Posters

mTOR pathway activation in severe keratoconus; the functional implications of GWAS identified loci

Poster Details

First Author: R. Wisse NETHERLANDS

Co Author(s):    J. Kuiper   G. de Veij Mestdagh   S. Imhof   T. Radstake   A. van der Lelij   J. Broen     

Abstract Details

Purpose:

Keratoconus (KC) is a corneal disease that can lead to a severe decrease in visual acuity and may warrant a corneal grafting procedure. KC onset and progression is more severe in younger patients. The underlying aetiology is multifactorial, but remains enigmatic. Recent meta-analyses of genome wide association studies have identified four susceptible loci for keratoconus, all involved in cellular metabolism. The contribution of these genes to disease biology however is currently unknown.

Setting:

Tertiary Academic Center Department of Ophthalmology, UMC Utrecht & Laboratory of Translational Immunology, UMC Utrecht

Methods:

Here, we investigated the gene expression profiles of these identified loci in corneal tissue in combination with an additional gene panel focussed on cellular ageing and cell cycle control. Keratoconus samples were compared to healthy controls and decompensated grafts (DG).

Results:

We report, for the first time, a unique deregulation of a myriad of genes involved in the mammalian target of rapamycin (mTORC1) pathway were convincingly up-regulated in the KC and DG samples, when compared to healthy controls. mTORC1 represents a principal pathway in cell cycle control and cellular metabolism. It implicates that KC corneas are severely exhausted on a cellular level. Strikingly, KC corneas show signs of cellular aging far exceeding their healthy, biological older, peers, to a level comparable to severely failed grafts.

Conclusions:

These functional implications strengthen previous genetic associations identified by genome-wide studies and narrow down true causal variants in the development of KC. Further research is warranted to strengthen our conclusions, with attention to the role of mTOR in the aetiology of progressive KC, and the clinical potential of mTOR inhibition for this debilitating disease.

Financial Disclosure:

NONE