Genetic Association between MMP9 and Choroidal Neovascularization in Age-Related Macular Degeneration

Elliott H Sohn; Ian C Han; Benjamin R Roos; Benjamin Faga; Meagan A Luse; Elaine M Binkley; H Culver Boldt; James C Folk; Stephen R Russell; Robert F Mullins; John H Fingert; Edwin M Stone; Todd E Scheetz

doi:10.1016/j.xops.2020.100002

Genetic Association between MMP9 and Choroidal Neovascularization in Age-Related Macular Degeneration

Ophthalmol Sci. 2021 Jan 11;1(1):100002. doi: 10.1016/j.xops.2020.100002. eCollection 2021 Mar.

Authors

Elliott H Sohn^{1

2}, Ian C Han^{1

2}, Benjamin R Roos^{1

2}, Benjamin Faga^{1

2}, Meagan A Luse^{1

2}, Elaine M Binkley^{1

2}, H Culver Boldt^{1

2}, James C Folk^{1

2}, Stephen R Russell^{1

2}, Robert F Mullins^{1

2}, John H Fingert^{1

2}, Edwin M Stone^{1

2}, Todd E Scheetz^{1

2}

Affiliations

¹ Department of Ophthalmology, The University of Iowa, Iowa City, Iowa.
² Institute for Vision Research, The University of Iowa, Iowa City, Iowa.

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: One thousand seven hundred twelve patients with AMD (672 nonexudative, 1040 exudative) of predominantly northern European descent seeking treatment at the University of Iowa Hospitals and Clinics.

Methods: We reanalyzed the International AMD Genetics Consortium (IAMDGC) data to validate the association of polymorphisms near MMP9 with exudative AMD and to identify additional associated single nucleotide polymorphisms (SNPs), especially MMP9 coding sequence SNPs. We genotyped a cohort of 1712 AMD patients from Iowa with 3 SNPs identified with our analysis of the IAMDGC cohort using commercially available real-time quantitative polymerase chain reaction (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 with nonexudative AMD patients in the Iowa cohort for MMP9 SNPs (rs4810482, rs17576, and rs17577) and STRP.

Results: We identified 3 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 also are associated with exudative AMD in the cohort of 1712 AMD patients from Iowa (rs4810482: odds ratio [OR], 0.82; P = 0.010; rs17576: OR, 0.86; P = 0.046; and rs17577: OR, 0.80; P = 0.041). We also genotyped the cohort of AMD patients from Iowa at rs142450006, another MMP9 polymorphism that previously was associated with exudative AMD. We detected a 4bp STRP, (TTTC)_n, at the rs142450006 locus that is highly polymorphic and associated significantly with exudative AMD (OR, 0.78; P = 0.016).

Conclusions: This study independently confirms and expands an association between the MMP9 locus and exudative AMD, further implicating a role for extracellular matrix abnormalities in choroidal neovascularization.

Keywords: Age-related macular degeneration; Choroidal neovascularization; Extracellular matrix; Exudative AMD; Genetics; MMP9.