Targeted deep sequencing identifies rare loss-of-function variants in IFNGR1 for risk of atopic dermatitis complicated by eczema herpeticum - 04/12/15
, Donald Y.M. Leung, MD, PhD jAbstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : IFNGR1, genetic variants, atopic dermatitis, eczema herpeticum
Abbreviations used : AD, ADEH+, ADEH−, ADRN, EASI, EH, GAS, HSV, IFNGR1, LD, MAF, NIH, pSTAT1, QC, SNP, STAT1, UTR, WT
Plan
| Supported by the Atopic Dermatitis Research Network National Institutes of Health/National Institute of Allergy and Infectious Diseases contracts HHSN272201000020C and HHSN272201000017C. K.C.B. was supported in part by the Mary Beryl Patch Turnbull Scholar Program. D.Y.M.L. was supported in part by the Edelstein Family Chair in Pediatric Allergy-Immunology. The CTRC is supported in part by NIH/NCATS Colorado CTSI grant no. UL1 TR000154. |
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| Disclosure of potential conflict of interest: L. Gao, N. M. Rafaels, and L. Huang have received grants from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID). J. Potee, R. A. Mathias, and D. Y. M. Leung have received grants from the NIH. T. H. Beaty has received grants from the National Heart, Lung, and Blood Institute (NHLBI). A. S. Paller has received grants and travel support from the Atopic Dermatitis Research Network; has consultant arrangements with Anacor, Chugai-Pharma, Galderma, GlaxoSmithKline-Stiefel, Novartis, Promius Pharma, and Regeneron; and is an investigator for Abbvie, Anacor, and Astellas. L. D. Schneider has received grants from the Atopic Dermatitis Research Network, the NIH, and the NIAID. L. A. Beck has received grants from the NIAID–Atopic Dermatitis Research Network; has consultant arrangements with Regeneron, Celgene, Novartis, MedImmune, AbbVie, Unilever, Genentech, and Array Biopharma; and has stock/stock options in Wyeth. K. C. Barnes has received grants from the NIH, is employed by Johns Hopkins University, and has received royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 136 - N° 6
P. 1591-1600 - décembre 2015 Retour au numéro
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