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Mark D P Willcox, Nagaraju Konda, Inderjeet Kaur, Preeji Sudharaman, Prashant Garg, Subhabrata Chakrabarti; Association of toll-like receptor gene polymorphisms with bacterial keratitis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4812.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the association of single nucleotide polymorphisms (SNPs) in Toll-like receptor (TLR) genes with susceptibility to keratitis.
Patients previously diagnosed as having different types of bacterial keratitis (n=145; MK, CLARE, CLPU, or IK) and unaffected controls (n=160) were enrolled after informed consent. SNPs in TLR2 (n=6), TLR4 (n=15), TLR5 (n=13) and in TLR9 (n=10) were selected based on their function, global minor allele frequency ( >0.05) and involvement in any infectious etiology, were screened in this cohort. Screening was accomplished through customized genotyping of these SNPs using a GoldenGate assay. Allele and genotype frequencies were calculated by the gene counting method and haplotypes were analyzed using with the Haploview software (version 4.2). The levels of association were determined by the statistical test of significance (p<0.05), permutation tests for correction (10,000 iterations) and odds ratios along with their 95% confidence intervals (CI).
There were no departure from Hardy Weinberg equilibrium for all the SNPs in the normal controls (p>0.05). The carriers of TLR5 SNP (rs2241096) had a higher risk of all forms of keratitis (p=0.02, OR=1.50, 95%CI, 1.0 - 1.95), Next, cases were categorized based on the diagnosis of inflammation or infection (i.e. microbial keratitis with or without contact lenses (MK), or bacterially-driven contact lens keratitis [CL-MK, CLARE, CLPU, IK; BCLK]. People with a copy of TLR2 (rs5743706) allele were protected for MK (p=0.001; OR=0.1, 95%CI, 0.03 - 0.4) Heterozygous carriers of TLR4 (rs4986791) SNP had a lower risk (p≤0.01) of MK (OR= 0.4, 95% CI, 0.2-0.7) and BCLK (OR=0.5, 95% CI, 0.3 - 0.8), while the heterozygous TLR5 SNP (rs2241096) was associated with a higher risk of MK (p=0.01; OR=2.3, 95% CI, 1.1 - 4.4). A strong to moderate linkage disequeilibrium was observed across the SNPs in these 5 TLR genes. Carriers of the TLR5 haplotype T-G-C-C-A (rs2072493-rs5744168-rs764535-rs5744140-rs2241096) had a lower risk of MK (p=0.039; OR=0.7, 95% CI, 0.5 - 1.0) compared to the other forms of keratitis. The remaining haplotypes did not have a significant bearing on keratitis susceptibility.
Activation of TLR receptors can induce corneal inflammation. Several associations between mutations in TLR genes and keratitis, some of which were protective.
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