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Genetic Polymorphisms in the Promoter of the Interferon Gamma Receptor 1 Gene Are Associated with Atopic Cataracts

¹From the Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan; the ²Laboratory for Genetics of Allergic Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan; the ³Department of Ophthalmology, Juntendo University School of Medicine, Tokyo, Japan; the ⁴Department of Ophthalmology, Yamaguchi University School of Medicine, Ube, Japan; ⁵Takao Hospital, Kyoto, Japan; the ⁶Department of Ophthalmology, Fujita Health University Banbuntane Hospital, Nagoya, Japan; the ⁷Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; the ⁸Departments of Ophthalmology and ⁹Dermatology, Yokohama City University School of Medicine, Yokohama, Japan; and the ¹⁰Experimental Medicine Unit, University of Wales Swansea, Swansea, United Kingdom.

PURPOSE. Previous reports have shown genetic predisposition for atopic dermatitis (AD). Some of the severe complications of AD manifest in the eye, such as cataract, retinal detachment, and keratoconjunctivitis. This study was conducted to examine the genetic association between the atopy-related genes and patients with ocular complications (ocular AD).

METHODS. Seventy-eighty patients with ocular AD and 282 healthy control subjects were enrolled in an investigation of the association between the atopy-related genes (FCERB, IL13, and IFNGR1) and ocular AD. Genetic association studies and functional analysis of single nucleotide polymorphisms (SNPs) were performed.

RESULTS. The –56TT genotype in the IFNGR1 promoter region was significantly associated with an increased risk of ocular AD under recessive models (² test, raw P = 0.0004, odds ratio 2.57). The –56TT genotype was more common in atopic cataracts. A reporter gene assay showed that, after stimulation with IFN-, the IFNGR1 gene promoter construct that contained the –56T allele, a common allele in ocular AD patients, manifested higher transcriptional activity in lens epithelial cells (LECs) than did the construct with the –56C allele. Real-time PCR analysis demonstrated higher IFNGR1 mRNA expression in the LECs in atopic than in senile cataracts. iNOS expression by IFNGR1-overexpressing LECs was enhanced on stimulation with IFN- and LPS.

CONCLUSIONS. The –56T allele in the IFNGR1 promoter results in higher IFNGR1 transcriptional activity and represents a genetic risk factor for atopic cataracts.