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.