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S. Chakrabarti, R. Reddy, R. Narayanan, A. Mathai, A. B. Majji, I. Kaur; The Susceptibility of Extracellular Matrix-Related Gene Variants in Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2479.
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Extracellular matrix (ECM) remodelling and degradation have been associated with atrophic changes in the retinal pigment epithelium and Bruch’s membrane leading to age-related macular degeneration (AMD). ECM-related genes have been associated with various forms of macular dystrophy. We undertook a screening of some ECM genes in an effort to understand their involvement in AMD in an Indian cohort.
We screened 7 genes (Fibulin5, Fibulin6, TIMP2, TIMP3, MMP1, MMP2, MMP3 and MMP9) involved in ECM regulation in a cohort of previously diagnosed AMD cases (n=250) and normal controls (n=250). A customized genotyping assay comprising 100 single nucleotide polymorphisms (SNPs) covering these genes was carried out followed by validation through resequencing. Allele and genotype frequencies, Hardy Weinberg equilibrium, odds ratios, linkage disequilibrium (LD) analysis and haplotype frequencies were calculated for these genes.
There was no deviation from Hardy Weinberg equilibrium for these 100 SNPs among the normal controls (p>0.05). There was a significant difference in the allele frequencies of SNPs in Fibulin 5, Fibulin 6, TIMP3 and MMP9, between cases and controls but only the association of two SNPs in TIMP3 withstood the Bonferroni correction for multiple testing (p<0.0005). These two TIMP3 SNPs were in complete LD (D’=1) and haplotypes generated with these indicated a risk (‘C-C’; p<10-5) and protective (‘T-C’; p<10-14) haplotypes that were consistent (p<10-4) even after permutation testing (n=10,000 permutations). The preliminary findings in our cohort are currently being replicated in some Caucasian cohorts. Variations in the other ECM genes (TIMP2, MMP1, MMP2 and MMP3) did not exhibit any association to AMD in the Indian cohort.
The data presents an initial finding on the ECM-related genes in AMD and suggests a potential role of TIMP3 in the disease pathogenesis that needs to be explored further.
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