Abstract
Systemic lupus erythematosus (SLE) is a typical autoimmune disease with a strong genetic disposition. Genetic studies have revealed that single-nucleotide polymorphisms (SNPs) in zinc finger protein (ZNF)-coding genes are associated with susceptibility to autoimmune diseases, including SLE. The objective of the current study was to evaluate the correlation between ZNF76 gene polymorphisms and SLE risk in Chinese populations. A total of 2801 individuals (1493 cases and 1308 controls) of Chinese Han origin were included in this two-stage genetic association study. The expression of ZNF76 was evaluated, and integrated bioinformatic analysis was also conducted. The results showed that 28 SNPs were associated with SLE susceptibility in the GWAS cohort, and the association of rs10947540 was successfully replicated in the independent replication cohort (Preplication = 1.60 × 10−2, OR 1.19, 95% CI 1.03–1.37). After meta-analysis, the association between rs10947540 and SLE was pronounced (Pmeta = 9.62 × 10−6, OR 1.29, 95% CI 1.15–1.44). Stratified analysis suggested that ZNF76 rs10947540 C carriers were more likely to develop relatively high levels of serum creatinine (Scr) than noncarriers (CC + CT vs. TT, p = 9.94 × 10−4). The bioinformatic analysis revealed that ZNF76 rs10947540 was annotated as an eQTL and that rs10947540 was correlated with decreased expression of ZNF76. Remarkably, significantly reduced expression of ZNF76 was confirmed by expression data from both our laboratory and an array-based expression database. Taken together, these results suggest that ZNF76 rs10947540 is a possible susceptibility factor associated with SLE susceptibility. The mechanism underlying the relationship between ZNF76 and SLE pathogenesis still requires further investigation.
Highlights
ZNF76 is a novel transcriptional repressor targeting TATA-binding protein that has been shown to have an inhibitory effect on p53 activity by reporter assays and on endogenous target gene e xpression[9]
To determine whether SNPs in the ZNF76 gene predispose patients to Systemic lupus erythematosus (SLE), we conducted a genetic replication of a previous GWAS genetic association result in an independent Chinese Han population
Our results showed that rs10947540 in ZNF76 predisposed patients to susceptibility to SLE
Summary
ZNF76 is a novel transcriptional repressor targeting TATA-binding protein that has been shown to have an inhibitory effect on p53 activity by reporter assays and on endogenous target gene e xpression[9]. Integrated analysis of three original datasets, GSE72509, GSE20864, and GSE39088, from the Gene Expression Omnibus (GEO) database identified that the p53 signalling pathway may be implicated in SLE p athogenesis[10]. Considering both genetic clues concerning variants in zinc finger protein-coding genes contributing to susceptibility to autoimmune diseases, including SLE, and the biological functions of ZNF76, we aimed to explore the role of ZNF76 in the pathogenesis of SLE. By using a public database, we explored the functional role of ZNF76 rs10947540 and the differential expression of ZNF76, which was validated by expression data from our centre
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