Genetics in Keratoconus: where are we?

Abstract

Keratoconus (KC) is a non-inflammatory thinning and protrusion of the cornea in which the cornea assumes a conical shape. Complex etiology of this condition at present remains an enigma. Although environmental factors have been involved in KC pathogenesis, strong underlining genetic susceptibility has been proven. The lack of consistent findings among early genetic studies suggested a heterogeneity and complex nature of the genetic contribution to the development of KC. Recently, genome-wide linkage studies (GWLS) and genome-wide association studies (GWAS) were undertaken. Next-generation sequencing (NGS)-based genomic screens are also currently being carried out. Application of these recently developed comprehensive genetic tools led to a much greater success and increased reproducibility of genetic findings in KC. Involvement of the LOX gene identified through GWLS has been confirmed in multiple cohorts of KC patients around the world. KC susceptibility region located at the 2q21.3 chromosomal region near the RAB3GAP1 gene identified through GWAS was independently replicated. Rare variants in the ZNF469 gene (mutated in corneal dystrophy Brittle Cornea Syndrome) and in the TGFBI gene (mutated in multiple corneal epithelial–stromal TGFBI dystrophies) have been repeatedly identified in familial and sporadic KC patients of different ethnicities. Additional comprehensive strategies using quantitative endophenotypes have been successfully employed to bring further understanding to the genetics of KC. Additional genetic determinants including the COL5A1 gene have been identified in the GWAS of KC-related trait central corneal thickness. These recent discoveries confirmed the importance of the endophenotype approach for studying complex genetic diseases such as KC and showed that different connective tissue disorders may have the same genetic determinants.

Genome-wide discovery of hidden genes mediating known drug-disease association using KDDANet

“…It is also expected that SNW1 and HDAC2 were contained in this meta-subnetwork as they were involved in notch signaling pathway which is down-regulated in keratoconus (You, et al, 2018). Interestingly, consistent with the associations between collagen genes and keratoconus (Bykhovskaya, et al, 2016), a novel collagens coding gene, COL1A1, was captured in this meta-subnetwork. Taken together, these shared gene interactions provided more valuable and general guides for drug repositioning and disease treatment as they characterized the common molecular mechanism among multiple KDDAs.…”

Accumulation of sequence variants in genes of Wnt signaling and focal adhesion pathways in human corneas further explains their involvement in keratoconus

“…However, the results of this pilot study gave additional insight into the role of the Wnt signaling and/or focal adhesion pathways in KTCN development and showed the possible indications for further KTCN research. The identification of rare variants in different genes further supports the heterogeneity of KTCN with multiple genes underlying its pathogenesis Abu-Amero, Al-Muammar & Kondkar, 2014;Bykhovskaya, Margines & Rabinowitz, 2016;Mas Tur et al, 2017;Valgaeren, Koppen & Van Camp, 2018).…”

Three novel variants identified within ECM-related genes in Chinese Han keratoconus patients

“…In our study, we found a new mutation (c.95 G > A) in LOX, accompanied by a reduction in LOX mRNA expression in KC patients. It can be well explained that destruction of normal LOX expression destroys ECM maturation by reduced cross-linking of collagen fibers in the cornea stroma, leading to cornea biomechanical instability and thinning 31,47 , which is a remarkable characteristic of KC. It can be further proved by observing reduced crosslinks between collagen and elastic fibers in LOX-null mice 48,49 .…”