Genome-wide Association Study Finds Angpt2 Locus Associated with Intraocular Pressure in Rats

Abstract

Purpose : Primary open angle glaucoma (POAG) is a multifactorial disease with increased intraocular pressure (IOP) being the major risk factor. Angiopoietins (ANGPT), a family of growth factors involved in the ANGPT-TEK (tunica interna endothelial cell kinase) pathway, have been previously shown in human genome-wide association studies (GWAS) to be potential candidate genes for increased IOP and POAG. We present the results of GWAS data from N/NIH heterogeneous stock (HS) rats highlighting the role of an Angiopoietin 2 (Angpt2) genomic locus associated with IOP.

Methods : The IOP of HS rats (N=835) was measured using a Tonolab tonometer. DNA from all test subjects was genotyped by sequencing. To identify a genomic region that modulated IOP, we mapped a quantitative trait locus (QTL). Permutation was used to determine the threshold for significance using an empirical p value of 0.05. A linear mixed model was used to control for type I error in the naive permutation. Confocal immunohistochemistry (IHC) is being performed using rat anti-tie2, rabbit anti-angiopoietin2, and mouse anti-VE-PTP antibodies to determine where these proteins are localized in whole eye samples from rats and human.

Results : Our GWAS data identified a peak on rat chromosome 16 with genome-wide significance. Angpt2 was identified as the strongest positional candidate gene that modulates IOP. Based on previous reports, Angpt2 shows strong evidence of being associated with IOP and POAG in multiple species. IHC in whole eye samples for ANGPT-TEK pathway proteins will provide further insight on how these molecules compare across species.

Conclusions : Our results provide evidence of Angpt2 as a candidate gene for IOP modulation in rats. Importantly, this relationship is also shared by humans and mice. We propose that these similarities between species might serve as a biological basis for strengthening the relationship between POAG in humans and future POAG rodent models.

This is a 2020 ARVO Annual Meeting abstract.