Abstract

Purpose: Cytomegalovirus (CMV) infection is associated with recurrent acute or chronic anterior uveitis/endotheliitis in apparently immunocompetent individuals without human immunodeficiency virus infection, systemic malignancies, autoimmune diseases or immunosuppressive treatment. The pathogenesis of this condition is still unknown and we hypothesize that these individuals may harbor an impaired immune defense against CMV control. We conducted an exome-wide association study to identify potential genetic risk factors and human leukocyte antigen (HLA) haplotype associations.

Methods: We contrasted exome-wide SNP genotypes between 42 immunocompetent Chinese individuals with aqueous humor polymerase chain reaction proven CMV anterior uveitis/endotheliitis and 2418 Chinese population controls using the Illumina HumanExome BeadChip. The coverage included functional exonic variants of >20,000 RefSeq entries and HLA haplotype single-nucleotide polymorphism (SNP) tags. Principal component analysis was performed to verify the ancestry matching between cases and controls.

Results: We observed 30 SNPs which were associated with CMV anterior uveitis/endotheliitis at suggestive significance (P < 1 x 10^-4). The top 4 susceptibility loci were exm1332135 (p=3.27x10(-06)), Exome_Asian_chr17-45369577-19 (p=3.79x10(-06)), exm1099900 (p=5.29x10(-06)) and exm-rs2304130 (p=8.13x10(-06)). These gene loci encoded for cell signal transduction protein EFCAB13 (EF-hand calcium binding domain 13), cell-surface signaling protein ITGB3 (Integrin beta chain beta 3), nuclear transcription factor inhibitor KLHDC2 (Kelch domain containing 2), and transcription factor ZNF101 (zinc finger protein 101) which is highly expressed in human T lymphoid cells. HLA haplotype SNPs were not significantly associated with disease (P > 0.05 for all comparisons).

Conclusions: Our data suggest that cell-signaling alterations may underlie susceptibility towards recurrent CMV uveitis. Further studies are needed to validate our observations.