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The  HLA-G  5’URR extending 1.4 kb from the ATG presents a unique set of regulatory elements among  HLA  genes. Several variable sites have been described that coincide with or are close to these elements, thus  HLA-G  5′URR polymorphism might influence the  HLA-G  expression level. We cloned the ten most frequent  HLA-G  5′URR haplotypes to evaluate their activity on a luciferase reporter gene in HLA-G +  cell lines (JEG-3/choriocarcinoma and FON + /melanoma). We also investigated associations between the plasma HLA-G (sHLA-G) levels and the  HLA-G  5′URR variability in 157 healthy individuals. Cell lines were transfected with pGL3-Basic vector constructions containing  HLA-G  5′URR sequences. The G010101a (in JEG-3) and G010101b (in FON + ) haplotypes exhibited higher promoter activity, whereas the G010101d (in JEG-3) and G010102a (in FON + ) haplotypes exhibited lower promoter activity. In the presence of  HLA-G  inducers (interferon-β and progesterone) or repressors (cyclopamine)  HLA-G  promoter activity was modulated, but certain haplotypes exhibited differential responses. No strict association was observed between plasma sHLA-G levels and the 5′URR haplotypes or genotypes; however, the G010101b haplotype was underrepresented among HLA-G-negative plasmas. Therefore, the  HLA-G  5′URR polymorphism may have an impact on the modulation of  HLA-G  gene expression, but alone provides a limited predictive value for sHLA-G levels  in vivo .

The genetic diversity within the 1.4 kb HLA-G 5′ upstream regulatory region moderately impacts on cellular microenvironment responses