Studies on the Polymorphism and Transcriptional Regulation of the ABO and P1PK Histo-blood Group Genes

Sammanfattning: Antigens of the clinically important ABO and P1PK blood group systems are carbohydrate structures. Thus the underlying genes do not encode antigens directly but glycosyltransferases that add specific sugar molecules to selected precursor chains. The aim of this study was to investigate the transcriptional regulation of ABO and A4GALT, with an emphasis on interindividual differences. The up-and downstream regions of the major ABO alleles were sequenced to identify allele-specific motifs. Transcript levels were evaluated in both peripheral blood and bone marrow samples. Considerable allelic variation was observed between the common ABO alleles although this did not appear to influence transcript levels. Strikingly, however transcripts from the two major A alleles, A1 and A2 were undetectable in peripheral blood while, B/O transcripts were readily found. Consequently all alleles were transcribed in bone marrow cells undergoing erythroid culture. In a second study, a novel ABO hybrid allele with an anomalous enhancer region was characterized in a A1Bweak sample. Contrary to current beliefs, the number minisatellite 43-bp elements in the enhancer region did not correlate with ABO transcript levels in these two studies. A4GALT gene transcripts were measured in P1 and P2 phenotypes samples. Regarding transcript levels and RBC surface antigen expression. Through the discovery of a novel A4GALT transcript containing a previously unrecognized and polymorphic A4GALT exon, the long-suspected link between the P1 and Pk antigens was established. A P1/P2 polymorphism was confirmed useful for genotyping in >200 donors. The P2 allele was shown to lower A4GALT transcript levels as well as P1 and Pk antigen expression. Accordingly P1/P2 zygosity appears to explain the well-known but poorly understood variability in P1 strength on erythrocytes. Based on these studies, the Pk antigen has now joined P1 in the former P blood group system, appropriately re-designated P1PK. In summary, these studies of ABO and A4GALT transcriptional have resulted in significant discoveries towards increased understanding of two clinically important blood group systems. The mechanisms underlying 1) the apparent absence of A transcripts in peripheral blood, and 2) how the P2-specific polymorphism down-regulates A4GALT transcripts remains to be explained.