*7.3.2 IL1A and IL1B*

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

study involved 752 keratoconus patients as compared with 974 British TwinsUK or 13,828 EPIC-Norfolk. The results showed a likely role in development of keratoconus with 5 associated loci in CH, *ANAPC1*, *ADAMTS8*, *ADAMTS17*, *ABCA6*, and

It is notable that there are a lot more keratoconus genes that are identified through studies on quantitative traits, especially central cornea thickness and cornea curvature, than on direct association with keratoconus against controls

Strategies of genomic search for disease genes are essentially free of a hypothesis to find genes or loci with susceptibility to a disease entity or quantitative trait. For keratoconus, mutation analysis in many candidate genes have also been attempted to find disease causative genes, some followed a biological hypothesis and some based on high GWAS significance. More than 50 SNPs in about 20 genes showing association with keratoconus have been studied in various ethnic populations [70, 95]. They include *FOXO1* [96]; ZNF469 [97]; *COL4A4* [98]; *COL4A3* [99]; *VSX*1 [100, 101]; *COL5A1* [102]; *MPDZ-NFIB* [102, 103]; *IL1B* [104, 105]; *HGF* [84]; *LOX* [85, 106]; and *IL1RN* [107]. Some of these genes have been studied in many popula-

The *VSX1* (visual system homeobox 1) gene has been regarded as a candidate keratoconus with about 20 missense variants being putatively disease causative [101, 108]. *VSX1* sequence variants have been extensively screened in different populations including Caucasians, Indians, Chinese, Iranians and Koreans. But segregation of *VSX1* missense variants with keratoconus has been inconsistent and there is no confirmed causative mutation in *VSX1* for keratoncous. p.Leu268His (c.803 T > A)

**62**

**Figure 1.**

*Cornea associated genes.*

*COL6A1* [36].

(**Figure 1**).

*7.3.1 VSX1*

**7.3 Candidate genes**

tions with inconsistent results.

The interleukin genes *IL1A* and *IL1B* have been studied in several keratoconus cohorts as they are mediators of keratocyte apoptosis which may occur in corneal injuries that lead to epithelial or endothelial-stromal reorganization as in keratoconus [110, 111]. Screening for *IL1* gene cluster mutations in a Korean cohort of 100 patients and 100 controls identified −31\*C (rs1143627) and − 511\*T (rs16944) in the *IL1B* promoter posed risk for keratoconus with a combined significance of P = 0.012, OR = 2.38, 95% CI = 1.116-5.05) [104]. Similar association in a Japanese study of 169 patients and 390 controls was reported with a haplotype of −31\*C and - 511\*T, P = 4.0 × 10<sup>−</sup><sup>5</sup> and OR = 1.72 [105]. The association was replicated in 115 Han Chinese patients and 101 healthy controls, with significance for −31\*C, P > 0.001, OR = 2.86, and P = 0.002, OR = 2.4 for −511\*T. SNP IL1A rs2071376 also showed association with P = 0.017, OR = 1.97. The respective ACA haplotype of these 3 promoter SNPs was found to contribute a high risk in this Chinese cohort, P < 0.001, OR = 12.91 [112]. Such statistical significance shows a link of *IL1A* and *IL1B* with keratoconus, and the reported associations are more consistent than other candidate genes. It should be of interest to study the biological effects of these promoter polymorphisms on corneal tissue cells.
