MiR-2964a-5p binding site SNP regulates ATM expression contributing to age-related cataract risk
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Han Rong1,2, Shanshan Gu1, Guowei Zhang1, Lihua Kang1, Mei Yang1, Junfang Zhang1, Xinyue Shen1 and Huaijin Guan1
1Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
2Eye Department, The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’an, Huai’an, Jiangsu, China
Huaijin Guan, email: [email protected]
Keywords: microRNA, DNA damage, single-nucleotide polymorphisms (SNPs), ataxia telangiectasia mutated (ATM) gene, age-related cataract
Received: December 05, 2016 Accepted: April 11, 2017 Published: May 03, 2017
This study was to explore the involvement of DNA repair genes in the pathogenesis of age-related cataract (ARC). We genotyped nine single nucleotide polymorphisms (SNPs) of genes responsible to DNA double strand breaks (DSBs) in 804 ARC cases and 804 controls in a cohort of eye diseases in Chinese population and found that the ataxia telangiectasia mutated (ATM) gene-rs4585:G>T was significantly associated with ARC risk. An in vitro functional test found that miR-2964a-5p specifically down-regulated luciferase reporter expression and ATM expression in the cell lines transfected with rs4585 T allele compared to rs4585 G allele. The molecular assay on human tissue samples discovered that ATM expression was down-regulated in majority of ARC tissues and correlated with ATM genotypes. In addition, the Comet assay of cellular DNA damage of peripheral lymphocytes indicated that individuals carrying the G allele (GG/GT) of ATM-rs4585 had lower DNA breaks compared to individuals with TT genotype. These findings suggested that the SNP rs4585 in ATM might affect ARC risk through modulating the regulatory affinity of miR-2964a-5p. The reduced DSBs repair might be involved in ARC pathogenesis.
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