| Keratoconus is a progressive disease characterized by central cornea thinning and ectasia in a cone-shape fashion,leading to myopia,irregular astigmatism and finally irreversible vision loss.As the primary indication for corneal transplantation,the pathogenesis of keratoconus remains elusive to date.Aiming to identify the global burden and pathogenesis of keratoconus,this article is divided following two parts :First,to systematically evaluate the global prevalence/incidence of keratoconus and to provide basis for the prevention and treatment of keratoconus,our study collected cross-sectional studies related to keratoconus prevalence/incidence,which were published from 2000 to 2020,from databases of Pubmed,EMbase and Web of Science.Data such as keratoconus prevalence/incidence,publication year,ethnic and gender,were retrieved from studies meeting the criteria of inclusion and exclusion.Finally,22 articles were included with a total keratoconus sample size of 18403,from 16 different countries.The results showed that the overall prevalence of keratoconus was 0.584%[ 95% CI(0.455%,0.729%)],with the overall incidence being 0.011% [ 95% CI(0.0056%,0.017%)].Then,the subgroup analysis was performed with publication year,ethnic and sample size as grouping factors,respectively.The overall prevalence /incidence of keratoconus in studies conducted from 2000 to 2010 was 0.755% [ 95% CI(0.584%,0.948%)]/0.011% [ 95% CI(0.0042%,0.021%)],which was lower than that of studies published between 2011 and 2020,whch showed 0.216% [ 95% CI(0.130%,0.325%)]/0.01% [ 95% CI(0.0049%,0.0169%)].As for studies on White population,the overall prevalence/incidence was 0.106% [ 95% CI(0.038%,0.207%)]/0.009% [ 95% CI(0.003%,0.018%)],evidently lower than studies on non-White population,which exhibited 1.65% [ 95% CI(0.63%,3.14%)]/0.014%[ 95% CI(0.004%,0.029%)].The big-size population studies showed an overall prevalence of 0.0729% [ 95% CI(0.0225%,0152%)],which was obviously lower than that of small-size studies showing 1.76% [ 95% CI(1.08%,2.59%)].In sum,the global prevalence/incidence of keratoconus was higher than expected,with an increasing tendancy.The global burden of keratoconus was influenced by ethnic,gender,sun exposure and et al.Glabally,effective public health strategies regarding keratoconus are needed to protect and prevent the public from vision loss.Second,to identify the genetic etiology of keratoconus,fifty-three keratoconus patients and one hundred healthy controls of Chinese Han population were enrolled in our study according to the inclusion and exclusion criteria.Mutation analysis of reported keratoconus-related genes by next-generation sequencing and Sanger sequencing was performed.Further confirmation by QPCR and immunohistochemistry was then performed,accompanied by transmission electron microscope for ultrastructure of conical cornea.Results showed that 14 new variants were discovered by next-generation sequencing and Sanger sequencing,three of which(c.95G>A,c.1372C>T,c.476C>T)were located on three extracellular-matrix-related genes LOX,COL5A1 and TIMP3,respectively.According to the results of QPCR,we found that the expression levels of LOX and TIMP3 were decreased in the keratoconus patients,while COL5A1 showed no significant difference of expression.The results of immunohistochemistry showed that the expression levels of LOX,COL5A1 and TIMP3 were lower in the keratoconus patient than in the healthy control.The results od transmission electron microscope showed that the number of collagen fibrils decreased obviously in a disordered fashion,with accumulation of abnormal substances in the cornea stroma of keratoconus patients.This is the first time to screen so many extracellular-matrix-related genes in Chinese Han keratoconus patients using next-generation sequencing.We find numerous underlying causal variants,enlarging lots of mutation spectrums and thus providing new sites for other investigators to replicate and for further research. |
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