**Table 2.**

*The keratoconus genes [138–146].*

comprehensive review of environmental risk factors and family history, genetic factors are taken to play a role in the etiology of keratoconus [39]. As of today all reported genes for keratoconus, whether mapped by candidate gene strategy or genomic search including GWAS and WES, are susceptibility genes and not causative genes that cause disease directly (**Table 2**). Keratoconus causative genes are still to be identified. As for the reported genes, there is no segregation of gene variants that accounts for higher occurrences of disease. There are also no hotspot variants that are present in a high proportion of patients. Molecular markers for pre- symptomatic detection and risk assessment of keratonocus are still to be established.

### **10. Genetic implications on treatment**

Findings in genetic studies help to delineate the molecular basis of diseases through identification of genes that are causative or susceptible to development of diseases. Investigation of their properties, functions, related pathways and mechanisms throw light on disease pathogenesis. Genetic information also helps to establish genetic markers used for early or even pre-symptomatic diagnosis. Prior to treatment timely detection is extremely important as keratoconus is progressive and the resultant corneal disruptions are hardly curable. With the advent of collagen cross-linking, disease progression can be halted in most patients with some partial recovery of vision. Some patients may respond less favorably and ultimately may require cornea transplantation. Genetic marker, if linked to response to clinical course and treatment, will be exceedingly useful. Over the years in keratoconus vigorous research has been conducted in different ethnic populations in its molecular genetics. However, with the repertoire of associated genes that has been identified at present, no definite genetic marker for diagnosis, risk assessment or prognosis has been established. Further work is warranted.

### **11. Conclusive remarks and future perspectives**

The pathogenesis of keratoconus is heterogeneous and complex. Epidemiological studies showed higher prevalence, earlier onset and greater progression in Asians than Europeans. Both environmental and genetic factors play roles in the etiology and pathogenesis, including age, gender, ocular atopy, eye rubbing, family history, and systemic diseases. While family aggregation and linkage studies indicated genetic abnormality in keratoconus, GWAS and candidate gene studies identified polymorphisms in genes/loci related to the risk of keratoconus. So far there are very few reported big family studies, which should help to identify the keratoconus causative gene. Also, big cohorts are needed to provide sufficient power to differentiate phenotypes and clinical courses of patients for association with genetic factors. Current epidemiological and genetic data are insufficient to provide conclusive evidence to establish the molecular mechanism and genetic markers for keratoconus. Notably, genetic studies on the corneal structure, principally central cornea thickness and cornea curvature have successfully mapped keratoconus genes. Corneal properties, as recently exemplified by a successful GWAS on corneal biomechanical properties [36], should provide a basis for genetic research. Rigorous and large multi-center population-based studies, with age-standardized rates, random sampling, progression follow-ups, and accurate and standardized diagnosis, are warranted for better understanding of pathogenesis of keratoconus and for establishment of genetic markers.

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**Author details**

Yu Meng Wang and Calvin C.P. Pang\*

provided the original work is properly cited.

\*Address all correspondence to: cppang@cuhk.edu.hk

Hong Kong, Hong Kong, China

Department of Ophthalmology and Visual Sciences, The Chinese University of

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Molecular Genetics of Keratoconus: Clinical Implications DOI: http://dx.doi.org/10.5772/intechopen.90623*

*Molecular Genetics of Keratoconus: Clinical Implications DOI: http://dx.doi.org/10.5772/intechopen.90623*

*Ocular Surface Diseases - Some Current Date on Tear Film Problem and Keratoconic Diagnosis*

comprehensive review of environmental risk factors and family history, genetic factors are taken to play a role in the etiology of keratoconus [39]. As of today all reported genes for keratoconus, whether mapped by candidate gene strategy or genomic search including GWAS and WES, are susceptibility genes and not causative genes that cause disease directly (**Table 2**). Keratoconus causative genes are still to be identified. As for the reported genes, there is no segregation of gene variants that accounts for higher occurrences of disease. There are also no hotspot variants that are present in a high proportion of patients. Molecular markers for pre- symptomatic detection and risk assessment of keratonocus are still to be

Findings in genetic studies help to delineate the molecular basis of diseases through identification of genes that are causative or susceptible to development of diseases. Investigation of their properties, functions, related pathways and mechanisms throw light on disease pathogenesis. Genetic information also helps to establish genetic markers used for early or even pre-symptomatic diagnosis. Prior to treatment timely detection is extremely important as keratoconus is progressive and the resultant corneal disruptions are hardly curable. With the advent of collagen cross-linking, disease progression can be halted in most patients with some partial recovery of vision. Some patients may respond less favorably and ultimately may require cornea transplantation. Genetic marker, if linked to response to clinical course and treatment, will be exceedingly useful. Over the years in keratoconus vigorous research has been conducted in different ethnic populations in its molecular genetics. However, with the repertoire of associated genes that has been identified at present, no definite genetic marker for diagnosis, risk assessment or prognosis

**66**

established.

**10. Genetic implications on treatment**

has been established. Further work is warranted.

and for establishment of genetic markers.

**11. Conclusive remarks and future perspectives**

The pathogenesis of keratoconus is heterogeneous and complex. Epidemiological studies showed higher prevalence, earlier onset and greater progression in Asians than Europeans. Both environmental and genetic factors play roles in the etiology and pathogenesis, including age, gender, ocular atopy, eye rubbing, family history, and systemic diseases. While family aggregation and linkage studies indicated genetic abnormality in keratoconus, GWAS and candidate gene studies identified polymorphisms in genes/loci related to the risk of keratoconus. So far there are very few reported big family studies, which should help to identify the keratoconus causative gene. Also, big cohorts are needed to provide sufficient power to differentiate phenotypes and clinical courses of patients for association with genetic factors. Current epidemiological and genetic data are insufficient to provide conclusive evidence to establish the molecular mechanism and genetic markers for keratoconus. Notably, genetic studies on the corneal structure, principally central cornea thickness and cornea curvature have successfully mapped keratoconus genes. Corneal properties, as recently exemplified by a successful GWAS on corneal biomechanical properties [36], should provide a basis for genetic research. Rigorous and large multi-center population-based studies, with age-standardized rates, random sampling, progression follow-ups, and accurate and standardized diagnosis, are warranted for better understanding of pathogenesis of keratoconus
