Genetic Aspects of Keratoconus: A Literature Review Exploring Potential Genetic Contributions and Possible Genetic Relationships with Comorbidities

Abstract

IntroductionKeratoconus (KC) is a complex, genetically heterogeneous, multifactorial degenerative disorder that is accompanied by corneal ectasia which usually progresses asymmetrically. With an incidence of approximately 1 per 2000 and 2 cases per 100,000 population presenting annually, KC follows an autosomal recessive or dominant pattern of inheritance and is, apparently, associated with genes that interact with environmental, genetic, and/or other factors. This is an important consideration in refractive surgery in the case of familial KC, given the association of KC with other genetic disorders and the imbalance between dizygotic twins. The present review attempts to identify the genetic loci contributing to the different KC clinical presentations and relate them to the common genetically determined comorbidities associated with KC.MethodsThe PubMed, MEDLINE, Google Scholar, and GeneCards databases were screened for KC-related articles published in English between January 2006 and November 2017. Keyword combinations of “keratoconus,” “risk factor(s),” “genetics,” “genes,” “genetic association(s),” and “cornea” were used. In total, 217 articles were retrieved and analyzed, with greater weight placed on the more recent literature. Further bibliographic research based on the 217 articles revealed another 124 relevant articles that were included in this review. Using the reviewed literature, an attempt was made to correlate genes and genetic risk factors with KC characteristics and genetically related comorbidities associated with KC based on genome-wide association studies, family-based linkage analysis, and candidate-gene approaches.ResultsAn association matrix between known KC-related genes and KC symptoms and/or clinical signs together with an association matrix between identified KC genes and genetically related KC comorbidities/syndromes were constructed.ConclusionTwenty-four genes were identified as potential contributors to KC and 49 KC-related comorbidities/syndromes were found. More than 85% of the known KC-related genes are involved in glaucoma, Down syndrome, connective tissue disorders, endothelial dystrophy, posterior polymorphous corneal dystrophy, and cataract.

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

“…[39,40] Molecular and linkage studies have suggested multiple candidate genes that might underlie the development of KC. [32] In the present work, we found two nonsynonymous mutations in LOX, namely Arg158Gln and Thr392Pro, and an intronic SOD1 deletion previously associated with KC development. Variant Thr392Pro in the LOX gene is a novel missense mutation that has not been previously described; this mutation was found in 1 out of 26 patients with advanced KC.…”

“…[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 meaning of the demarcation line after riboflavin-UVA corneal collagen crosslinking

“…So far, the most reliable approach to the estimate of the biomechanical effects of CXL must be based on numerical analysis using realistic geometrical and material models of the cornea, e.g., the finite element analysis (FEA) 84,103,104 , that accounts for the exact geometry, the complex microstructure of the stroma, and furthermore for the presence of the fluids filling the anterior chamber 105,106,107 . Numerical approaches must be combined with experimental testing conducted with advanced devices conceived to provide accurate information on the variability of the material parameters of the stroma, such as the ones based on Bruilloin microscopy 27 .…”

Absence of the c.169+50delTAAACAG mutation of SOD1 gene in a sample of keratoconus patients in Brazilian population

“…Keratoconus (KC) is an asymmetrically bilateral corneal dystrophy characterized by progressive thinning of the cornea, which becomes cone-shaped in a process called ectasia, with a prevalence of approximately 1 in 2000 people [1][2][3][4][5][6][7]. It is currently known that KC is a multifactorial disease, involving genetic, environmental, and behavioral factors and etiology remains poorly understood [3,[7][8][9][10][11][12][13][14].…”