Molekulare Blutgruppenbestimmung

Zusammenfassung

Die erste molekulare Analyse einer menschlichen Blutgruppe erfolgte 1983 mittels eines Restriktions-Fragment-Längen-Polymorphismus (RFLP) am System Xg. Seither wurden in unzähligen Studien die molekularen Ursachen für Blutgruppen und deren Antigene erforscht,und das resultierende Wissen für eine ständige Verbesserung der entsprechenden Analysemethoden verwendet. Die Untersuchung kausaler Punktmutationen (Single Nucleotide Polymorphism, SNP) aller 36 von der International Society for Blood Transfusion (ISBT) anerkannten Blutgruppensysteme erlaubt heute eine der Serologie ebenbürtige, exakte Vorhersage der Blutgruppenantigene. In Patienten wird die molekulare Blutgruppenbestimmung bevorzugt in Form von Einzelprobenanalytik für die Diagnose von RhD-Varianten eingesetzt, um damit transfusionsrelevante Entscheidungen bezüglich RhD zu treffen und um die Rh-Prophylaxe noch zielsicherer zu steuern. An Spenderproben und im Hochdurchsatz ermöglicht die Blutgruppen-Genotypisierung die Schaffung einer ausreichenden Anzahl von Spender-Datensätzen, um immunisierte Patienten bestverträglich zu transfundieren oder deren Immunisierung bereits im Ansatz zu vermeiden. Gleichzeitig werden heutzutage an den gleichen Proben zusätzlich eine Vielzahl weiterer SNPs zur Identifikation von Spendern mit seltener Negativität für hochfrequente Antigene getestet. Derartig umfassende Spender-Datensätze werden bereits ideal genutzt für „In-silico-Kreuzproben“ eingesetzt. Next Generation Sequencing (NGS) ist auch in der Transfusionsmedizin der „neue Stern am Horizont“ und wird vermutlich innert weniger Jahre eine wichtige Rolle in der Analyse kompletter Blutgruppengenome (chronischer) Empfänger spielen. Blutgruppenbestimmung als frühestes Beispiel echter personalisierter Medizin wird in ihrer molekularen Version mit dazu beitragen, den gebührenden Platz der Transfusionsmedizin in der modernen Medizin zu behaupten.

Abstract

The first molecular analysis of a human blood group was performed using a Restriction Fragment Length Polymorphism (RFLP) on Xg in 1983. Since then, a panoply of studies addressing the genetic background of human blood groups has enormously broadened knowledge, with steady improvement of blood group genotyping procedures. Targeting Single Nucleotide Polymorphisms (SNPs) of all 36 human blood group systems, as currently recognized by the International Society for Blood Transfusion ISBT, allows for exact blood group antigen predictions, with accuracies comparable to those of serology. Blood group genotyping in patients is mainly done for the discrimination of RhD-variants due to their relevance for blood transfusion and in order to improve guided Rh prophylaxis. Among donors, high-throughput genotyping is used to assure supply of well-matched blood to recipients with existent allo-antibodies, or to avoid allo-immunizations up front. Capability of modern techniques for the simultaneous analysis of dozens of SNPs, allows for parallel identification of donors with rare negativity for high-frequency-antigens. Comprehensive donor-data sets have already been used in an ideal way for “in silico-matching” approaches. Next Generation Sequencing is a new star on the horizon and is envisioned for improved (chronic) recipient blood group analysis. Using molecular techniques, transfusion medicine the earliest example of truly personalized medicine, will keep its place in modern medicine.

