Genome-wide association study of recalcitrant atopic dermatitis in Korean children

Abstract

Background: Atopic dermatitis (AD) is a heterogeneous chronic inflammatory skin disease. Most AD during infancy resolves during childhood, but moderate-to-severe AD with allergic sensitization is more likely to persist into adulthood and more often occurs with other allergic diseases.

Objective: We sought to find susceptibility loci by performing the first genome-wide association study (GWAS) of AD in Korean children with recalcitrant AD, which was defined as moderate-to-severe AD with allergic sensitization.

Methods: Our study included 246 children with recalcitrant AD and 551 adult control subjects with a negative history of both allergic disease and allergic sensitization. DNA from these subjects was genotyped; sets of common single nucleotide polymorphisms (SNPs) were imputed and used in the GWAS after quality control checks.

Results: SNPs at a region on 13q21.31 were associated with recalcitrant AD at a genome-wide threshold of significance (P < 2.0 × 10(-8)). These associated SNPs are more than 1 Mb from the closest gene, protocadherin (PCDH)9. SNPs at 4 additional loci had P values of less than 1 × 10(-6), including SNPs at or near the neuroblastoma amplified sequence (NBAS; 2p24.3), thymus-expressed molecule involved in selection (THEMIS; 6q22.33), GATA3 (10p14), and S-phase cyclin A-associated protein in the ER (SCAPER; 15q24.3) genes. Further analysis of total serum IgE levels suggested 13q21.31 might be primarily an IgE locus, and analyses of published data demonstrated that SNPs at the 15q24.3 region are expression quantitative trait loci for 2 nearby genes, ISL2 and proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1), in immune cells.

Conclusion: Our GWAS of recalcitrant AD identified new susceptibility regions containing genes involved in epithelial cell function and immune dysregulation, 2 key features of AD, and potentially extend our understanding of their role in pathogenesis.

Keywords: Genome-wide association study; IgE; allergic sensitization; atopic dermatitis; children; severity.

Figure 1

(a) Quantile-quantile plot of P values for the test statistics (Cochran-Armitage trend tests) in the GWAS. Horizontal and vertical axes show expected P values under a null distribution and observed P values, respectively. Black data points correspond to the P values of all SNPs in the GWAS. (b) Manhattan plot showing the –log₁₀ P values of 2,501,352 SNPs in the GWAS for 246 Korean children with recalcitrant atopic dermatitis and 551 Korean adult controls without a history of allergic diseases and allergic sensitization plotted against their respective positions on the autosomes. The red line shows the genome-wide significance threshold (P = 2.0 × 10⁻⁸). The gray line shows the threshold at P = 1 × 10⁻⁶. Locations of the NBAS (2p24.3), THEMIS (6q22.33), GATA3 (10p14), PCDH9 (13q21.31), SCAPER (15q24.3) loci are indicated.

Figure 1

(a) Quantile-quantile plot of P values for the test statistics (Cochran-Armitage trend tests) in the GWAS. Horizontal and vertical axes show expected P values under a null distribution and observed P values, respectively. Black data points correspond to the P values of all SNPs in the GWAS. (b) Manhattan plot showing the –log₁₀ P values of 2,501,352 SNPs in the GWAS for 246 Korean children with recalcitrant atopic dermatitis and 551 Korean adult controls without a history of allergic diseases and allergic sensitization plotted against their respective positions on the autosomes. The red line shows the genome-wide significance threshold (P = 2.0 × 10⁻⁸). The gray line shows the threshold at P = 1 × 10⁻⁶. Locations of the NBAS (2p24.3), THEMIS (6q22.33), GATA3 (10p14), PCDH9 (13q21.31), SCAPER (15q24.3) loci are indicated.

Figure 2

Regional association plots at the 15q24.3 locus for recalcitrant atopic dermatitis. Significant SNPs are located within the SCAPER gene and include cis-eQTLs for the ISL2 gene in whole blood and for PSTPIP1 in CD14+ monocytes after treatment with LPS for 24 hours. The –log₁₀ P value (left y axis) of each SNP is shown according to its chromosomal position (x axis). Genetic recombination rates are shown by the blue line, and horizontal arrows indicate the locations of genes and direction of transcription. The most associated SNP (labeled by rs number) is shown as a purple circle, and its LD (r²) with all other SNPs is indicated by color.