Summary of single nucleotide polymorphisms in filaggrin associated with atopic dermatitis

BackgroundLoss of function mutations in the filaggrin gene (FLG) play an important role in the pathogenesis of atopic dermatitis (AD). However, FLG is structurally challenging to sequence using conventional high-throughput techniques. Genome-wide association studies (GWAS) chips and imputation panels are also not designed to detect most of these mutations. Furthermore, bioinformatics tools have variable sensitivity for identification of loss of function variants. Targeted sequencing is often performed for AD but requires a comprehensive list of potential variants.ObjectivesThis study sought to compile all published FLG single nucleotide polymorphisms (SNPs) in AD and characterize the methods for assessing the associated phenotype.MethodsWe searched nine electronic databases for studies that reported measures of association between FLG and AD. Data regarding FLG SNPs and participant demographics were extracted. The identified SNPs were compared to those available in the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) GWAS Catalogue and the 1000Genomes reference panel.ResultsWe identified 168 SNPs in FLG that have been associated with AD, with the most studied being R501X, 2282del4, R2447X, 3321delA, S3247X and p.S2554 in European and Asian ancestries. A total of 153 of these SNPs are not available from GWAS studies, and 78 are not included in the 1000Genomes reference panel.ConclusionsBecause FLG is a complex gene, current GWAS chips do not capture most of the polymorphisms that have been associated with AD. This study compiles all currently published FLG SNPs in atopic dermatitis and their phenotypic characteristics to develop a comprehensive list of potential variants. The study identified 168 SNPs, with the most studied SNPs being in European and Asian ancestries. Comparison of the identified SNPs with reference panels showed many SNPs that were not included, suggesting limitations of bioinformatics tools in identifying FLG loss-of-function mutations and the need for targeted sequencing in diverse populations. image