Genetic Association of JMJD7-PLA2G4B Variants with Early-Onset Primary Open-Angle Glaucoma in African Americans

Abstract

Purpose: Primary open-angle glaucoma (POAG) is a complex inherited disorder. We have previously identified an 11 cM region on chromosome 15 (GLC1I) linked to African American and Caucasian multiplex POAG families with an early adult onset of disease. Fine-mapping in the GLC1I region suggests the potential association of the JMJD7-PLA2G4B locus. The purpose of this study was to examine the association of this genomic region with POAG in African Americans.

Methods: The study dataset included 550 African American POAG patients and 660 African American controls. Fourteen tagging SNPs in this region were selected for genotyping using TaqMan-based allelic assays from ABI. Association analysis was performed using logistic regression with an additive model. OSACC (Ordered subset analysis for case-control studies) was performed for all 14 SNPs to stratify the analysis by age-at-diagnosis (AAD) of POAG. A PLA2G4B knockout mouse was further used to examine the presence of glaucoma-related morphological abnormalities, including intraocular pressure and histological changes of mouse eyes.

Results: SNP rs7174710 was nominally associated with POAG in African Americans (p=0.04). OSACC analyses based on AAD identified significant association of four SNPs in the JMJD7-PLA2G4B region with early onset POAG (AAD less than 42 years of age), with permutation p value ranging from 2 x 10-4 to 2 x 10-3. The number of POAG cases in this sub-group accounts for approximately 19% of all cases. Homozygous PLA2G4B knockout mice had normal IOP and ocular morphology compared to wild-type mice.

Conclusions: We have identified a significant association between variants in the JMJD7-PLA2G4B gene with early onset POAG in the GLC1I locus. JMJD7-PLA2G4B contains a partial JmjC domain, downstream C2 and phospholipase A2 domain. This protein is involved in alpha-linolenic acid metabolism and the Fc epsilon RI signaling pathway, which was recently found to be significantly associated with POAG in pathway analysis of the NEIGHBOR genome-wide association data. The mouse model did not demonstrate a glaucoma phenotype, however, knockout mice frequently do not recapitulate phenotypes caused by gain of function mutations. The evidence for association in POAG patients with early adult onset disease suggests this gene may play a functional role in the GLC1I locus.

Keywords: 539 genetics