The differential expression of the blood group P¹-A4GALT and P²-A4GALT alleles is stimulated by the transcription factor early growth response 1

BACKGROUND: The P₁/P₂ phenotypic polymorphism is one of the earliest blood groups discovered in humans. These blood groups have been connected to different levels of expression of the A4GALT gene in P₁ and P₂ red blood cells; however, the detailed molecular genetic mechanism that leads to these two phenotypes has not been established. STUDY DESIGN AND METHODS: After our previous identification of an association between the single-nucleotide polymorphisms (SNPs) rs2143918 and rs5751348 in A4GALT gene and the P₁/P₂ phenotype, we conduct a survey of transcription factors that might connect these SNPs with the differential expression of the P¹-A4GALT and P²-A4GALT alleles. An in silico analysis of potential transcription factor binding motifs within the polymorphic SNPs rs2143918 and rs5751348 genomic regions was performed, and this was followed by reporter assays examining the candidate transcription factors, gene expression profiling, electrophoretic mobility shift assays, and P¹-A4GALT and P²-A4GALT allelic expression analysis. RESULTS: The results revealed that the differential binding of transcription factor early growth response 1 to the SNP rs5751348 genomic region with the different genotypes in the A4GALT gene leads to differential activation of P¹-A4GALT and P²-A4GALT expression. CONCLUSION: The present investigation, together with our previous study (Lai et al., Transfusion 2014;54:3222-31), have elucidated the molecular genetic details associated with the P₁/P₂ blood groups.