*7.3.1 VSX1*

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)

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

promoter polymorphisms on corneal tissue cells.

*7.3.2 IL1A and IL1B*

and - 511\*T, P = 4.0 × 10<sup>−</sup><sup>5</sup>

*7.3.3 MPDZ-NF1B*

nus, *P* = 5.2 × 10<sup>−</sup><sup>6</sup>

other studies on Indian, Iranian, Korean and other populations.

was proposed to be foundation mutation as a shared haplotype occurred in 5 Indian keratoconus patients from 2 unrelated families [109]. But it has not been reported in

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

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

The *MPDZ* (multiple PDZ domain crumbs cell polarity complex component) and *NFIB* (nuclear factor I B *NF1B*) genes was found to confer risk to keratoconus based on GWAS on central corneal thickness (CCT) of multi-ethnic Asian populations in Singapore. rs1324183 of *MPDZ-NF1B* gave a significance of *P* = 8.72 × 10<sup>−</sup><sup>8</sup> [113]. The association was replicated inn Australian Caucasian cohort, P = 0.001, OR = 1 [114]. Further examination of the CCT loci in keratoconus patients from two independent Caucasian cohorts also revealed association rs1324183 for keratoco-

controls in northern China, the association was p = 0.005, OR = 3.1 [115]. However, no association was found in a Saudi Arabia study of 108 patients and 300 controls [116]. In contrast, very high risk of rs1324183 to keratoconus, *P* = 4.30 × 10<sup>−</sup><sup>4</sup>

OR = 2.22 was shown after genotyping of 133 patients and 367 controls who are Han Chinese in Hong Kong in southern China [117]. In addition, rs1324183 conferred a higher risk to severe keratoconus (OR = 5.10) than the moderate (OR = 2.05) or mild (OR 2.36) form. There was significant correlation between the risk allele A of rs1324183 with the corneal mechanic parameters of anterior Kf, anterior AvgK, posterior Kf and apex pachymetry, indicating association with corneal thickness and curvature. Therefore rs1324183 has been proposed to be a genetic marker for severity and progression of keratoconus [117]. Taken together, there is no evidence of direct causation to keratoconus by *MPDZ-NF1B,* which, however, does pose

The collagen genes *COL4A3*, *COL4A4* and *COL5A1* are related to corneal collagen structure and development during embryonic development. Its association with keratoconus was first reported in a Slovenia study of white study subjects,

susceptibility to development and progression of keratoconus.

*7.3.4 COL4A3, COL4A4 and COL5A1*

, OR = 1.33 [79]. In a Han Chinese cohort of 210 patients and 191

and OR = 1.72 [105]. The association was replicated in

**Figure 1.** *Cornea associated genes.*

was proposed to be foundation mutation as a shared haplotype occurred in 5 Indian keratoconus patients from 2 unrelated families [109]. But it has not been reported in other studies on Indian, Iranian, Korean and other populations.
