Blood Groups: Molecular Genetic Basis


Human blood groups are of clinical significance in transfusion medicine and blood group incompatible pregnancy. Blood groups are due to polymorphic structures on human red cells, may arise from carbohydrates or proteins and include most species of proteins found in red cell membranes including transporters, adhesion molecules, structural proteins, complement control proteins, receptors and membrane‐bound enzymes. The molecular background of most clinically significant blood group antigens has been defined at the level of the gene, and there are (as of 2017) 36 blood group systems, with the clinically relevant VEL system being described in 2015 being the most important recent addition. Mass‐scale sequencing projects have revealed yet further complexities in the blood group genes, indicating the possibility for alloimmunisation by these variants. Despite significant advances in SNP genotyping and next‐generation sequencing, routine sequencing of blood donors and patients has not yet materialised.

Key Concepts

  • Blood group antigen expression can be divided into two broad categories: carbohydrate and protein.
  • Protein‐based blood group antigens can be further divided by their functional consequences as membrane transporters, adhesion molecules, receptors/structural components, complement control proteins and membrane‐bound enzymes.
  • The accrual of thousands of complete genome sequences has indicated the occurrence of large numbers of blood group alleles in all blood groups. These may or may not include antigenic polymorphisms that have yet to be identified clinically.
  • Blood group antigen classification and identification of null phenotypes in particular have acted as naturally occurring human knockouts and have revealed the functional significance of the carrier molecules.
  • Blood group genotyping (BGG) has emerged as a useful supplementary analysis for fetuses and patients that are multi‐transfused, e.g. sickle cell patients

Keywords: blood group polymorphisms; single nucleotide polymorphisms; genotyping; red cell membrane; blood groups; molecular basis; erythrocyte membrane

Figure 1. Biosynthesis of the carbohydrate‐dependent antigens of the erythrocyte. Panel (a) indicates the glycosyltransferases involved in the biosynthesis of the ABH blood group active carbohydrates, indicated by arrows. The genetic basis of these differences is indicated in the text, but A → B transferases (α1,3‐N‐acetylgalactosaminyl and α1,3‐galactosaminyl transferases, respectively) differ by four amino acids and group O individuals are devoid of any A/B transferase. The A/B transferase transfers UDP‐GalNAc/UDP‐Gal to H substance, generated by action of the H‐transferase (FUT1; an α1,2‐fucosyltransferase) that can act on a wide variety of precursor carbohydrate chains attached to type 2, 3 and 4 chain glycosphingolipids (Lacto‐series), to O‐ and N‐glycosylated proteins. Panel (b) depicts the biosynthesis of Lewis antigens from type 1 precursor. The Lea antigen is synthesised by the action of the Le glycosyltransferase (FUT3), an α1,3/4‐fucosyltransferase that adds fucose to the subterminal GlcNAc. Sequential additions by Se (FUT2) or A transferase can yield Leb, Led or ALeb substances as depicted earlier. Fuc: fucose; GlcNAc: N‐acetylglucosamine; Gal: galactose, GalNAc: N‐acetylgalactosamine.
Figure 2. Protein antigens of the red cell membrane. This figure depicts representations of the 19 human blood groups that arise from proteins of the red cell. Minor blood group active proteins (e.g. JR, RAPH, AUG, CD59, GIL and LAN) are omitted for clarity. The broad functional classes of each blood group system are shown (adhesion molecule, receptor, membrane‐bound enzyme, structural protein or membrane transporter). The identity of each protein species is shown above each cartoon, while the blood group system that it carries lies beneath. N‐ and O‐glycans are represented as branches and circles, respectively, while polymorphic amino acids are shown as circles (the major clinically relevant antigens are shown only for clarity).


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Web Links


Genew: Human Gene Nomenclature Database Search Engine. Approved gene names and symbols plus links to further information.

Human blood group antigen mutation database.

ISBT nomenclature (blood group terminology)

LocusLink. A single query interface to curated sequence and descriptive information about genetic loci. Information on official nomenclature, aliases, sequence accessions, phenotypes, map locations etc. and related websites.

NCBI mapview. Enter gene symbol in search engine and obtain information about chromosomal location

NCBI nucleotide database. Enter the accession number given in Table 1 (for example NM_020469) and search

ABO blood group (transferase A, alpha 1‐3‐N‐acetylgalactosaminyltransferase; transferase B, alpha 1‐3‐galactosyltransferase) (ABO); Locus ID: 28.

Fucosyltransferase 3 (galactoside 3(4)‐l‐fucosyltransferase, Lewis blood group included) (FUT3); Locus ID: 2525.

Rhesus blood group, D antigen (RHD); Locus ID: 6007.

Solute carrier family 4, anion exchanger, member 1 (erythrocyte membrane protein band 3, Diego blood group) (SLC4A1); Locus ID: 6521.

Xg blood group (pseudoautosomal boundary‐divided on the X chromosome) (XG); Locus ID: 7499.

ABO blood group (transferase A, alpha 1‐3‐N‐acetylgalactosaminyltransferase; transferase B, alpha 1‐3‐galactosyltransferase) (ABO); MIM number: 110300. OMIM:‐post/Omim/dispmim?110300

Fucosyltransferase 3 (galactoside 3(4)‐l‐fucosyltransferase, Lewis blood group included) (FUT3); MIM number: 111100. OMIM:‐post/Omim/dispmim?111100

Rhesus blood group, D antigen (RHD); MIM number: 111680. OMIM:‐post/Omim/dispmim?111680

Solute carrier family 4, anion exchanger, member 1 (erythrocyte membrane protein band 3, Diego blood group) (SLC4A1); MIM number: 109270. OMIM:‐post/Omim/dispmim?109270

Xg blood group (pseudoautosomal boundary‐divided on the X chromosome) (XG); MIM number: 314700. OMIM:‐post/Omim/dispmim?314700

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Avent, Neil D(Mar 2018) Blood Groups: Molecular Genetic Basis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006034.pub2]