Characterization of a prolactin gene polymorphism and its associations with systemic lupus erythematosus.
Stevens A., Ray D., Alansari A., Hajeer A., Thomson W., Donn R., Ollier WE., Worthington J., Davis JR.
OBJECTIVE: Hyperprolactinemia is associated with systemic lupus erythematosus (SLE), but the mechanism is unknown. Prolactin is expressed in T lymphocytes and is under the control of an alternative promoter region. We characterized a G/T single-nucleotide polymorphism (SNP) at position -1149 of this promoter and assessed its prevalence in patients with SLE. METHODS: Electrophoretic mobility shift assays (EMSAs) were performed to determine DNA protein complex formation in the prolactin promoter. Transient transfection of reporter gene constructs containing the G/T promoter alleles into the Jurkat T cell line were used to determine transcription activity. Peripheral blood lymphocytes (PBLs) were treated in vitro with phytohemagglutinin (PHA) to determine levels of prolactin messenger RNA (mRNA). RESULTS: EMSAs indicated that binding of a GATA-related transcription factor was altered by the G/T SNP at position -1149. Transient transfection studies in Jurkat cells showed that the G allele consistently produced higher promoter activity. PHA treatment of PBLs in vitro induced a greater increment of prolactin mRNA from patients with the GG(-1149) genotype than from those with the TT(-1149) genotype. Disease association studies in a cohort of SLE patients demonstrated an increased frequency of the prolactin -1149 G allele compared with control subjects. CONCLUSION: We found a functionally significant polymorphism that alters prolactin promoter activity and mRNA levels in the lymphocytes. Altered local prolactin production by immune cells may contribute to disease progression by affecting T cell function.