Functionally significant polymorphisms of the MMP9 gene are associated with primary open-angle glaucoma in the population of Russia

Abstract

Purpose The aim of this study was to investigate the role of functionally significant loci of the matrix metalloproteinases genes 1, 3, 9 ( MMP1, MMP3, and MMP9) in the development of primary open-angle glaucoma (POAG) in Caucasians of the Central region of Russia. Methods In total 604 participants were recruited for the study, including 208 patients with POAG and 396 healthy controls. They were genotyped at eight single nucleotide polymorphisms (SNPs) of the three MMP genes. The association was analyzed using logistic and log-linear regression. POAG-associated loci and their proxies were in silico assessed for their functional prediction. Results Variant allele G*rs2250889 of MMP9 was significantly associated with higher risk of POAG (ORcov = 1.57–1.71). Haplotype CCA [rs3918242-rs3918249-rs17576] of the MMP9 gene was associated with lower risk of POAG (ORcov = 0.33). Allele А*rs3787268 of MMP9 was associated with the low intraocular pressure in the POAG patients (βcov = −0.176 - −0.272), and so were haplotypes AA [rs17576-rs3787268] (βcov = −0.577) and AAC [rs17576-rs3787268- rs2250889] (βcov = −0.742) of the same gene, whereas allele 2G*rs1799750 of MMP1 was associated with the earlier onset of the disease (βcov = −0.112 - −0.218). In silico analysis of the polymorphisms suggested the functionality of POAG-associated SNPs and their proxies (epigenetic potential, expression and alternative splicing effects for several genes). Conclusions The MMP9 gene polymorphisms are associated with POAG and intraocular pressure in POAG patients; rs1799750 of MMP1 was associated with the earlier age of manifestation of the disease symptoms.

Matrix Metalloproteinases and Glaucoma

“…One meta-analysis suggested that rs1799750 is associated with a risk of developing PACG and XFG [ 123 ]. In addition to the increased risk of POAG, Ponomarenko et al [ 126 ] reported that rs1799750 is related to earlier onset of POAG development. However, Mossböck et al [ 127 ] reported that G was not associated with POAG and XFG development in Caucasians.…”

“…Several studies on rs3918249 have reported a decreased risk of glaucoma [ 126 , 131 , 132 ]. A reduced risk of POAG has been reported in the Russian population [ 126 ].…”

“…Several studies on rs3918249 have reported a decreased risk of glaucoma [ 126 , 131 , 132 ]. A reduced risk of POAG has been reported in the Russian population [ 126 ]. Two studies reported a decreased risk of XFG and glaucoma in Caucasians [ 131 , 132 ].…”

“…Few studies regarding rs2250889 have shown an increased risk of developing glaucoma, and none have shown a protective effect [ 126 , 132 , 137 ]. In the Russian population, rs2250889 increased the risk of POAG, but interestingly, IOP was lower in the POAG population that had a relationship with rs2250889 [ 126 ]. Another study in Russia reported that rs2250889 increased the risk of XFG in Caucasians [ 132 ].…”

“…However, other studies have reported that rs17576 has no relationship with POAG and PACG [ 127 , 131 , 136 , 138 ]. In Russian individuals [ 126 ], rs17576 decreased the risk of POAG and reduced IOP in POAG patients with rs17576. Caucasians with rs17576 showed a decreased risk of developing glaucoma [ 139 ].…”