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The genes in the 9p21 locus (<i>CDKN2B-AS1</i> & <i>CDKN2B</i>) are widely associated with Primary open-angle glaucoma (POAG). However, the functional importance of this locus in POAG pathogenesis is still unexplored. This study investigated the role of <i>CDKN2BAS1-CDKN2B</i> axis in POAG. We observed significant association of <i>CDKN2B-AS1</i> SNP rs4977756 with POAG and its endophenotypic traits (vertical cup-disc ratio (<i>p</i> = 0.033) and central corneal thickness (<i>p</i> = 0.008)) by screening African American POAG cases (<i>n</i> = 1567) and controls (<i>n</i> = 1600). A luciferase reporter assay in Human embryonic kidney 293T (HEK293T) cells revealed that the region surrounding rs4977756 likely serves as a transcriptional repressor. siRNA-mediated knockdown of <i>CDKN2B-AS1</i> in HEK293T cells and trabecular meshwork (TM) cells resulted in significantly increased expression of <i>CDKN2B</i>, which was also observed in human POAG ocular tissues. Pathway focused qRT-PCR gene expression analysis showed increased cellular senescence, TGFβ signaling and ECM deposition in TM cells after <i>CDKN2B-AS1</i> suppression. In conclusion, we report that <i>CDKN2B-AS1</i> may act as a regulator, and it could function by modulating the expression of <i>CDKN2B</i>. In addition, increase in CDKN2B levels due to <i>CDKN2B-AS1</i> suppression may result in the senescence of trabecular meshwork cells leading to POAG pathogenesis.