An analytical enrichment‐based review of structural genetic studies on keratoconus

Abstract

Keratoconus is a progressive bilateral corneal protrusion that leads to irregular astigmatism and impairment of vision. Keratoconus is an etiologically heterogeneous corneal dystrophy and both environmental and genetic factors play a role in its etiopathogenesis. In this analytical review, we have studied all the genes that are structurally associated with keratoconus and have tried to explain the function of each gene and its association with other eye disorders in a concise way. In addition, using gene set enrichment analysis, it was attempted to find the most important impaired metabolic pathways in keratoconus. Several genetic studies have been carried out on keratoconus and several genes have been identified as risk factors involved in the etiology of the disease. In the current study, 16 studies, including nine association studies, five genome‐wide association studies, one linkage study, and one meta‐analysis, were reviewed and based on the 19 genes found, enrichment was performed and the most important metabolic pathways involved in the disease were identified. The enrichment results indicated that the two pathways, interleukin 1 processing and assembly of collagen fibrils, are significantly associated with the disease. Obviously, the results of this study, in addition to providing information about the genes involved in the disease, can provide an integrated insight into the gene‐based etiology of keratoconus and therapeutic opportunities thereof.

Screening for Novel LOX and SOD1 Variants in Keratoconus Patients from Brazil

“…An mRNA analysis of SOD1 carrying this deletion showed, in addition of the wild-type transcript, two splice variants lacking exon 2, or both exon 2 and 3 simultaneously, which exclude SOD1 protein active site and lead to a loss of function protein. [27] Another study with 33 Greek patients found that homozygote carriers for this deletion were significantly overrepresented among KC patients compared to healthy subjects. [29] We also verified a similar frequency of IVS2 + 50del7bp allele found with other studies.…”

“…[29] The involvement of SOD1 in other ocular diseases such as primary open-angle glaucoma has also been described. [31] Although already well studied, [32,33] the genetic basis of KC is still poorly understood. [34] Despite the availability of data on the involvement of SOD1 and LOX mutations in the development of KC in specific cohorts, little information is available regarding Brazilian patients.…”

“…The implication of SOD1 and LOX mutations on KC development may be important risk factors for the disease and their involvement in disease pathogenesis depends on additional studies on different ethnicities. [25,33] Considering that this pathology is considered a major public health issue in Brazil, the aim of this study was to investigate the presence of genetic variants in SOD1 and LOX genes in individuals affected by advanced KC.…”

Genetic Screening Revealed Latent Keratoconus in Asymptomatic Individuals

“…Single nucleotide variants and indel variants were identified by GATK and annotated by ANNOVAR. For variant analyses, we summarized 40 candidate genes related to KC (Supplementary Table 2), based on several genetics reviews of KC and PubMed database (Bykhovskaya et al, 2016;Loukovitis et al, 2018;Panahi et al, 2019). The pathogenicity of variants in candidate genes with MAF ≤ 0.01 in all of the variant databases, including gnomAD, ExAC, and 1,000 Genomes, was compared with that of variants identified by Sanger sequencing.…”

Molecular Genetics of Keratoconus: Clinical Implications

“…MMP-1 and MMP-9, are upregulated in corneal tissue and affect collagen properites and dyregulate proteolysis [128]. In a pathways enrichment analysis of 19 keratoconus genes consistently reported as risk genes to keratoconus in 16 studies, interleukin-1 processing and assembly of collagen fibrils are associated with keratoconus pathology [129]. MMPs have been assayed in tears.…”