L12
Targeted Resequencing Identified Damaging Rare Variants in IFNGR1 Associated with Atopic Dermatitis Complicated By Eczema Herpeticum
Tuesday, March 4, 2014
Exhibit Hall B (Convention Center)
Li Gao, MD PhD, Ryan Heiser, PhD, Nicholas M. Rafaels, Lili Huang, MPH, Joseph Potee, Rasika A. Mathias, ScD, Lisa A. Beck, MD FAAAAI, Kathleen C. Barnes, PhD FAAAAI, Donald Y.M. Leung, MD PhD FAAAAI
Genetic variations in IFNGR1 gene have been reported that abrogate IFN-γ signaling leading to enhanced susceptibility to mycobacterial infection. However, the causality of IFNGR1 variants in atopic dermatitis with eczema herpeticum (ADEH+) has not been established. Utilizing targeted resequencing, we assess the influence of rare functional variations in IFNGR1 to ADEH+ susceptibility.

We performed targeted resequencing in 122 European American (EA) ADEH+ cases and 107 ADEH- controls followed by validation genotyping for 3 rare missense variants in the entire cohort including a total of 411 EA patients (133 ADEH+, 157 ADEH- and 121 non-atopic controls (NA)). Association tests between rare variants and risk of ADEH+ was performed using SKAT-O. The IFN-γ induced CD80 expression on peripheral blood mononuclear cells (PBMC) was examined in a selected group of patients.

We identified 18 common and 118 rare variants in IFNGR1. Among the rare variants, 6 were missense with 3 as possibly damaging (Val14Met, Val61Ile and Tyr397Cys) including one novel variant (Tyr397Cys). The 3 damaging rare variants conferred greater risk for ADEH+ (P<0.031) when we compared 133 ADEH+ patients including 5 heterozygous carriers to 278 non-ADEH+ subjects (157 ADEH-, 121 NA). Enhanced signal was observed (P<7.48E-14) when we compared findings to an unphenotyped control population (4300 EAs) from the Exome Sequencing Project. In functional studies conducted thus far, we observed that an 8-year-old boy carrying the Val14Met variant had a blunted response to IFN-γ induced CD80 expression.

Our novel findings provide evidence that functional polymorphisms in IFNGR1 contribute to ADEH+ susceptibility. Additional functional studies are underway.