Association of alpha A-crystallin polymorphisms with susceptibility to nuclear age-related cataract in a Han Chinese population

BACKGROUND: Alpha A-crystallin (CRYAA) is considered critical for the maintenance of lens transparency and is related to the pathogenesis of age-related cataracts (ARCs), especially the nuclear subtype. As the 5′ untranslated region (5′ UTR) modulates gene expression, the purpose of current study was to investigate whether single nucleotide polymorphisms (SNPs) in the 5′ UTR of CRYAA were associated with susceptibility to ARC in a Han Chinese population and to clarify the mechanism of this association. METHODS: SNPs in the 5′ UTR (−1 to −1000) of CRYAA were identified in 243 nuclear ARC patients and 263 controls using polymerase chain reaction and DNA sequencing. Allele and genotype frequencies were calculated and compared between two groups. Haploview 4.2 was used to calculate the linkage disequilibrium index, and the SHEsis analysis platform was used to infer haplotype construction. A dual-luciferase reporter gene assay was used for transcription of CRYAA in the presence of a protective haplotype with individual SNP alteration, Chromatin immunoprecipitation (ChIP) was employed to determine whether SNPs regulated CRYAA expression by altering the binding affinity of transcription factors. RESULTS: Three polymorphisms were identified in the 5′ UTR of CRYAA: rs3761381 (P = 0.000357, odds ratio [OR] = 1.837), rs13053109 (P = 0.788, OR = 1.086), and rs7278468 (P = 0.00136, OR = 0.652). The haplotype C-G-T (P = 0.0014, OR = 1.536) increased the risk of nuclear ARC, whereas the haplotype T-G-G (P = 0.00029, OR = 0.535) decreased the risk. The haplotype C-G-T decreased CRYAA transcription through rs7278468, which is located in the binding site of specificity protein 1 (Sp1). Furthermore, the G allele of rs7278468 increased CRYAA transcription by enhancing the binding affinity of Sp1. CONCLUSIONS: These data indicate that the CRYAA polymorphism is a genetic marker of inter-individual differences in the risk of nuclear ARC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12886-017-0529-9) contains supplementary material, which is available to authorized users.