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).


CONCLUSIONS
Our results provide evidence that both genetic variants in the gene encoding IFNGR1 are implicated in susceptibility to the ADEH+ phenotype.
Johns Hopkins Asthma & Allergy Center, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD.
Li
L
Gao
Department of Pediatrics, National Jewish Health, 1400 Jackson St, Denver, CO.
Lianghua
L
Bin
Johns Hopkins Asthma & Allergy Center, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD.
Nicholas M
NM
Rafaels
Johns Hopkins Asthma & Allergy Center, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD.
Lili
L
Huang
Johns Hopkins Asthma & Allergy Center, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD.
Joseph
J
Potee
Department of Biostatistics, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD.
Ingo
I
Ruczinski
Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD.
Terri H
TH
Beaty
Northwestern University and Children's Memorial Hospital, Chicago, IL.
Amy S
AS
Paller
Division of Immunology, Children's Hospital Boston, Boston, MA.
Lynda C
LC
Schneider
Division of Dermatology, University of California San Diego, San Diego, CA.
Rich
R
Gallo
Department of Dermatology, Oregon Health & Science University, Portland, OR.
Jon M
JM
Hanifin
Department of Dermatology, University of Rochester Medical Center, Rochester, NY.
Lisa A
LA
Beck
Department of Pediatrics, Harvard Medical School, Boston, MA.
Raif S
RS
Geha
Johns Hopkins Asthma & Allergy Center, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD.
Rasika A
RA
Mathias
Johns Hopkins Asthma & Allergy Center, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD.
Kathleen C
KC
Barnes
Department of Pediatrics, National Jewish Health, 1400 Jackson St, Denver, CO.
Donald Y M
DYM
Leung
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003876:Dermatitis, Atopic / Q000235:genetics*; D005260:Female; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000235:genetics; D007617:Kaposi Varicelliform Eruption / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017471:Receptors, Interferon / Q000235:genetics*; D012306:Risk; D050794:STAT1 Transcription Factor / Q000378:metabolism; D055815:Young Adult; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D000096743:Interferon gamma Receptor; C494079:STAT1 protein, human
IFNGR1; atopic dermatitis; eczema herpeticum; genetic variants