Posters

Interplay between local gene expression and genetics: nature and nurture factors in keratoconus

Poster Details

First Author: P.Ahuja INDIA

Co Author(s):    A. Karunakaran   A. Ghosh   R. Shetty   P. Khamar           

Abstract Details

Purpose:

Inherent genetic abnormalities (nature) can lead to a variety of medical conditions including Keratoconus (KC) or predispose subjects to develop a disease in presence of additional risk factors. Environmental factors or habits such as eye rubbing (nurture), can cause dysregulated gene expression of various extracellular matrix and inflammatory factors in the KC cornea. We therefore propose a model where the interplay of genetic predisposition and epigenetic response of the cornea in response to inflammatory triggers leads to disease.

Setting:

Narayana Nethralaya and Grow laboratories,Bangalore

Methods:

Blood from probands and familial controls from 3 KC families were analysed by exome sequencing. The gene expression was evaluated from the corneal epithelium   for alterations in collagen isoforms (COLI,COLIV), inflammatory markers (IL6,TNFα) and collagen cross linking enzyme (LOX) in 23KC eyes and 25control subjects. Corneal topography(Oculus, Pentacam) and biomechanics (Corvis ST) of 68 KC families were evaluated for abnormalities of first-degree relatives of patients with keratoconus and co related with the progression of the disease.

Results:

There was a statistically significant difference in thinnest pachymetry, BAD-D (by corneal topography) and deflection amplitude (p<0.05) in the first degree family members as compared to healthy normal controls. The greater difference in first degree relatives correlated with higher grade of KC in the probands and early progression. We found novel mutations in Collagen IV (COLIV) and Collagen VI (COLVI) in KC families. Reduced gene expression of COL IV was observed in KC patient epithelium when compared to controls(p<0.05).

Conclusions:

The association of abnormal topography in relatives of KC subjects with rapid disease progression in proband suggests a genetic basis for KC. The novel mutations found in collagens may be involved in weakening the extracellular matrix leading to disease. This is validated by the reduction in Col IV gene expression in an independent cohort of KC subjects who are exposed to other risk factors such as eye rubbing and inflammation. Thus, both genes and their regulation contribute to KC suggesting that topography measurements in relative of KC subjects may indicate signs of early progression.

Financial Disclosure:

None