Keratoconus (KC) is the most common cornea ectatic disorder. It is characterized by a cone-shaped thin cornea leading to myopia, irregular astigmatism, and vision impairment. It affects all ethnic groups and both genders. Both environmental and genetic factors may contribute to its pathogenesis. This review is to summarize the current research development in KC epidemiology and genetic etiology. Environmental factors include but are not limited to eye rubbing, atopy, sun exposure, and geography. Genetic discoveries have been reviewed with evidence from family-based linkage analysis and fine mapping in linkage region, genome-wide association studies, and candidate genes analyses. A number of genes have been discovered at a relatively rapid pace. The detailed molecular mechanism underlying KC pathogenesis will significantly advance our understanding of KC and promote the development of potential therapies.

TRPV1 ion channels mediate the response to painful heat, extracellular acidosis, and capsaicin, the pungent extract from plants in the Capsicum family (hot chili peppers) (Szallasi, A., and P.M. Blumberg. 1999. Pharmacol. Rev. 51:159–212; Caterina, M.J., and D. Julius. 2001. Annu. Rev. Neurosci. 24:487–517). The convergence of these stimuli on TRPV1 channels expressed in peripheral sensory nerves underlies the common perceptual experience of pain due to hot temperatures, tissue damage and exposure to capsaicin. TRPV1 channels are nonselective cation channels (Caterina, M.J., M.A. Schumacher, M. Tominaga, T.A. Rosen, J.D. Levine, and D. Julius. 1997. Nature. 389:816–824). When activated, they produce depolarization through the influx of Na+, but their high Ca2+ permeability is also important for mediating the response to pain. In particular, Ca2+ influx is thought to be required for the desensitization to painful sensations over time (Cholewinski, A., G.M. Burgess, and S. Bevan. 1993. Neuroscience. 55:1015–1023; Koplas, P.A., R.L. Rosenberg, and G.S. Oxford. 1997. J. Neurosci. 17:3525–3537). Here we show that in inside-out excised patches from TRPV1 expressed in Xenopus oocytes and HEK 293 cells, Ca2+/calmodulin decreased the capsaicin-activated current. This inhibition was not mimicked by Mg2+, reflected a decrease in open probability, and was slowly reversible. Furthermore, increasing the calmodulin concentration in our patches by coexpression of wild-type calmodulin with TRPV1 produced inhibition by Ca2+ alone. In contrast, patches excised from cells coexpressing TRPV1 with a mutant calmodulin did not respond to Ca2+. Using an in vitro calmodulin-binding assay, we found that TRPV1 in oocyte lysates bound calmodulin, although in a Ca2+-independent manner. Experiments with GST-fusion proteins corresponding to regions of the channel NH2-terminal domain demonstrated that a stretch of ∼30 amino acids adjacent to the first ankyrin repeat bound calmodulin in a Ca2+-dependent manner. The physiological response to pain involves an influx of Ca2+ through TRPV1. Our results indicate that this Ca2+ influx may feed back on the channels, inhibiting their gating. This type of feedback inhibition could play a role in the desensitization produced by capsaicin.

The prevalence of keratoconus in Jerusalem was found to be much higher than that seen in other parts of the world, except India. This may be related to a combination of genetic and environmental factors. Positive family history, male gender and atopy were shown to be significant predictors. The results of this study signal a need for public health outreach and intervention for keratoconus.

TRPV2 is a member of the transient receptor potential family of ion channels involved in chemical and thermal pain transduction. Unlike the related TRPV1 channel, TRPV2 does not appear to bind either calmodulin or ATP in its N-terminal ankyrin repeat domain. In addition, it does not contain a calmodulin-binding site in the distal C-terminal region, as has been proposed for TRPV1. We have found that TRPV2 channels transiently expressed in F-11 cells undergo Ca 2ϩ -dependent desensitization, similar to the other TRPVs, suggesting that the mechanism of desensitization may be conserved in the subfamily of TRPV channels. TRPV2 desensitization was not altered in whole-cell recordings in the presence of calmodulin inhibitors or on coexpression of mutant calmodulin but was sensitive to changes in

This study supports the hypothesis that consanguinity is a significant risk factor for KC and provides strong support for a genetic contribution to the disease. Wearing sunglasses in this environment is beneficial, and the study confirmed that eye rubbing, allergy, and education are also significantly associated with KC after adjusting for other predictors.

Background:The purpose of this study was to describe the characteristics of keratoconic patients seen in a specialised contact lens practice from a general population with a high prevalence of the disease. Methods: Patients attending a contact lens practice for management of keratoconus were asked to complete a questionnaire. Data were collected on demographic characteristics, general health, family history, eye rubbing, allergy, asthma, eczema, education level, history of keratoplasty and smoking. Results: Two hundred and forty-four patients completed the questionnaire. There was a male bias (54.5 per cent). The majority of the patients (78.7 per cent) wore contact lenses, of whom 67.7 per cent wore hard, 13 per cent soft and 4.2 per cent scleral contact lenses. Some of the patients (21.3 per cent) had undergone corneal graft surgery. Eighteen per cent had an associated systemic disease, the most common of which was type 2 diabetes, although this disease was less prevalent, but not significantly, in the keratoconic sample than in the general population (p = 0.19). The prevalence of eye rubbing (65.6 per cent) was similar to other studies. Compared to the general population, asthma (13.2 per cent) was slightly, but not significantly, less prevalent (p = 0.17), eczema (6.6 per cent) was significantly less (p < 0.001) and allergy (34.4 per cent) was more prevalent (p < 0.001). A high proportion of patients reported a family history of the disease (27.9 per cent) and most were better educated than the general population. Conclusion:The results of this survey concur with those of other studies with regard to most known characteristics of keratoconus; however, the proportion of asthma and eczema tended to be less than in other surveys and may be linked to the environmental influence of a hot and sunny country. The high prevalence of positive family history of the disease in this cohort suggests a genetic influence.

Keratoconus is a noninflammatory disorder characterized by ectasia of the central or inferior portion of the cornea. This review presents the scant epidemiological information known to date and the factors believed to cause the development of the disease. They are the genetic factors for which evidence come from family studies, twin studies and genetic loci. There appears to be multiple genes causing a keratoconus phenotype with variable penetration. However, the genetic predisposition might not be enough; environmental factors, such as eye rubbing, atopy and UV exposure, may have a role in generating the disease.

Eye rubbing, parents' education (as a measure of socio-economic status) and having family members with KC emerged as significant risk factors for KC. The role of sun exposure in KC remains equivocal and warrants further research.