Novel Data about Association of the Functionally Significant Polymorphisms of the <b><i>MMP9</i></b> Gene with Exfoliation Glaucoma in the Caucasian Population of Central Russia
Dina Starikova, Irina Ponomarenko, Evgeny Reshetnikov, Volodymyr Dvornyk, Mikhail Churnosov
Abstract
<b><i>Aim:</i></b> This study aimed to investigate the role of functionally significant polymorphisms of the <i>MMP1, MMP3,</i> and <i>MMP9</i> genes in the development of exfoliation glaucoma (XFG) in the Caucasian population of Central Russia. <b><i>Methods:</i></b> The study sample consisted of 724 participants, including 328 patients with XFG and 396 individuals in the control group. The participants were of Russian ethnicity (self-reported) born in Central Russia. The participants were genotyped at 8 functionally significant polymorphisms of the <i>MMP</i> genes (rs3918242, rs3918249, rs17576, rs3787268, rs2250889, rs17577 <i>MMP9,</i> rs679620 <i>MMP3</i>, and rs1799750 <i>MMP1</i>). The association analysis was performed using logistic regression. Two polymorphisms, which were associated with XFG, and 12 polymorphisms linked to them (<i>r</i><sup>2</sup> ≥ 0.8) were analyzed for their functional significance in silico. <b><i>Results:</i></b> Allele C of rs3918249 <i>MMP9</i> was associated with XFG according to the additive model (OR = 0.75, 95% CI: 0.56–0.93, <i>p</i><sub>perm</sub> = 0.015), and allele G of the rs2250889 <i>MMP9</i> locus was associated with XFG according to the additive (OR = 1.59, 95% CI: 1.10–2.29, <i>p</i><sub>perm</sub> = 0.013) and dominant (OR = 1.68, 95% CI: 1.11–2.56, <i>p</i><sub>perm</sub> = 0.016) models. Two XFG-associated loci of the <i>MMP9</i> gene and 12 SNPs linked to them had a significant regulatory potential (they are located in the evolutionarily conserved regions, promoter and enhancer histone marks, the DNAase-hypersensitivity regions, a region binding to regulatory protein, and a region of regulatory motifs) and may influence the expression of 13 genes and alternative splicing of 4 genes in various tissues and organs related to the pathogenesis of XFG. <b><i>Conclusion:</i></b> Allele C rs3918249 <i>MMP9</i> decreased risk for XFG (OR = 0.75), and allele G of the rs2250889 <i>MMP9</i> locus increased risk for XFG (OR = 1.59–1.68) in the Caucasian population of Central Russia.