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Genetic Characterisation of Human ABO Blood Group Variants with a Focus on Subgroups and Hybrid Alleles

Hosseini Maaf, Bahram LU (2007) In 2007 39.
Abstract
ABO is the most important blood group system in transfusion medicine and transplantation immunology. The ABO blood groups differ by the presence or absence of antigens on RBCs and antibodies in plasma. Accurate determination of ABO status is critical. Genomic typing can increase the precision of blood group determination in complicated cases, e.g. when variant expression of A or B antigen is encountered.



The overall aim of this study was to compare the molecular diversity of ABO alleles with various phenotypes, and to contribute to our knowledge of the ABO gene and encoded glycosyltransferases.



Novel alleles (six Aweak, eleven Bweak, seven O) were identified containing single-point mutations.... (More)
ABO is the most important blood group system in transfusion medicine and transplantation immunology. The ABO blood groups differ by the presence or absence of antigens on RBCs and antibodies in plasma. Accurate determination of ABO status is critical. Genomic typing can increase the precision of blood group determination in complicated cases, e.g. when variant expression of A or B antigen is encountered.



The overall aim of this study was to compare the molecular diversity of ABO alleles with various phenotypes, and to contribute to our knowledge of the ABO gene and encoded glycosyltransferases.



Novel alleles (six Aweak, eleven Bweak, seven O) were identified containing single-point mutations. Structure/function studies explained the weakening of some B subgroup glycosyltransferases. Two new hybrid Ax alleles were characterised. Analysis of introns 2-5 revealed 44 previously unknown, allele-related polymorphisms that proved valuable allelic markers. These findings enabled localisation of cross-over regions in two other new hybrids: 1) an O1v allele fused with an A2 allele, 2) the novel O1bantu-A2 combination that explained the Abantu phenotype. Phylogenetic and population analyses indicated that O1bantu is a unique and distinct evolutionary lineage so far only found among individuals of African descent.



Of clinical importance, a new approach to ABO genotyping was developed that identifies all common alleles, most null and weak A/B subgroups as well as hybrid alleles resulting from recombinational crossing-over events.



In summary, 30 novel alleles were identified and characterized, representing 30% of all alleles reported since the start of this study in 2001. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Karl Landsteiner upptäckte blodgruppssystemet ABO och beskrev principen för den antigen-antikroppsreaktion som gäller än idag. För att utföra en säker blodtransfusion krävs det att individens ABO-blodgrupp är känd och därefter kan passande givarblod transfunderas.



A- och B-generna ger upphov till enzymen A- respektive B-transferas. Blodgrupp O beror på olika defekter som orsakar ett inaktivt enzym. Det finns även ett stort antal undergrupper inom A/B-blodgrupperna som uppvisar svagare reaktioner vid försök till blodgruppering. Olika mutationer, d.v.s. ärftliga och bestående förändringar i cellens genetiska material, har upptäckts i ABO-genen. Dessa mutationer kan leda till... (More)
Popular Abstract in Swedish

Karl Landsteiner upptäckte blodgruppssystemet ABO och beskrev principen för den antigen-antikroppsreaktion som gäller än idag. För att utföra en säker blodtransfusion krävs det att individens ABO-blodgrupp är känd och därefter kan passande givarblod transfunderas.



A- och B-generna ger upphov till enzymen A- respektive B-transferas. Blodgrupp O beror på olika defekter som orsakar ett inaktivt enzym. Det finns även ett stort antal undergrupper inom A/B-blodgrupperna som uppvisar svagare reaktioner vid försök till blodgruppering. Olika mutationer, d.v.s. ärftliga och bestående förändringar i cellens genetiska material, har upptäckts i ABO-genen. Dessa mutationer kan leda till minskning av enzymaktivitet och följaktligen till en minskning av antalet antigen på erytrocyterna.



Denna avhandling är en fördjupad studie av de bakomliggande orsakerna till och konsekvenser av den överraskande mångfald av mutationer som ses i ABO-genen.



De fem första artiklarna klargjorde den molekylärgenetiska bakgrunden och blodgruppsolikheter med fokus på svaga ABO-blodgrupper. Nya punktmutationer, både s.k. missense och nonsense-mutationer identifierades, sammanlagt klargjordes den genetiska bakgrunden hos 17 nya undergrupper inom ABO-systemet. Dessutom hittades tre olika hybridalleler varav en visade att en fusion av en vanlig O-allel (O1v) och en vanlig A2-allel hade bildats. En annan hybridbildning visades hos den välkända ABO-undergruppen Abantu: denna gång mellan den vanliga A2-allelen och en aldrig tidigare beskriven O-allel (O1bantu) som utgör en helt egen evolutionär utvecklingslinje inom ABO-allelfamiljen. Den tredje visade sig vara en hybrid mellan B-O1v-B. Sju nya O-alleler i ABO-genen identifierades, något som kan få stor betydelse för säkerheten vid genetisk blodgruppering. Analys av enzymaktivitet, datormodellering och röntgenkristallografi visade att de nya mutationerna med stor sannolikheten är orsaken till de svaga reaktioner som observerades vid serologiska undersökningar.



Genetiska metoder finner allt fler applikationer inom det transfusionsmedicinska fältet.



Att detektera komplexa alleler är viktigt när blodgivare och/eller -mottagares prover ger svårtolkade resultat vid blodgruppering. Vi har utvecklad en ny metod vilket kan detektera de allt fler ABO-allelerna med hjälp av en DNA-baserad analys vilket kommer att vara ett komplement till de serologiska undersökningarna. Detta kan minska risken för falska provsvar, som skulle kunna leda till felaktiga konklusioner och transfusionsrekommendationer.



