Sid blood group system

Beta-1,4 N-acetylgalactosaminyltransferase 2
Identifiers
Symbol	B4GALNT2
Alt. symbols	Cad, Sd(a) antigen
NCBI gene	124872
HGNC	24136
OMIM	111730
RefSeq	NP_001152859.1
UniProt	Q8NHY0
Other data
EC number	2.4.1.165
Locus	Chr. 17 q21.32
Search for Structures Swiss-model Domains InterPro

The Sid blood group system is a human blood group defined by the presence or absence of the Sd(a) antigen (also known as Sid antigen) on a person's red blood cells.^[1] About 96% of people are positive for the Sd(a) antigen,^[2]: 224 which is inherited as a dominant trait. Among Sd(a) positive individuals, the expression of the antigen ranges from extremely weak to extremely strong. Very strong expression of the antigen is referred to as a Sd(a++) phenotype. In addition to being expressed on red blood cells, Sd(a) is secreted in bodily fluids such as saliva and breast milk, and is found in the highest concentrations in urine. Urine testing is considered the most reliable method for determining a person's Sid blood type.^{[3]: 505–6}

Antibodies against the Sd(a) antigen are naturally occurring, meaning people produce them without having been exposed to Sd(a) positive blood through transfusion or pregnancy.^{[3]: 505–6} These antibodies are not usually considered to be clinically significant, but there have been two cases of transfusion reactions associated with transfusion of Sd(a++) blood to people with anti-Sd(a) antibodies.^[2]: 224 Sid was officially designated a blood group in 2019 after its genetic basis was discovered.^[1]

Molecular biology

The Sd(a) negative blood type is caused by missense mutations in B4GALNT2, a gene located on chromosome 17q21.32 which encodes a glycosyltransferase that catalyzes the final step in the synthesis of the Sd(a) antigen.^[1][4] The Sd(a) antigen exhibits autosomal dominant inheritance.^[3]: 506 The antigen is not only expressed on the surface of red blood cells but is found in soluble form in human plasma, breast milk, saliva and meconium, and is present in very high quantities in the urine,^[3]: 504 where it is carried on Tamm-Horsfall glycoprotein.^[5] It is also expressed in the stomach, colon, kidneys, and lymph nodes.^[6]: 686 Newborns do not express Sd(a) on their red cells until about 10 weeks after birth (although they do express the antigen in their bodily fluids),^{[2]: 224 [3]: 507} and expression of Sd(a) antigen on red blood cells often decreases during pregnancy.^[2]: 224

Clinical significance

The expression of Sd(a) antigen in positive individuals is highly variable, and ranges from expression so weak that it is barely detectable, to expression so strong that the cells are agglutinated by plasma from most human donors (polyagglutination). Extremely strong expression of Sd(a) is denoted as Sd(a++).^[3]: 505

The Sd(a++) phenotype is sometimes referred to as the Cad phenotype, after a 1968 paper that identified a novel antigen in members of the Cad family from Mauritius.^[7] The Cad positive cells showed polyagglutination and reacted with Dolichos biflorus lectin, a reagent used to identify type A₁ red blood cells, even though the cells were type B or O. Later research showed that strong examples of Sd(a) also exhibited polyagglutination and reaction with Dolichos biflorus, and that Cad was likely an exceptionally strong Sd(a) positive phenotype.^[3]: 505 It is believed that Sd(a) and Cad share the same antigenic determinant and are likely synthesized by the same enzyme, but there may be structural and quantitative differences in the expression of the two substances.^[5] The Cad/Sd(a++) phenotype, like the Sd(a) positive phenotype, shows autosomal dominant inheritance.^[3]: 505

Anti-Sd(a) is a naturally occurring antibody, meaning Sd(a) negative individuals produce it without having been exposed to Sd(a) positive blood through transfusion or pregnancy.^[2]: 224 Anti-Sd(a) is not typically considered to pose a hazard in blood transfusion, but as of 2018, two cases of transfusion reactions following the transfusion of Sd(a++) blood have been documented.^{[2]: 224 [8]} It is suggested that people with anti-Sd(a) are transfused with "least incompatible" blood (the blood unit that gives the weakest reactions during crossmatching) to avoid potential exposure to Sd(a++) units.^[8] Anti-Sd(a) is not known to cause hemolytic disease of the newborn.^[6]: 687

Epidemiology

Approximately 91% of people test positive for Sd(a) through blood typing, and 96% test positive through urine testing.^[2]: 224 The Sd(a++) phenotype is rare, especially in Europe, but may be more common in East Asian populations.^[3]: 506

Laboratory testing

Urine is considered the optimal specimen for Sd(a) phenotyping.^[3]: 506 The Sd(a) antigen can be detected in urine using hemagglutination inhibition testing: anti-Sd(a) is added to the urine, followed by Sd(a) positive blood cells. If Sd(a) is present in the urine, it will bind the antibody and prevent the red blood cells from agglutinating.^[6]: 687

