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Laura Contreras-Ruiz, Bruce Turpie, Denise Ryan, Rose Sia, Kraig Bower, Darlene Dartt, Sharmila Masli; Association of Thrombospondin-1 Polymorphism with Predisposition to Chronic Dry Eye. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2036.
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© ARVO (1962-2015); The Authors (2016-present)
Thrombospondin-1 (TSP-1) is a matricellular protein with immunomodulatory properties. Our previous work showed that TSP-1 deficient mice develop ocular surface inflammation. The purpose was to determine if polymorphism in TSP-1 gene (THBS-1) correlates with the development of the chronic ocular surface inflammatory conditions of dry eye that develops after refractive surgery.
Genomic DNA and RNA were obtained from conjunctival impression cytology samples of 75 patients before and 3 months after refractive surgery. The samples were assigned to 2 groups: patients with post surgery dry eye (n=59) or healthy controls (n=16). Five TSP-1 single nucleotide polymorphisms (SNPs) were assessed using Sequenom iPLEX Gold platform: SNP1 (rs2228262) A>G, SNP2 (rs2228261) C>T, SNP3 (rs229305) A>G, SNP4 (rs1478604) T>C and SNP5 (rs3743125) G>A. Their association with the development of dry eye was analyzed with gPLINK software and Fisher’s exact test. In addition, expression of TSP-1, and IL-1β (inflammatory marker associated with dry eye) were quantified by RT-PCR on both dry eye and control samples.
Frequencies of TT or CT genotypes (T allele carriers) of SNP2, as well as the GG or GA genotypes (G allele carriers) of SNP3, were 39% in dry eye patients compared to 25% in controls (p = 0.048, odds ratio [OR] 1.9, 95% confidence interval (95% CI) 1.1-3.5). The G allele of SNP1 was detected in 19% of subjects in both groups (p = 1.0, OR 1.0, 95% CI 05 - 2.0). The frequency of SNP4 C allele carriers in dry eye patients was 63% as against 44% in control group (p = 0.003, OR 2.5, 95% CI 1.4 - 4.5). The SNP5 was excluded from analysis due to departure from Hardy-Weinberg equilibrium. Allelic association analysis indicated significant association between SNP4 and development of dry eye (p=0.03) while remaining SNPs did not show any significant allelic associations. Expression of TSP-1 in SNP4 C allele carriers (CC+CT) compared to normal allele (TT) carriers was significantly reduced, while expression of inflammatory cytokine IL-1β was significantly increased.
Our results indicate a significant association between polymorphism in THBS-1 gene and ocular surface inflammation as seen in dry eye. This study provides the very first evidence of a genetic association in dry eye disease and suggests THBS1 as a susceptibility factor of this ocular condition.
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