A variant in a microRNA binding site in NEIL2 3′UTR confers susceptibility to age‐related cataracts

ABSTRACTDNA damage in lens cells is considered a critical trigger for the onset of age‐related cataracts (ARCs). Among DNA repair pathways, the base excision repair (BER) pathway is responsible for mending single‐strand breaks in DNA. In this case‐control study with 993 ARC cases and 993 healthy controls, we genotyped 9 single‐nucleotide polymorphisms (SNPs) within microRNA (miRNA) regions of 6 BER pathway genes and examined their associations with ARC susceptibility. We identified rs4639:T > C in the Nei‐like DNA glycosylase 2 (NEIL2) gene as significantly associated with ARCs. Individuals carrying different rs4639 alleles had distinct NEIL2 expression in lens capsule tissues from ARC cases and controls. Bioinformatics predicts that the rs4639 T allele could disrupt hsa‐miR‐3912‐5p binding. The results of the luciferase reporter assay were in concordance with this prediction. This study has added more evidence that SNP‐modified posttranscriptional gene regulation by miRNA might be a potential pathogenic mechanism of ARCs. SNPs potentially affecting miRNA binding to the 3′UTR of BER pathway genes could contribute to discrepant disease susceptibility. NEIL2‐rs4639T was strongly associated with a protective role in ARCs. This protective role might be fulfilled by maintaining normal expression of NEIL2 in the mediation of disrupted binding of rs4639T with hsa‐miR‐3912‐5p. A further study to generate model systems (cell lines or animal models) with NEIL2 variants is warranted. The results provide 2 molecular targets (e.g., NEIL2 and hsa‐miR‐3912‐5p) for intervention strategies of ARC in the future.—Kang, L., Zou, X., Zhang, G., Xiang, J., Wang, Y., Yang, M., Chen, X., Wu, J., Guan, H. A variant in a microRNA binding site in NEIL23′UTR confers susceptibility to age‐related cataract. FASEB J. 33, 10469–10476 (2019). www.fasebj.org