Follow-Up Study of the First Genome-Wide Association Scan in Alopecia Areata: IL13 and KIAA0350 as Susceptibility Loci Supported with Genome-Wide Significance

Abstract

Recently, the first genome-wide association study (GWAS) of alopecia areata (AA) was conducted in a North-American sample, and this identified eight susceptibility loci surpassing genome-wide significance. The aim of the present follow-up association analysis was to confirm five of these eight loci (single-nucleotide polymorphisms (SNPs) from the CTLA4, IL-2RA, and HLA regions were not included due to previous own findings) and test 12 other loci from the GWAS, which did not surpass the threshold for genome-wide significance. Twenty-three SNPs from the 17 loci were investigated using a sample of 1,702 Central European AA patients and 1,723 controls. Of the five loci with previously reported genome-wide significance, association was confirmed for all of these: ULBP3/ULBP6, PRDX5, IL-2/IL-21, STX17, and IKZF4/ERBB3 (P-value <0.05). To detect robust evidence for association among the 12 other loci, a meta-analysis of the present association data and the data of the recent GWAS was performed. Genome-wide significant association was found for rs20541 (P(comb)=7.52 × 10(-10); odds ratio (OR)=1.30 (1.23-1.38)) and rs998592 (P(comb)=1.11 × 10(-11); OR=1.28 (1.21-1.36)), thus establishing IL-13 and KIAA0350/CLEC16A as susceptibility loci for AA. Interestingly, IL-13 and KIAA0350/CLEC16A are susceptibility loci for other autoimmune diseases, supporting the hypothesis of shared pathways of autoimmune susceptibility.

The Role of Hair Follicle Immune Privilege Collapse in Alopecia Areata: Status and Perspectives

“…NK, NKT, and some CD8 þ T cells) as well as NKG2D-activating ligands from the MICA (MHC I-related chain A) family may also have a key role in AA pathogenesis (Ito et al, 2008a, b;Petukhova et al, 2010). This is supported by genotyping (Barahmani et al, 2006) and genome-wide association study evidence (Petukhova et al, 2010;Jagielska et al, 2012). Interestingly, the injection of peripheral blood mononuclear cells from healthy individuals that were enriched for NKG2D þ or CD56 þ cells and activated by IL-2 into healthy human scalp skin transplanted onto severecombined immunodeficient mice can induce a hair loss pattern that copies the human AA phenotype (Gilhar et al, 2013).…”

The Immunological Association between Alopecia Areata and Respiratory Diseases: A Systematic Review

“…A strong genetic links exists between AA and atopy (AR and asthma) through the IL-13 and KIAA0350/CLEC16A susceptibility loci which have been identified in AA, as well as other autoimmune diseases [27, 48]. Additionally, AA and atopy share a Th2 cytokine pattern with increased levels of IgE, antibodies, mast cells, and eosinophils [49, 50].…”

The Genetic Architecture of Alopecia Areata

“…Importantly, each of the GWAS regions identified in AA has been confirmed through independent replication studies or previous candidate gene studies (Petukhova et al, 2010;John et al, 2011;Jagielska et al, 2012). More recently, a second GWAS was performed for AA in which a pooled genotyping strategy was used to analyze approximately 700 cases and 700 controls (Forstbauer et al, 2012).…”