Abstract
The Vel blood group antigen is expressed on the red blood cells of most individuals. Recently, we described that homozygosity for inactivating mutations in SMIM1 defines the rare Vel-negative phenotype. Still, Vel-positive individuals show great variability in Vel antigen expression, creating a risk for Vel blood typing errors and transfusion reactions. We fine-mapped the regulatory region located in SMIM1 intron 2 in Swedish blood donors, and observed a strong correlation between expression and rs1175550 as well as with a previously unreported tri-nucleotide insertion (rs143702418; C > CGCA). While the two variants are tightly linked in Caucasians, we separated their effects in African Americans, and found that rs1175550G and to a lesser extent rs143702418C independently increase SMIM1 and Vel antigen expression. Gel shift and luciferase assays indicate that both variants are transcriptionally active, and we identified binding of the transcription factor TAL1 as a potential mediator of the increased expression associated with rs1175550G. Our results provide insight into the regulatory logic of Vel antigen expression, and extend the set of markers for genetic Vel blood group typing.
Highlights
We and two other research groups identified a previously unreported erythroid gene, Small Integral Membrane Protein 1 (SMIM1), as the locus of the Vel blood group system[1,2,3]
Hypothesising that the linkage disequilibrium (LD) between rs1175550 and rs143702418 might be different in other populations, we examined the repertoire of SMIM1 intron 2 alleles in the 1000 Genomes catalog
Fine-mapping the genomic neighbourhood of rs1175550, a regulatory region in SMIM1 intron 2, we discovered that the previously unreported trinucleotide insertion rs143702418 correlates with SMIM1 and Vel antigen expression
Summary
The variation in antigen expression among Vel+individuals is clinically important, as it may lead to erroneous typing of Vel+blood as Vel− with anti-Vel sera[15,16]. Insight into what governs blood group expression levels on erythroid cells can be important for our understanding of host-pathogen interactions since many blood group molecules serve as involuntary receptors for microbial agents and may act as susceptibility markers for disease Even if no such role has yet been proven for SMIM1, it has been hypothesised to be a long-sought malaria receptor[1]. We exploited pre-existing population-based data sets and trans-ancestry association analysis to deconvolve highly correlated effects. We predict that these approaches will be increasingly important for identifying the molecular-genetic effects of GWAS loci
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