Association of TIMP-1 and COL4A4 Gene Polymorphisms with Keratoconus in an Iranian Population

Purpose: Keratoconus (KC) is a bilateral and noninflammatory disease, characterized by progressive thinning and anterior protrusion of the cornea and may result in severe visual impairment due to irregular astigmatism. Matrix metalloproteinases (MMP) are the main group of enzymes that degrade extracellular matrix proteins including collagens; Type IV collagen is found in the corneal stroma. MMP enzymatic activity is inhibited by tissue inhibitor of metalloproteinase-1 (TIMP-1). A decrease in TIMP-1 level is associated with the development of KC. In the present study, we investigated the impact of COL4A4 rs2228557 C/T and TIMP-1 rs4898 C/T (X-chromosome) variants on the odds of KC development in a sample of Iranian population. Methods: This case–control study was conducted on 140 patients with KC and 150 healthy control subjects. We used modified methods of Nested-PCR and ARMS-PCR in combination (Nested- ARMS-PCR) and confirmed their validity with RFLP–PCR. Results: Significant differences were noticed between KC patients and healthy individuals regarding the genotype TY or T allele frequencies of rs4898 in the male subjects (OR = 0.43, 95%CI: 0.20–0.92, P = 0.03), whereas no significant differences were identified in the female subjects (OR = 1.07, 95%CI: 0.52–2.20, P = 0.85). The rs2228557, T allele was associated with KC (OR = 0.69, 95% CI: 0.50–0.97, P = 0.035). Conclusion: In the rs2228557 variant, T allele acts as a protective factor from the disease and decreases the risk of KC compared with the C allele. Also, in our investigation about rs4898, we found that TY genotype or T allele decreased the risk of KC compared with the C allele in males and was a protective factor for KC in our population

Association of <i>Lysyl oxidase (LOX)</i> polymorphisms with the risk of Keratoconus in an Iranian population

<div><p></p><p><i>Background</i>: Keratoconus is a connective tissue-related eye disease with unknown etiology that causes the loss of visual acuity. Lysyl oxidase (LOX) is an amine oxidase that catalyzes the covalent cross-link of collagens and elastin in the extracellular environment, thus determining the mechanical properties of connective tissue. The current study aimed to investigate the possible associations between two <i>LOX</i> polymorphisms, rs1800449 and rs2288393, and susceptibility to keratoconus.</p><p><i>Methods</i>: A total of 262 Iranian subjects including 112 patients with keratoconus and 150 healthy individuals as controls were recruited. Genotyping for the <i>LOX</i> variants was performed using allele-specific PCR.</p><p><i>Results</i>: A significant difference was found between two groups regarding allelic and genotyping distribution of <i>LOX</i> polymorphism at position rs1800449 G>A. The frequency of AA and GA + AA genotypes were increased in patients compared to controls (17% versus 8% and 62.5% versus 50%, respectively), showing a statistically significant difference (OR = 2.827, 95% CI: 1.251–6.391, <i>p</i> = 0.012). The A allele was associated with an increased risk for keratoconus, with the frequency of 39.9% and 29% in patients and controls, respectively (OR = 1.614, 95% CI: 1.119–2.326, <i>p</i> = 0.011). Furthermore, the haplotype analysis revealed that the rs1800449G/rs2288393C is a protective factor against keratoconus (OR = 0.425, 95% CI = 0.296–0.609, <i>p</i> = 0.001). Conversely, the +473A/rs2288393C (OR = 3.703, 95% CI = 2.230–6.149, <i>p</i> = 0.001) and +473G/rs2288393G (OR = 15.48, 95% CI = 3.805–63.03, <i>p</i> = 0.001) haplotypes were identified as risk factors for keratoconus.</p><p><i>Conclusion</i>: Our study demonstrated that the LOX rs1800449 genotypes (AA and GA + AA) and allele (A) appears to confer risk for susceptibility to keratoconus.</p></div