Allele-specific expression identified rs2509956 as a novel long-distancecis-regulatory SNP forSCGB1A1, an important gene for multiple pulmonary diseases

SCGB1A1 (secretoglobin family 1A member 1) is an important protein for multiple pulmonary diseases, especially asthma, chronic obstructive pulmonary disease, and lung cancer. One single-nucleotide polymorphism (SNP) at 5′-untranslated region of SCGB1A1, rs3741240, has been suggested to be associated with reduced protein expression and further asthma susceptibility. However, it was still unclear whether there were other cis-regulatory elements for SCGB1A1 that might further contribute to pulmonary diseases. Allele-specific expression (ASE) is a novel approach to identify the functional region in human genome. In the present study, we measured ASE on rs3741240 in lung tissues and observed a consistent excess of G allele over A ( P < 10−6), which indicated that this SNP or the one(s) in linkage disequilibrium (LD) could regulate SCGB1A1 expression. By analyzing 1000 Genomes Project data for Chinese, one SNP locating ~10.2 kb away and downstream of SCGB1A1, rs2509956, was identified to be in strong LD with rs3741240. Reporter gene assay confirmed that both SNPs could regulate gene expression in the lung cell. By chromosome conformation capture, it was verified that the region surrounding rs2509956 could interact with SCGB1A1 promoter region and act as an enhancer. Through chromatin immunoprecipitation and overexpression assay, the related transcription factor RELA (RELA proto-oncogene, NF-kB subunit) was recognized to bind the region spanning rs2509956. Our work identified a novel long-distance cis-regulatory SNP for SCGB1A1, which might contribute to multiple pulmonary diseases.