it is no longer thought to be entirely non - inflammatory as was described in the past . with different diagnostic criteria utilized in a variety of studies , it is a multifactorial disease , does not exhibit classical mendelian patterns of inheritance , characteristically involves several genes that interact in complex mode with multiple environmental factors and systemic conditions . it has been proved beyond doubt that kc is a complex heterogeneous disorder with multifactorial etiology , associated with genetic ( familial inheritance ) and environmental factors like contact lens wear , chronic eye rubbing , and atopy of the eye . cellular level changes in cornea found in patients with keratoconus kc is well - documented as a genetic predisposition with increased incidence in familial and monozygotic twins . most of the kc patients are sporadic and family history is reported in 610% of patients . so far the modes of disease inheritance in kc families are dominant and recessive , but in autosomal dominant inheritance , the disease shows incomplete penetrance with variable phenotype . in addition , cellular pathways ( inflammatory , apoptosis ) are involved in the development of kc . the exact cause of kc is uncertain , but has been associated with abnormal enzyme activity within the cornea . a genetic link seems likely , as the incidence rate is greater if a family member has been diagnosed . due to genetic heterogeneity many eye diseases have a genetic basis and researchers often focus in identifying the genes responsible , for enabling early detection and possible treatments . hence , the basic idea is to analyze the presence of the gene mutations in affected patients when compared with normal unaffected individuals . the candidate gene approach thus directly tests the effects of mutations located in specific genes for their  association  to the disease . the potential candidate genes in kc were selected based on the previously published association with other corneal disorders ( corneal dystrophies ) and their known functions in the eye development . here , we discuss some of the candidate genes related to kc phenotype and their role in the pathogenesis . visual system homeobox 1 is a protein that in humans is encoded by the vsx1 gene , plays a role in craniofacial and ocular development . vsx1 gene missense mutations ( r166w and l159 m ) were identified in kc patients . vsx1 is a member of the paired - like homeodomain transcription factors ( tfs ) which may regulate expression of the cone opsin genes during the embryonic development . although it plays a role in the development of retinal bipolar interneurons , no expression has been detected in the mouse and human cornea . thus , although vsx1 mutations are responsible for a very small fraction of kc cases it may not play a major role in the pathogenesis of kc . the dedicator of cytokinesis 9 ( dock9 ) is a possible candidate gene , which encodes a member of the dock protein family that possesses guanosine triphosphate / guanosine diphosphate ( gtp / gdp ) exchange factor activity and specifically activates g - protein cdc42 involved in intracellular signaling networks . the expression patterns were observed in keratoconic and non - keratoconic corneas as well as in lymphoblastoid cell lines . recently , mutation ( gln754his ) was reported through sequencing candidate genes in a previously identified linkage locus , 13q32 . a mutation screening of eight candidate genes within the 13q32 locus identified three different sequence variants in the dock9 gene . this locus contains additional genes , ipo5 ( importin 5 ) and stk24 ( serine / threonine kinase 24 ) . all these three genes are expressed in the human cornea but detailed expression analyses are required to determine their role in kc pathogenesis . another gene called transforming growth factor beta - induced ( tgfi ) gene which is a cytokine , is responsible for many dominant corneal dystrophies . it is a potent regulator of the extracellular matrix formation , during tissue injury and repair . recently , a novel nonsense mutation of tgfi ( g535x ) , was observed in a chinese patient with kc . though in contrast mouse embryos that lack tgf1 , have normal signs of ocular development . oxidative stress has been demonstrated to be involved in several human diseases including corneal diseases . sod1 maps to the 20p11.2 and encodes a major cytoplasmic antioxidant enzyme that metabolizes superoxide radicals and provides a defense against oxygen toxicity . a unique genomic 7 bp deletion within intron 2 close to the 5 splice junction of the antioxidant previously , sod1 gene mutations were identified in familial amyotrophic lateral sclerosis ( als ) patients , but no significant corneal phenotype was noted . however , recently , several reports have shown the high levels of oxidative stress markers such as cytotoxic byproducts , mitochondrial dna damage in kc corneas . another hypothetical explanation for kc pathogenesis could be related to underlying changes in the corneal collagen structure , function and/or during embryonic development . however , col4a3 and col4a4 mutation analysis revealed no pathogenic variants in 107 patients with kc . interestingly , significant allele frequency ( genetic variants ) was found in kc cases that are d326y variant in col4a3 and m1237v and f1644f in col4a4 . another mutation study on 15 ecuadorian families with kc identified missense mutations but none of them segregated in with family members . in parallel 50 patients were investigated for col8a1 and col8a2 , but yet again no pathogenic mutation was detected . recent investigation has shown the keratocyte apoptosis observed in keratoconic cornea , emphasized the role of apoptotic processes in the pathogenesis . the apoptosis related genetic risk factor for atopic dermatitis is filaggrin ( flg ) mutations , expressed in the corneal epithelium . loss