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J Allergy Clin Immunol. 2015 Dec;136(6):1591-1600. doi: 10.1016/j.jaci.2015.06.047. Epub 2015 Sep 3.

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

Author information

1
Johns Hopkins Asthma & Allergy Center, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD.
2
Department of Pediatrics, National Jewish Health, 1400 Jackson St, Denver, CO.
3
Department of Biostatistics, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD.
4
Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD.
5
Northwestern University and Children's Memorial Hospital, Chicago, IL.
6
Division of Immunology, Children's Hospital Boston, Boston, MA.
7
Division of Dermatology, University of California San Diego, San Diego, CA.
8
Department of Dermatology, Oregon Health & Science University, Portland, OR.
9
Department of Dermatology, University of Rochester Medical Center, Rochester, NY.
10
Department of Pediatrics, Harvard Medical School, Boston, MA.
#
Contributed equally

Abstract

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.

KEYWORDS:

IFNGR1; atopic dermatitis; eczema herpeticum; genetic variants

PMID:
26343451
PMCID:
PMC4679503
DOI:
10.1016/j.jaci.2015.06.047
[Indexed for MEDLINE]
Free PMC Article

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