Schlüsselwörter

Blutgruppe - Gen - Genotyp - molekulare Blutgruppenbestimmung - Blutgruppen-Genotypisierung

Key words

blood group - gene - genotype - molecular blood group typing - blood group genotyping

• Literatur

• 1 Sarfarazi M, Harper PS, Kingston HM. et al. Genetic linkage relationship between the Xg blood group system and two X chromosome DNA polymorphisms in families with Duchenne and Becker muscular dystrophy. Hum Genet 1983; 65: 169-171
• 2 Colin Y, Rahuel C, London J. et al. Isolation of cDNA clones and complete amino acid sequence of human erythrocyte glycophorin C. J Biol Chem 1986; 261: 229-233
• 3 Huang CH, Johe K, Moulds JJ. et al. Delta glycophorin (glycophorin B) gene deletion in two individuals homozygous for the S–s–U– blood group phenotype. Blood 1987; 70: 1830-1835
• 4 Daniels G. Human Blood Groups. 3rd ed.. Oxford: Wiley-Blackwell; 2013
• 5 ISBT. Committee on Terminology for RBC Surface Antigens. 2016 Im Internet: http://www.isbtweb.org/working-parties/red-cell-&%236;immunogenetics-and-blood-group-terminology/ Stand: 31.03.2017
• 6 Daniels G, Reid ME. Blood groups: the past 50 years. Transfusion 2010; 50: 281-289
• 7 Tilley L, Green C, Poole J. et al. A new blood group system, RHAG: three antigens resulting from amino acid substitutions in the Rh-associated glycoprotein. Vox Sang 2010; 98: 151-159
• 8 Saison C, Helias V, Ballif BA. et al. Null alleles of ABCG2 encoding the breast cancer resistance protein define the new blood group system Junior. Nat Genet 2012; 44: 174-177
• 9 Zelinski T, Coghlan G, Liu XQ. et al. ABCG2 null alleles define the Jr(a-) blood group phenotype. Nat Genet 2012; 44: 131-132
• 10 Helias V, Saison C, Ballif BA. et al. ABCB6 is dispensable for erythropoiesis and specifies the new blood group system Langereis. Nat Genet 2012; 44: 170-173
• 11 Andolfo I, Alper SL, Delaunay J. et al. Missense mutations in the ABCB6 transporter cause dominant familial pseudohyperkalemia. Am J Hematol 2013; 88: 66-72
• 12 Storry JR, Joud M, Christophersen MK. et al. Homozygosity for a null allele of SMIM1 defines the Vel-negative blood group phenotype. Nat Genet 2013; 45: 537-541
• 13 Ballif BA, Helias V, Peyrard T. et al. Disruption of SMIM1 causes the Vel- blood type. EMBO Mol Med 2013; 5: 751-761
• 14 Cvejic A, Haer-Wigman L, Stephens JC. et al. SMIM1 underlies the Vel blood group and influences red blood cell traits. Nat Genet 2013; 45: 542-545
• 15 Yamamoto M, Cid E, Yamamoto F. Molecular genetic basis of the human Forssman glycolipid antigen negativity. Sci Rep 2012; 2: 975
• 16 Svensson L, Hult AK, Stamps R. et al. Forssman expression on human erythrocytes: biochemical and genetic evidence of a new histo-blood group system. Blood 2013; 121: 1459-1468
• 17 Anliker M, von Zabern I, Hochsmann B. et al. A new blood group antigen is defined by anti-CD59, detected in a CD59-deficient patient. Transfusion 2014; 54: 1817-1822
• 18 Daniels G, Ballif BA, Helias V. et al. Lack of the nucleoside transporter ENT1 results in the Augustine-null blood type and ectopic mineralization. Blood 2015; 125: 3651-3654
• 19 Wienzek-Lischka S, Flegel WA. Zur klinischen Bedeutung des Antigen D und seiner Varianten. Transfusionsmedizin 2016; 6: 57-64
• 20 Matassi G, Cherif-Zahar B, Pesole G. et al. The members of the RH gene family (RH50 and RH30) followed different evolutionary pathways. J Mol Evol 1999; 48: 151-159
• 21 Newton CR, Graham A, Heptinstall LE. et al. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res 1989; 17: 2503-2516
