Remote regulation of rs80245547 and rs72673891 mediated by transcription factors C-Jun and CREB1 affect GSTCD expression

Chronic obstructive pulmonary disease (COPD), is consideredthe a third leading cause of death worldwide, and similarly to many other diseases it is also under the influenced by of genetic factors. The genetic signal rs10516526 or its linkage locus found in the glutathione S-transferase C-terminal domain containing (GSTCD) gene, has been revealed previously by genome-wide association studies (GWAS) as is a highly significant and reproducible signal known to be associated with lung function and COPD on chromosome 4q24. However, the relationship between rs10516526, GSTCD, and COPD has so far not well been described. In this study, comprehensive bioinformatics analyses and experimental verifications including RT-PCR, chromatin conformation capture assay, dual fluorescence report analysis, chromatin immunoprecipitation assays, RNAi, and electrophoretic mobility shift assays, were detailly implemented to explore the regulation mechanism of rs10516526 and GSTCD in COPD. The results suggested that low expression of GSTCD was associated with COPD (P = 0.010). And It was found that both rs80245547 and rs72673891 could bind C-Jun and CREB1 transcription factors, which were found to be essential for the regulation of GSTCD by rs80245547 and rs72673891 to regulate GSTCD. Moreover, we observed that rs80245547T and rs72673891G showed had a stronger binding ability to these transcription factors, which may promote the allele-specific long-range enhancer-promoter interactions on GSTCD. Our study reveals that rs10516526 linkage sites rs80245547T and rs72673891G upregulate GSTCD expression over long distances by enhancing the binding of transcription factors C-Jun and CREB1, thus making COPD less susceptible. Our study provides a new insight into the relationship between rs10516526, GSTCD, and COPD.