of function of flg alleles ( r501x and 2282del4 ) were found in five kc cases , suggesting the role of flg in pathogenesis . zeb1 is a transcription factor that has a role on modulating epithelial - to - mesenchymal transition ( emt ) and negative regulatory binding sites on il2 . mutations in zeb1 are reported in patients with kc and isolated patients ( posterior polymorphous corneal dystrophy ) with steep cornea without kc . recently , a mutation altering the mir-184 seed region was reported in a family with kc and early - onset anterior polar cataract and kc . many eye diseases have a genetic basis and researchers often focus in identifying the genes responsible , for enabling early detection and possible treatments . hence , the basic idea is to analyze the presence of the gene mutations in affected patients when compared with normal unaffected individuals . the candidate gene approach thus directly tests the effects of mutations located in specific genes for their  association  to the disease . the potential candidate genes in kc were selected based on the previously published association with other corneal disorders ( corneal dystrophies ) and their known functions in the eye development . here , we discuss some of the candidate genes related to kc phenotype and their role in the pathogenesis . visual system homeobox 1 is a protein that in humans is encoded by the vsx1 gene , plays a role in craniofacial and ocular development . vsx1 gene missense mutations ( r166w and l159 m ) were identified in kc patients . vsx1 is a member of the paired - like homeodomain transcription factors ( tfs ) which may regulate expression of the cone opsin genes during the embryonic development . although it plays a role in the development of retinal bipolar interneurons , no expression has been detected in the mouse and human cornea . thus , although vsx1 mutations are responsible for a very small fraction of kc cases it may not play a major role in the pathogenesis of kc . the dedicator of cytokinesis 9 ( dock9 ) is a possible candidate gene , which encodes a member of the dock protein family that possesses guanosine triphosphate / guanosine diphosphate ( gtp / gdp ) exchange factor activity and specifically activates g - protein cdc42 involved in intracellular signaling networks . the expression patterns were observed in keratoconic and non - keratoconic corneas as well as in lymphoblastoid cell lines . recently , mutation ( gln754his ) was reported through sequencing candidate genes in a previously identified linkage locus , 13q32 . a mutation screening of eight candidate genes within the 13q32 locus identified three different sequence variants in the dock9 gene . this locus contains additional genes , ipo5 ( importin 5 ) and stk24 ( serine / threonine kinase 24 ) . all these three genes are expressed in the human cornea but detailed expression analyses are required to determine their role in kc pathogenesis . another gene called transforming growth factor beta - induced ( tgfi ) gene which is a cytokine , is responsible for many dominant corneal dystrophies . it is a potent regulator of the extracellular matrix formation , during tissue injury and repair . recently , a novel nonsense mutation of tgfi ( g535x ) , was observed in a chinese patient with kc . though in contrast mouse embryos that lack tgf1 , have normal signs of ocular development . oxidative stress has been demonstrated to be involved in several human diseases including corneal diseases . sod1 maps to the 20p11.2 and encodes a major cytoplasmic antioxidant enzyme that metabolizes superoxide radicals and provides a defense against oxygen toxicity . a unique genomic 7 bp deletion within intron 2 close to the 5 splice junction of the antioxidant previously , sod1 gene mutations were identified in familial amyotrophic lateral sclerosis ( als ) patients , but no significant corneal phenotype was noted . however , recently , several reports have shown the high levels of oxidative stress markers such as cytotoxic byproducts , mitochondrial dna damage in kc corneas . another hypothetical explanation for kc pathogenesis could be related to underlying changes in the corneal collagen structure , function and/or during embryonic development . however , col4a3 and col4a4 mutation analysis revealed no pathogenic variants in 107 patients with kc . interestingly , significant allele frequency ( genetic variants ) was found in kc cases that are d326y variant in col4a3 and m1237v and f1644f in col4a4 . another mutation study on 15 ecuadorian families with kc identified missense mutations but none of them segregated in with family members . in parallel 50 patients were investigated for col8a1 and col8a2 , but yet again no pathogenic mutation was detected . recent investigation has shown the keratocyte apoptosis observed in keratoconic cornea , emphasized the role of apoptotic processes in the pathogenesis . the apoptosis related genetic risk factor for atopic dermatitis is filaggrin ( flg ) mutations , expressed in the corneal epithelium . loss of function of flg alleles ( r501x and 2282del4 ) were found in five kc cases , suggesting the role of flg in pathogenesis . zeb1 is a transcription factor that has a role on modulating epithelial - to - mesenchymal transition ( emt ) and negative regulatory binding sites on il2 . mutations in zeb1 are reported in patients with kc and isolated patients ( posterior polymorphous corneal dystrophy ) with steep cornea without kc . recently , a mutation altering the mir-184 seed region was reported in a family with kc and early - onset anterior polar cataract and kc . multiple approaches have been used to identify common genetic factors that influence health and complex diseases . these include , whole - genome sequencing , whole - exome sequencing , targeted resequencing , and functional studies in transcriptome level . the genetic etiology of many complex diseases , including fuchs corneal dystrophies ( fecd ) and central corneal thickness , gwas are useful tools to identify single nucleotide polymorphisms . the allele frequency differs significantly between cases and controls , which is taken into account in identifying the associated risk or protective nature of the genetic factors . recent gwas reveals few candidate genes identified including il1b , cdh11 , nub1 , col27a1 , and hepatocyte growth factor ( hgf ) rab3gap1 and lox which are associated with risk factor for kc . interleukin 1 ( il1 ) released and triggered by the corneal epithelial cell during keratocyte apoptosis has been reported in 60% keratoconic cornea . the guanosine triphosphatase ( gtpase ) activating protein subunit 1 ( rab3gap1 ) gene mutations have been previously reported to be associated with warburg micro syndrome with ocular disorders . hgf expression in corneal keratinocytes is upregulated in response to corneal injury , which has binding site for proinflammatory cytokine il-6 , which is elevated in kc patients . the association of hgf with kc suggests the potential involvement of inflammatory pathway , moreover it has been shown as a risk factor for refractive error in several populations including han chinese and caucasians . lu and colleagues recently identified multiple loci associated with central corneal thickness ( cct ) and kc . gwas further showed that two cct - associated loci , foxo1 and fndc3b , conferred relatively large risks for kc . recently , nonparametric linkage analysis identified a substitution at il1rn and deletion at slc4a11 that segregated with phenotype in familial kc in ecuadorian origin . il1rn gene , member of cytokine family and modulator inflammatory response , mutations in slc4a11 , which encodes a membrane - bound sodium - borate co - transporter associated with corneal endothelial dystrophy ( ched2 ) and fuchs endothelial corneal dystrophy ( fecd ) . so far genetic studies have suggested that kc has clinical variability and may be linked to multiple chromosomal regions , consistent with polygenic mode of inheritance . despite several genomic loci , mutations were reported for disease susceptibility [ table 2 ] , but lack of validation in larger numbers suggests genetic heterogeneity in kc . the whole - exome or genome sequencing and gwas are significantly useful techniques , to explore novel genes and their functions in cellular pathways , which will provide the exact pathology of kc , thereby , aiding in designing better treatment modules . in example , lox polymorphisms are associated with the treatment of collagen cross - linking to ensure that only  genotypically suitable  patients hopefully will undergo the gene - specific treatment , thus fulfilling the promise of personalized genomic medicine . increasing our knowledge of genome sequence functionality will take us one step further in personalized medicine . these studies may enable prediction of genetic variant induced consequences beyond simple mapping for single nucleotide polymorphisms ( snps ) . emerging genomic approaches such as whole exome or genome sequencing will be very efficient to identify the disease causing mutations in families with kc . however , the kc genetics and genomics approach is currently facing several challenges , including phenotype / genotype correlation , biological validation of variant function , and correlation with clinical interpretation . these challenges of genomic research pertain to all complex diseases like kc , making it imperative to stringently classify the kc stages and phenotypes . the emerging potential to subclassify clinical populations based on increasing number of disease trait phenotype ( clinical study ) and multi - omics study , offers new opportunity to dissect the genetic components of disease . finally , as the literature suggests , kc is a complex disorder and possibly involves multiple genes and various mechanisms that contribute to the clinical disease etiology . as such , devising a gene therapy strategy for this disease is fraught with risk and requires a better molecular understanding of the disease . however , certain genes such as vsx1 , dock9 , or tgfb1 may have an essential , albeit sufficient role in the disease . such a gene ( or set of genes ) delivered to the cornea via viral vectors or nanoparticles under the control of a cornea - specific promoter could hold promise for treatment . a gene therapy strategy can therefore be envisaged in conjunction with anti - inflammatory treatment to obtain better results . nonetheless , such gene therapy studies must be done in an appropriate tissue or animal model , a lack of which represents a very important hurdle currently . in conclusion , both genetic and proteomic approaches together should provide further information on disease pathogenesis which can lead to better management of the disease .
keratoconus ( kc ; mendelian inheritance in man ( omim ) 14830 ) is a bilateral , progressive corneal defect affecting all ethnic groups around the world . it is the leading cause of corneal transplantation . 
 the age of onset is at puberty , and the disorder is progressive until the 3rd4th decade of life when it usually arrests . 
 it is one of the major ocular problems with significant social and economic impacts as the disease affects young generation . 
 although genetic and environmental factors are associated with kc , but the precise etiology is still elusive . 
 results from complex segregation analysis suggests that genetic abnormalities may play an essential role in the susceptibility to kc . due to genetic heterogeneity , 
 a recent study revealed 17 different genomic loci identified in kc families by linkage mapping in various populations . 
 the focus of this review is to provide a concise update on the current knowledge of the genetic basis of kc and genomic approaches to understand the disease pathogenesis .