Targeted deep sequencing identifies rare loss-of-function variants in IFNGR1 for risk of atopic dermatitis complicated by eczema herpeticum.

BACKGROUND: A subset of atopic dermatitis is associated with increased susceptibility to eczema herpeticum (ADEH+). We previously reported that common single nucleotide polymorphisms (SNPs) in the IFN-γ (IFNG) and IFN-γ receptor 1 (IFNGR1) genes were associated with the ADEH+ phenotype. OBJECTIVE: We sought to interrogate the role of rare variants in interferon pathway genes for the risk of ADEH+. METHODS: We performed targeted sequencing of interferon pathway genes (IFNG, IFNGR1, IFNAR1, and IL12RB1) in 228 European American patients with AD selected according to their eczema herpeticum status, and severity was measured by using the Eczema Area and Severity Index. Replication genotyping was performed in independent samples of 219 European American and 333 African American subjects. Functional investigation of loss-of-function variants was conducted by using site-directed mutagenesis. RESULTS: We identified 494 single nucleotide variants encompassing 105 kb of sequence, including 145 common, 349 (70.6%) rare (minor allele frequency <5%), and 86 (17.4%) novel variants, of which 2.8% were coding synonymous, 93.3% were noncoding (64.6% intronic), and 3.8% were missense. We identified 6 rare IFNGR1 missense variants, including 3 damaging variants (Val14Met [V14M], Val61Ile, and Tyr397Cys [Y397C]) conferring a higher risk for ADEH+ (P = .031). Variants V14M and Y397C were confirmed to be deleterious, leading to partial IFNGR1 deficiency. Seven common IFNGR1 SNPs, along with common protective haplotypes (2-7 SNPs), conferred a reduced risk of ADEH+ (P = .015-.002 and P = .0015-.0004, respectively), and both SNP and haplotype associations were replicated in an independent African American sample (P = .004-.0001 and P = .001-.0001, respectively). CONCLUSION: Our results provide evidence that both genetic variants in the gene encoding IFNGR1 are implicated in susceptibility to the ADEH+ phenotype.

Phenotype of atopic dermatitis subjects with a history of eczema herpeticum.

BACKGROUND: A subset of subjects with atopic dermatitis (AD) are susceptible to serious infections with herpes simplex virus, called eczema herpeticum, or vaccina virus, called eczema vaccinatum. OBJECTIVE: This National Institute of Allergy and Infectious Diseases-funded multicenter study was performed to establish a database of clinical information and biologic samples on subjects with AD with and without a history of eczema herpeticum (ADEH(+) and ADEH(-) subjects, respectively) and healthy control subjects. Careful phenotyping of AD subsets might suggest mechanisms responsible for disseminated viral infections and help identify at-risk individuals. METHODS: We analyzed the data from 901 subjects (ADEH(+) subjects, n = 134; ADEH(-) subjects, n = 419; healthy control subjects, n = 348) enrolled between May 11, 2006, and September 16, 2008, at 7 US medical centers. RESULTS: ADEH(+) subjects had more severe disease based on scoring systems (Eczema Area and Severity Index and Rajka-Langeland score), body surface area affected, and biomarkers (circulating eosinophil counts and serum IgE, thymus and activation-regulated chemokine, and cutaneous T cell-attracting chemokine) than ADEH(-) subjects (P < .001). ADEH(+) subjects were also more likely to have a history of food allergy (69% vs 40%, P < .001) or asthma (64% vs 44%, P < .001) and were more commonly sensitized to many common allergens (P < .001). Cutaneous infections with Staphylococcus aureus or molluscum contagiosum virus were more common in ADEH(+) subjects (78% and 8%, respectively) than in ADEH(-) subjects (29% and 2%, respectively; P < .001). CONCLUSION: Subjects with AD in whom eczema herpeticum develops have more severe T(H)2-polarized disease with greater allergen sensitization and more commonly have a history of food allergy, asthma, or both. They are also much more likely to experience cutaneous infections with S. aureus or molluscum contagiosum.