A4GALT gene single-nucleotide polymorphisms and the expression of P1 antigen on red blood cells
Date Issued
2015
Date
2015
Author(s)
Liao, Jia-Ching
Abstract
P1 and Pk are two different carbohydrate antigens present on cell surfaces. The expressions of the P1 and Pk antigen on red blood cells (RBCs) are different among individuals; however, the molecular genetic mechanism leading to this difference is still unclear. The formations of the P1 and Pk antigens are determined by the activity of an α-1,4-galactosyltransferase, encoded from the A4GALT gene. According to previous studies, the common phenotypic polymorphisms of the P1+ and P1– phenotypes on RBCs, which are designated as the P1 and P2 blood groups, respectively, depend on the different A4GALT gene expression levels among individuals. In RBCs with the P2 phenotype, the expression level of A4GALT mRNA and the amount of the P1 antigen are both lower than the RBCs with the P1 phenotype. In our previous investigation, we have demonstrated two single-nucleotide polymorphisms (SNPs), rs2143918 (SNP5) and rs5751348 (SNP6), located in the intron 1 region of the A4GALT gene, are associated with the P1/P2 phenotypes. In the present study, we aim to demonstrate the factor leading to the different expression levels between the A4GALT genes with the P1 and P2 genotypes. Several transcription factors, including ETS2, AML1, EGR3, KLF, and CEBPD, were predicted in silico to have differential binding affinity to the SNP5 or SNP6 regions with the different P1 and P2 genotypes. In further investigations using reporter assay and K-562 erythryoleukemia cells as a study model, we found that ectopic expression of the EGR3 transcription factor leads to a significant induction of the transcriptional activity in the reporter construct with the A4GALT SNP6-P1 genotype and also promote the expression of the A4GALT gene in K-562 cells. These results highly suggested that EGR3 may play an important role in activating the expression of the A4GALT gene with the P1 genotype at the SNP6 position. In our further investigation, we plan to demonstrate whether EGR3 will differentially stimulate the expression the A4GALT genes with the P1 and P2 genotypes in a P1/P2 heterozygous cell line to substantiate the functional role of EGR3 transcription factor in the formation of the P1/P2 blood groups.
Subjects
P1/P2 blood groups
A4GALT
Single-nucleotide polymorphism (SNP)
Type
thesis
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