• 22 Olerup O, Zetterquist H. HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens 1992; 39: 225-235
• 23 Gassner C, Schmarda A, Nussbaumer W. et al. ABO glycosyltransferase genotyping by polymerase chain reaction using sequence-specific primers. Blood 1996; 88: 1852-1856
• 24 Lo YM, Patel P, Newton CR. et al. Direct haplotype determination by double ARMS: specificity, sensitivity and genetic applications. Nucleic Acids Res 1991; 19: 3561-3567
• 25 Hashmi G, Shariff T, Seul M. et al. A flexible array format for large-scale, rapid blood group DNA typing. Transfusion 2005; 45: 680-688
• 26 Avent ND, Martinez A, Flegel WA. et al. The Bloodgen Project of the European Union, 2003–2009. Transfus Med Hemother 2009; 36: 162-167
• 27 Delaney M, Harris S, Haile A. et al. Red blood cell antigen genotype analysis for 9087 Asian, Asian American, and Native American blood donors. Transfusion 2015; 55: 2369-2375
• 28 Lopez M, Apraiz I, Rubia M. et al. Performance evaluation study of ID CORE XT, a high throughput blood group genotyping platform. Blood Transfus 2016; DOI: 10.2450/2016.0146-16.
• 29 Drago F, Karpasitou K, Poli F. Microarray beads for identifying blood group single nucleotide polymorphisms. Transfus Med Hemother 2009; 36: 157-160
• 30 Goldman M, Nuria N, Castilho LM. An overview of the Progenika ID CORE XT: an automated genotyping platform based on a fluidic microarray system. Immunohematology 2015; 31: 62-68
• 31 Hong YJ, Chung Y, Hwang SM. et al. Genotyping of 22 blood group antigen polymorphisms and establishing a national recipient registry in the Korean population. Ann Hematol 2016; 95: 985-991
• 32 Gassner C, Meyer S, Frey BM. et al. Matrix-assisted laser desorption/ionisation, time-of-flight mass spectrometry-based blood group genotyping–the alternative approach. Transfus Med Rev 2013; 27: 2-9
• 33 Meyer S, Trost N, Frey BM. et al. Parallel donor genotyping for 46 selected blood group and 4 human platelet antigens using high-throughput MALDI-TOF mass spectrometry. Methods Mol Biol 2015; 1310: 51-70
• 34 Meyer S, Vollmert C, Trost N. et al. MNSs genotyping by MALDI-TOF MS shows high concordance with serology, allows gene copy number testing and reveals new St(a) alleles. Br J Haematol 2016; 174: 624-636
• 35 Montpetit A, Phillips MS, Mongrain I. et al. High-throughput molecular profiling of blood donors for minor red blood cell and platelet antigens. Transfusion 2006; 46: 841-848
• 36 Polin H, Danzer M, Proll J. et al. Introduction of a real-time-based blood-group genotyping approach. Vox Sang 2008; 95: 125-130
• 37 Hopp K, Weber K, Bellissimo D. et al. High-throughput red blood cell antigen genotyping using a nanofluidic real-time polymerase chain reaction platform. Transfusion 2010; 50: 40-46
• 38 Jungbauer C, Hobel CM, Schwartz DW. et al. High-throughput multiplex PCR genotyping for 35 red blood cell antigens in blood donors. Vox Sang 2012; 102: 234-242
• 39 Haer-Wigman L, Ji Y, Lodén M. et al. Comprehensive genotyping for 18 blood group systems using a multiplex ligation-dependent probe amplification assay shows a high degree of accuracy. Transfusion 2013; 53 (11 Suppl. 2): 2899-2909
• 40 Meyer S, Vollmert C, Trost N. et al. High-throughput Kell, Kidd, and Duffy matrix-assisted laser desorption/ionization, time-of-flight mass spectrometry-based blood group genotyping of 4000 donors shows close to full concordance with serotyping and detects new alleles. Transfusion 2014; 54: 3198-3207
• 41 McBean RS, Hyland CA, Flower RL. Approaches to determination of a full profile of blood group genotypes: single nucleotide variant mapping and massively parallel sequencing. Comput Struct Biotechnol J 2014; 11: 147-151