Anti-Sd(a) is usually composed of immunoglobulin M and is reactive at room temperature, but it also displays reactivity in the indirect antiglobulin test. The antibody displays a characteristic pattern of mixed-field agglutination during testing. Under the microscope, small, shiny clumps of red blood cells are visible, surrounded by unagglutinated cells.^[2]: 224 The reactivity of anti-Sd(a) is enhanced by enzyme treatment with ficin, papain, and trypsin, and the antibody is resistant to treatment with dithiothreitol.^[6]: 686 Guinea pig urine contains very high concentrations of Sd(a) antigen and is sometimes used to identify anti-Sd(a) antibodies by inhibition testing.^[3]: 406

History

The antigen was named for Sid, an employee at the Lister Institute whose red blood cells were used for antibody screening. They were found to react strongly with samples containing an unidentified antibody, which was later characterized as anti-Sd(a).^[2]: 224 Although the Sd(a) antigen was named in 1967,^[9][10] and had been studied since at least 10 years earlier,^[3]: 505 it was only connected to B4GALNT2 in 2003^{[6]: 687 [11][12]} and assigned to a blood group in 2019 following the discovery of the molecular basis of the Sd(a) negative phenotype. It had previously been classified as part of the ISBT 901 series of high-incidence antigens.^[1]

References

1. Stenfelt L, Hellberg Å, Möller M, Thornton N, Larson G, Olsson ML (September 2019). "B4GALNT2-encoded glycosyltransferase underlying the Sd(a-) phenotype". Biochemistry and Biophysics Reports. 19: 100659. doi:10.1016/j.bbrep.2019.100659. PMC 6646742. PMID 31367682.
2. Harmening DM (30 November 2018). Modern Blood Banking & Transfusion Practices. F.A. Davis. ISBN 978-0-8036-9462-0.
3. Daniels G (2013). Human Blood Groups (3rd ed.). West Sussex, UK: John Wiley & Sons. ISBN 978-1-118-49354-0.
4. Hartz PA (16 Jan 2013). "BETA-1,4-N-ACETYL-GALACTOSAMINYLTRANSFERASE 2; B4GALNT2". Online Mendelian Inheritance in Man. Retrieved 16 May 2020.
5. Dall'Olio F, Malagolini N, Chiricolo M, Trinchera M, Harduin-Lepers A (January 2014). "The expanding roles of the Sd(a)/Cad carbohydrate antigen and its cognate glycosyltransferase B4GALNT2" (PDF). Biochimica et Biophysica Acta (BBA) - General Subjects. 1840 (1): 443–53. doi:10.1016/j.bbagen.2013.09.036. hdl:11383/1863119. PMID 24112972. S2CID 30838200.
6. Reid ME, Lomas-Francis C, Olsson ML (21 November 2012). The Blood Group Antigen FactsBook. Academic Press. ISBN 978-0-12-415849-8.
7. Cazal P, Monis M, Caubel J, Brives J (October 1968). "[Herediatry dominant polyagglutinability: private antigen (Cad) corresponding to a public antibody and a lectin of Dolichos biflorus]". Revue Française de Transfusion. 11 (3): 209–21. doi:10.1016/S0035-2977(68)80050-1. PMID 5727552.
8. Lomas-Francis C (2019). "Clinical significance of antibodies to antigens in the International Society of Blood Transfusion collections, 700 series of low-incidence antigens, and 901 series of high-incidence antigens" (PDF). Immunohematology. 34 (2): 39–45. doi:10.21307/immunohematology-2018-007. PMID 29989417. S2CID 51606082.
9. Macvie SI, Morton JA, Pickles MM (1967). "The Reactions and Inheritance of a New Blood Group Antigen, Sda". Vox Sanguinis. 13 (6): 485–492. doi:10.1111/j.1423-0410.1967.tb03795.x. S2CID 70807952.
10. Renton PH, Howell P, Ikin EW, Giles CM, Goldsmith DK (1967). "Anti-Sda, a New Blood Group Antibody". Vox Sanguinis. 13 (6): 493–501. doi:10.1111/j.1423-0410.1967.tb03796.x. ISSN 0042-9007. S2CID 72024299.
11. Lo Presti L, Cabuy E, Chiricolo M, Dall'Olio F (November 2003). "Molecular cloning of the human beta1,4 N-acetylgalactosaminyltransferase responsible for the biosynthesis of the Sd(a) histo-blood group antigen: the sequence predicts a very long cytoplasmic domain". Journal of Biochemistry. 134 (5): 675–82. doi:10.1093/jb/mvg192. PMID 14688233.
12. Montiel MD, Krzewinski-Recchi MA, Delannoy P, Harduin-Lepers A (July 2003). "Molecular cloning, gene organization and expression of the human UDP-GalNAc:Neu5Acalpha2-3Galbeta-R beta1,4-N-acetylgalactosaminyltransferase responsible for the biosynthesis of the blood group Sda/Cad antigen: evidence for an unusual extended cytoplasmic domain". The Biochemical Journal. 373 (Pt 2): 369–79. doi:10.1042/bj20021892. PMC 1223490. PMID 12678917.