Sammanfattningsvis har studierna i denna avhandling lett till upptäckten av 30 nya alleler, vilket innefattar 30 % av alla alleler som har publicerats sedan 2001, samt till en bättre förståelse kring de funktionella och genetiska sambanden inom ABO-systemet. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Påhlsson, Peter, Linköping
organization
publishing date
type
Thesis
publication status
published
subject
keywords
glycosyltransferase, SNP, computer modelling, ABO genotyping, Immunology, serology, hybrid, Blood group ABO, transplantation, subgroup, Immunologi, serologi, rare O allele
in
2007
volume
39
pages
191 pages
publisher
Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University
defense location
Segerfalksalen, Wallenberg Neurocentrum, BMC, Sölvegatan 17, Lund
defense date
2007-03-16 09:00:00
ISSN
1652-8220
ISBN
978-91-85559-16-9
language
English
LU publication?
yes
additional info
L. Martin Olsson, Nidal M. Irshaid, Bahram Hosseini-Maaf, Åsa Hellberg, Marilyn K Moulds, Hannele Sareneva and M. Alan Chester. 2001. Genomic analysis of clinical samples with serological ABO blood grouping discrepancies:Identification of 15 novel A and B subgroup alleles Blood, vol 98 pp 1585-1593.
Bahram Hosseini-Maaf, Åsa Hellberg, Maria J Rodrigues, M. Alan Chester and L. Martin Olsson. 2003. ABO exon and intron analysis in individuals with the AwB phenotype reveals a novel O1v-A2 hybrid allele that causes four missense mutations in the A transferase BMC Genetic, vol 4 pp 11 pages.
Bahram Hosseini-Maaf, Nidal M. Irshaid, Åsa Hellberg, Thomas Wagner, Cyril Levene, Hein Hustinx, Rudi Steffensen, M. Alan Chester and L. Martin Olsson. 2005. New and unusual O alleles at the ABO locus are implicated in unexpected blood group phenotypes Transfusion, vol 45 pp 70-81.
Bahram Hosseini-Maaf, Elizabeth Smart, M. Alan Chester and L. Martin Olsson. 2005. The Abantu phenotype in the ABO blood group system is due to a splice-site mutation in a hybrid between a new O1-like allelic lineage and the A2 allele Vox Sanguinis, vol 88 pp 256-264.
Bahram Hosseini-Maaf, James A Letts, Mattias Persson, Elizabeth Smart, Pierre-Yves LePennec, Hein Hustinx, Zhihon Zhao, Monica M Palcic, Stephen V Evans, M. Alan Chester and L. Martin Olsson. . Structural basis for red cell phenotypic changes in newly-identified, naturally-occurring subgroup mutants of the human blood group B glycosyltransferase Transfusion, (inpress)
Bahram Hosseini-Maaf, Åsa Hellberg, M. Alan Chester and L. Martin Olsson. . An Extensive PCR-ASP Strategy for Clinical ABO Blood Group Genotyping that Avoids Potential Errors Caused by Null, Subgroup and Hybrid Alleles (submitted)
id
5819bb24-235e-4fed-b0b3-f2df9a9dd96d (old id 548187)
date added to LUP
2016-04-01 16:23:25
date last changed
2025-04-04 14:14:18
@phdthesis{5819bb24-235e-4fed-b0b3-f2df9a9dd96d,
  abstract     = {{ABO is the most important blood group system in transfusion medicine and transplantation immunology. The ABO blood groups differ by the presence or absence of antigens on RBCs and antibodies in plasma. Accurate determination of ABO status is critical. Genomic typing can increase the precision of blood group determination in complicated cases, e.g. when variant expression of A or B antigen is encountered.<br/><br>
<br/><br>
The overall aim of this study was to compare the molecular diversity of ABO alleles with various phenotypes, and to contribute to our knowledge of the ABO gene and encoded glycosyltransferases.<br/><br>
<br/><br>
Novel alleles (six Aweak, eleven Bweak, seven O) were identified containing single-point mutations. Structure/function studies explained the weakening of some B subgroup glycosyltransferases. Two new hybrid Ax alleles were characterised. Analysis of introns 2-5 revealed 44 previously unknown, allele-related polymorphisms that proved valuable allelic markers. These findings enabled localisation of cross-over regions in two other new hybrids: 1) an O1v allele fused with an A2 allele, 2) the novel O1bantu-A2 combination that explained the Abantu phenotype. Phylogenetic and population analyses indicated that O1bantu is a unique and distinct evolutionary lineage so far only found among individuals of African descent.<br/><br>
<br/><br>
Of clinical importance, a new approach to ABO genotyping was developed that identifies all common alleles, most null and weak A/B subgroups as well as hybrid alleles resulting from recombinational crossing-over events.<br/><br>
<br/><br>
In summary, 30 novel alleles were identified and characterized, representing 30% of all alleles reported since the start of this study in 2001.}},
  author       = {{Hosseini Maaf, Bahram}},
  isbn         = {{978-91-85559-16-9}},
  issn         = {{1652-8220}},
  keywords     = {{glycosyltransferase; SNP; computer modelling; ABO genotyping; Immunology; serology; hybrid; Blood group ABO; transplantation; subgroup; Immunologi; serologi; rare O allele}},
  language     = {{eng}},
  publisher    = {{Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University}},
  school       = {{Lund University}},
  series       = {{2007}},
  title        = {{Genetic Characterisation of Human ABO Blood Group Variants with a Focus on Subgroups and Hybrid Alleles}},
  url          = {{https://lup.lub.lu.se/search/files/4658560/548189.pdf}},
  volume       = {{39}},
  year         = {{2007}},
}