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Inderjeet Kaur, Jay K Chhablani, Raja Narayanan, Rajeev R Pappuru, Annie Mathai, Subhabrata Chakrabarti; Are Genetic Signatures in Age-Related Macular Degeneration Suggestive of Disease Progression?. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2233.
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Genes involved in complement regulation, inflammation, extracellular matrix (ECM) remodeling, mitochondrial inserts and lipid synthesis have been associated with age-related macular degeneration (AMD). Variants in these genes have either indicated susceptibility or protection to AMD across different populations worldwide, but have rarely been implicated in disease progression. The present study was therefore aimed at understanding the involvement of specific genetic signatures as indicators of progression from dry to wet AMD in a cohort of clinically well characterized subjects (n=500), based on the modified AREDS criteria
We selected 45 genes involved in AMD susceptibility based on the effect size of their associated alleles (GRR>2.0). Screening was accomplished through a combination of microarray-based customized genotyping and resequencing of SNPs (n=400) harboring these genes. The mean duration of follow up since the onset of AMD was 6.41+1.92 years (range 4-10 years). Progression from dry to wet AMD was assessed through clinical examination. Statistical analysis of the data was done using the PLINK and Haploview (version 4.2) softwares, respectively.
All the 400 variants were in Hardy Weinberg equilibrium in the controls (p>0.05). Cases of wet AMD were strongly associated with variants in CFH, C2/BF, C3, C1, ARMS2/HTRA1 and TIMP3 that withstood Bonferroni corrections (p<10-3). Strong LD patterns (D'=0.8 -1.0) were observed across the associated SNPs in these genes. However, cases of dry AMD exhibited minor allelic associations that did not withstand further correction. The 12% of subjects who progressed from dry to wet AMD did not exhibit any significant differences (p>0.05) in their genetic signatures. Further, the strongly associated CFH (Y402H) and ARMS2 (A69S) alleles were inconclusive for the gene-gene interactions (OR=0.9, 95% CI, 0.6-1.3) in these cases. A similar finding was recently observed in two large population-based Beaver Dam Eye Study and Central India Eye and Medical Study.
The AMD-associated alleles largely represent a strong association with wet and not dry AMD. Progression to wet AMD may be associated with rarer alleles in genes that may not hitherto be part of the overall genetic signature in AMD susceptibility
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