• 42 Rozman P, Dovc T, Gassner C. Differentiation of autologous ABO, RHD, RHCE, KEL, JK, and FY blood group genotypes by analysis of peripheral blood samples of patients who have recently received multiple transfusions. Transfusion 2000; 40: 936-942
• 43 Sandler SG, Flegel WA, Westhoff CM. et al. Itʼs time to phase in RHD genotyping for patients with a serologic weak D phenotype. College of American Pathologists Transfusion Medicine Resource Committee Work Group. Transfusion 2015; 55: 680-689
• 44 Swissmedic. Transfusionsmedizinische Laboruntersuchungen an Patientenproben. 2014 Im Internet: https://www.swissmedic.ch/&%236;marktueberwachung/00138/00982/ Stand: 31.03.2017
• 45 Gassner C. Blutgruppendiagnostik auf molekularer Ebene. Pipette, Offizielles Publikationsorgan der SULM 2009; Nr. 4: 9 – 12.
• 46 AGES. Hämovigilanzbericht 2014 (Österreich), Bundesamtes für Sicherheit im Gesundheitswesen AGES Medizinmarktaufsicht, Institut Überwachung. 2015 Im Internet: http://www.basg.gv.at/fileadmin/user_&%236;upload/H%25C3%25A4movigilanzbericht_2014.pdf Stand: 31.03.2017
• 47 Blutspende SRK Schweiz. Blutspende SRK Jahresbericht 2015. 2016 Im Internet: http://www.blutspende.ch/de/suche?utf8=%25E2%259C%2593&q=Blutspende+SRK+Jahresbericht+2015 Stand: 31.03.2017
• 48 Flegel WA. Red cell alloimmunisation: incidence and prevention. Lancet Haematol 2016; 3: e260-e261
• 49 Flegel WA, Gottschall JL, Denomme GA. Integration of red cell genotyping into the blood supply chain: a population-based study. Lancet Haematol 2015; 2: e282-e289
• 50 Tormey CA, Hendrickson JE. Routine non-ABO blood group antigen genotyping in sickle cell disease: the new frontier in pretransfusion testing?. Transfusion 2015; 55 (6 Pt 2): 1374-1377
• 51 Fasano RM, Chou ST. Red blood cell antigen genotyping for sickle cell disease, thalassemia, and other transfusion complications. Transfus Med Rev 2016; 30: 197-201
• 52 Hustinx H. BlutspendeSchweiz. Rare Donors – Seltene Spender – Rare donneurs. 2017 Im Internet: http://www.iblutspende.ch/rare-donors/seltene-spender.html Stand: 31.03.2017
• 53 Gowland P, Gassner C, Hustinx H. et al. Molecular RHD screening of RhD negative donors can replace standard serological testing for RhD negative donors. Transfus Apher Sci 2014; 50: 163-168
• 54 Crottet SL, Henny C, Meyer S. et al. Implementation of a mandatory donor RHD screening in Switzerland. Transfus Apher Sci 2014; 50: 169-174
• 55 BluspendeCH-SRK, SVTM. Kapitel 11B, Spendenanalytik: Blutgruppen-serologische Untersuchung an Spenderproben. 2017 Im Internet: https://sbsc-bsd.ch/dokuman2/de-de/bsd/vorschriften/kapitel.aspx Stand: 31.03.2017
• 56 Storry JR, Casthilho L, Chen Q. et al. International society of blood transfusion working party on red cell immunogenetics and terminology: report of the Seoul and London meetings. ISBT Science Series 2016; 11: 118-122
• 57 Lane WJ, Westhoff CM, Uy JM. et al. Comprehensive red blood cell and platelet antigen prediction from whole genome sequencing: proof of principle. Transfusion 2016; 56: 743-754
• 58 Fichou Y, Mariez M, Le Marechal C. et al. The experience of extended blood group genotyping by next-generation sequencing (NGS): investigation of patients with sickle-cell disease. Vox Sang 2016; 111: 418-424
• 59 Belsito A, Magnussen K, Napoli C. Emerging strategies of blood group genotyping for patients with hemoglobinopathies. Transfus Apher Sci 2016; DOI: 10.1016/j.transci.2016.11.007.