Genetic association between MMP9 and choroidal neovascularization in age-related macular degeneration

Abstract Purpose To evaluate the first association specific to exudative age-related macular degeneration (AMD), located near the matrix metalloproteinase-9 (MMP9) gene. Design Genetic association study Participants 1712 subjects with AMD (672 non-exudative, 1040 exudative) of predominantly northern European descent presenting to the University of Iowa Hospitals and Clinics. Methods We re-analyzed the International AMD Genetics Consortium (IAMDGC) data to validate the association of polymorphisms near MMP9 with exudative AMD and to identify additional associated SNPs, especially MMP9 coding sequence SNPs. We genotyped a cohort of 1712 AMD patients from Iowa with three SNPs identified with our analysis of the IAMDGC cohort using commercially available real-time quantitative PCR assays. Firth regression was used to measure the association between MMP9 SNP genotypes and exudative AMD in our cohort of patients from Iowa. In addition, we developed a PCR-based assay to genotype the Iowa cohort at a short tandem repeat polymorphism (STRP) at the MMP9 locus. Main outcome measures Odds ratios and p-values for exudative compared to non-exudative AMD subjects in the Iowa Cohort for MMP9 SNPs (rs4810482, rs17576, and rs17577) and STRP. Results We identified three SNPs in the MMP9 locus (rs4810482, rs17576, and rs17577) that are highly associated with exudative AMD in patient cohorts of the IAMDGC. These MMP9 SNPs are also associated with exudative AMD in our cohort of 1712 AMD patients from Iowa (rs4810482, odds ratio 0.83, p=0.010; rs17576, odds ratio 0.86, p=0.046; and rs17577, odds ratio 0.81, p=0.041). We also genotyped our cohort of AMD patients from Iowa at rs142450006, another MMP9 polymorphism that was previously associated with exudative AMD. We detected a 4bp STRP, (TTTC)n, at the rs142450006 locus that is highly polymorphic and significantly associated with exudative AMD (odds ratio 0.77, p=0.016). Conclusions This study is the first to independently confirm and expand an association between the MMP9 locus and exudative AMD, further implicating a role for extracellular matrix abnormalities in choroidal neovascularization.