title: SMIM1 variants rs1175550 and rs143702418 independently modulate Vel blood group antigen expression.
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.
authors.affiliation: Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Mikael K
authors.initials: MK
authors.lastname: Christophersen
authors.affiliation: Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Clinical Immunology and Transfusion Medicine, Laboratory Medicine, Office of Medical Services, Lund, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Jöud
authors.affiliation: Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Ram
authors.initials: R
authors.lastname: Ajore
authors.affiliation: Laboratory of Immunohematology and Genomics, New York Blood Center, New York City, NY, USA.
authors.forename: Sunitha
authors.initials: S
authors.lastname: Vege
authors.affiliation: Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Klara W
authors.initials: KW
authors.lastname: Ljungdahl
authors.affiliation: Laboratory of Immunohematology and Genomics, New York Blood Center, New York City, NY, USA.
authors.forename: Connie M
authors.initials: CM
authors.lastname: Westhoff
authors.affiliation: Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Clinical Immunology and Transfusion Medicine, Laboratory Medicine, Office of Medical Services, Lund, Sweden.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Olsson
authors.affiliation: Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.|Clinical Immunology and Transfusion Medicine, Laboratory Medicine, Office of Medical Services, Lund, Sweden.
authors.forename: Jill R
authors.initials: JR
authors.lastname: Storry
authors.affiliation: Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Nilsson
mesh_terms: D000483:Alleles; D001483:Base Sequence; D001789:Blood Group Antigens / Q000378:metabolism*; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011485:Protein Binding; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1 / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D001789:Blood Group Antigens; D008565:Membrane Proteins; C584052:SMIM1 protein, human; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C067143:TAL1 protein, human; D008156:Luciferases