCTURE (3). To assess the significance of FLG mutations as clinical biomarkers, statistical tests were performed, and Review Manager (RevMan) (4) was employed for population pooled analysis and graphical presentation of results. Detailed information on 'Materials and Methods' can be found in the (Data S1). ResultsThe geographic distribution of FLG mutations is summarized in Fig. 1a, with several notable patterns. First, c.3321delA was re-confirmed as a pan-Asian mutation, found in all populations. Meanwhile, some mutations showed south-to-north (or north-to-south) distribution gradient: p.K4022X, the most prevalent FLG mutation in northern China and Korea, declined in frequency moving southward; in contrast, c.6950del8 (p.Q2417X, p.E2422X, etc.) showed the reverse. Finally, several mutations (p.S2554X/p.S2889X/p.S329 6X/Q1701X) were Japanese-specific and not found elsewhere.Phylogenetic tree clearly showed separation of Asian from European (Irish) and branching of Japanese, Korean, northern/southern Chinese Han successively (Fig. 1b, far-left). STRUCTURE analysis revealed that at least three ancestries contributed to the current genetic make-up of East Asian AD patients: south-to-north, northto-south and Japanese-specific ancestries (Fig. 1b,. These three ancestries were replicated in other genetic data, such as autosomal (Fig. 1b Table S1 for details). Hypothetical human migration routes are depicted by blue arrows. data sets (Fig. 1b, far-right) (6). For the presence of Japanese-specific FLG mutations, so-called dual origin of Japanese could provide possible explanations. Historic/archaeological data suggested two ancestries for current Japanese: Jom...

Epidemiology and Characterization of Atopic Dermatitis in East Asian Populations: A Systematic Review

“…Certain genetic variations may uniquely contribute to AD in Asian skin. A number of mutations in the filaggrin (FLG) gene have been identified in Asian populations, most notably c.3321delA, which has been associated with AD in China, Korea and Japan [25][26][27][28][29], whereas R501X and 2282del4 mutations are commonly found in European populations [30]. Loss-offunction mutations in SPINK5 have been identified in several Asian populations as well, including those of Japan, China, and Taiwan [31][32][33][34].…”

Efficacy and Safety of Specific Immunotherapy with Aeroallergens in the Management of Atopic Dermatitis: A Systematic Review and Meta-analysis

“…The difference in appearance is because of the epidermal gene expression between Asians, Caucasians, and colored people. (50,51) Local and systemic adverse events showed no signi cant differences with speci c immunotherapy in our study. The reactions shown were dizziness, swelling of the mouth, face, itching of the lips, rhinitis, erythema, and some reactions will recover without treatment.…”

Association ofDOCK8,IL17RA, andKLK12Polymorphisms with Atopic Dermatitis in Koreans

“…allowing the prediction of early-onset AD from such genetic information or family history 6 . Hence, the genetic diversity of FLG mutations can be mapped in East Asian countries, and visualized using phylogenetic trees 7 , and the search for new genetic candidate markers can continue. Identification of genetic variants for early diagnosis will prevent AD development and being a major part of personalized therapy.…”