Genetic variants in interferon regulatory factor 2 (IRF2) are associated with atopic dermatitis and eczema herpeticum

Pei-Song Gao, Donald Y M Leung, Nicholas M Rafaels, Mark Boguniewicz, Tracey Hand, Li Gao, Tissa R Hata, Lynda C Schneider, Jon M Hanifin, Terri H Beaty, Lisa A Beck, Adriana Weinberg, Kathleen C Barnes, Pei-Song Gao, Donald Y M Leung, Nicholas M Rafaels, Mark Boguniewicz, Tracey Hand, Li Gao, Tissa R Hata, Lynda C Schneider, Jon M Hanifin, Terri H Beaty, Lisa A Beck, Adriana Weinberg, Kathleen C Barnes

Abstract

Interferon regulatory factor 2 (IRF2) is a member of a family of transcriptional factors involved in the modulation of IFN-induced immune responses to viral infection. To test whether genetic variants in IRF2 predict risk of atopic dermatitis (AD) and ADEH (atopic dermatitis complicated by eczema herpeticum), we genotyped 78 IRF2 tagging single-nucleotide polymorphisms (SNPs) in both European-American (n = 435) and African-American (n = 339) populations. Significant associations were observed between AD and two SNPs (rs793814, P = 0.007, odds ratio (OR) = 0.52; rs3756094, P = 0.037, OR = 0.66) among European Americans and one SNP (rs3775572, P = 0.016, OR = 0.46) among African Americans. Significant associations were also observed between ADEH and five SNPs (P = 0.049-0.022) among European Americans. The association with ADEH was further strengthened by haplotype analyses, wherein a five-SNP (CAGGA) haplotype showed the strongest association with ADEH (P = 0.0008). Eight IRF2 SNPs were significantly associated with IFN-γ production after herpes simplex virus (HSV) stimulation (P = 0.048-0.0008), including an AD-associated SNP (rs13139310, P = 0.008). Our findings suggest that distinct markers in IRF2 may be associated with AD and ADEH, which may depend upon ethnic ancestry, and genetic variants in IRF2 may contribute to an abnormal immune response to HSV.

Conflict of interest statement

CONFLICT OF INTEREST

The authors state no conflict of interest.

Figures

Figure 1
Figure 1
Haplotype results showing Omnibus P-values constructed across sliding windows of sizes 2–5 for 78 IRF2 SNPs and AD (a) and ADEH (b). Black vertical lines represent all individual SNP tests, and colored horizontal lines represent 2-, 3, 4, 5, haplotype tests. *See detailed data in Table 2. Lower plots illustrate patterns of LD (D’) in these samples: red squares for strong LD, blue squares for non-significant LD, and white squares for little or no LD; numerical values were generated using HAPLOVIEW software.
Figure 2
Figure 2
Association of IRF2 SNP rs13139310 with IFNγ production. IFNγ production was determined by the log10-transformed mean SFC/106 cells and expressed as Spot Forming Units (SFU). IRF2 SNP rs13139310 was significantly associated with HSV-stimulated IFNγ levels (GG (n=44) vs GA+AA (n=12), P = 0.008).
Figure 3
Figure 3
IRF2 gene expression was decreased in VV-treated non-lesional skin biopsies from human subjects with ADEH compared with subjects with AD. a) IRF2 expression was detected by geneChip array in VV-treated non-lesional skin biopsies from ADEH patients (n = 5), AD patients (n=11), and non-atopic controls (NA, n=13). Y axis represents the fold changes for both AD and ADEH relative to NA. P value was determined by comparison made between mean fold changes for AD and ADEH. b) IRF2 expression was validated by qRT-PCR in VV-treated non-lesional skin biopsies from ADEH (n=8) and AD (n=10) patients. IRF2 expression was normalized to the corresponding GAPDH and expressed as IRF2 mRNA expression relative to GAPDH expression (2−ΔCt).

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