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Studies of Thai blood group and platelet polymorphism. Implications for malaria susceptibility.

Jongruamklang, Philaiphon LU (2020) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
The objectives of the thesis were to seek a better understanding of polymorphic RBC surface molecules in the Thai, and to investigate the role of certain blood groups in malarial invasion. MALDI-TOF MS was employed in Study I as an efficient method for genotyping to establish the common blood group and platelet antigen genotypes of 396 blood donors. Investigation of outliers identified variation among these samples, both expected and novel. The expected high prevalence of the Mi(a+) phenotype was observed, and identified that 2.3% of samples carried FY c.265T, a polymorphism carried on FY*01 instead of FY*02 as found in the Caucasians. Of potential clinical relevance in a region where transfusion-dependent thalassemia is common, we... (More)
The objectives of the thesis were to seek a better understanding of polymorphic RBC surface molecules in the Thai, and to investigate the role of certain blood groups in malarial invasion. MALDI-TOF MS was employed in Study I as an efficient method for genotyping to establish the common blood group and platelet antigen genotypes of 396 blood donors. Investigation of outliers identified variation among these samples, both expected and novel. The expected high prevalence of the Mi(a+) phenotype was observed, and identified that 2.3% of samples carried FY c.265T, a polymorphism carried on FY*01 instead of FY*02 as found in the Caucasians. Of potential clinical relevance in a region where transfusion-dependent thalassemia is common, we identified two RHCE*02 alleles known to encode an e-variant antigen. Allelic discrimination assays for extended testing of platelet polymorphism predicted the expected antigen distribution for Southeast Asia.
In Study II, homozygosity for a novel nonsense mutation (c.420T>G) in B3GALNT1 (GLOB*01N.13) was identified in two Thai sisters suffering from recurrent spontaneous abortions due to the Pk phenotype, adding to the twelve null alleles already known in the GLOB system. Screening of the blood donor cohort revealed another individual carrying this allele, suggesting regional occurrence of this rare allele.
In Study III, DNA sequencing not only confirmed that GYP*Mur is the most frequent allele of the variant glycophorin genes in Thai blood donors, but also identified a GYP*Bun-like allele (designated GYP*Thai) that was shown to be relatively common (MAF = 0.01) in this group. These hybrid alleles have a previously uncharacterized effect on s antigen expression on RBCs, qualitatively and quantitatively, that has implications for reagent selection in transfusion medicine.
Study IV turned to platelets, which showed an inhibitory effect on RBC invasion by P. falciparum under physiological platelet:RBC ratios (approx. 1:10 - 1:40) in a dose-dependent manner and that was still effective at levels considered to be thrombocytopenic. At higher platelet concentrations, the trend was reversed so that platelets did not increase the inhibitory effect on RBC invasion further. However, platelet-dependent killing, as witnessed by increased extracellular parasites, remained effective.
Despite all we know about blood group polymorphism, much remains to learn. This thesis has explored allelic variation in a region of the world where malaria has long been endemic and the observed blood cell traits highlight our intriguing ability to adapt. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor Flower, Robert, Brisbane, Australia
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Thai, Blood group polymorphism, Human platelet antigens, Malaria susceptibility, Plasmodium falciparum
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2020:63
pages
97 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
defense date
2020-05-20 13:00:00
ISSN
1652-8220
ISBN
978-91-7619-924-4
project
Blood group polymorphism and its relationship to malaria susceptibility
language
English
LU publication?
yes
id
144d8aca-f1ba-4d3c-8f10-2377284eda25
date added to LUP
2020-04-27 18:57:01
date last changed
2020-04-28 13:21:45
@phdthesis{144d8aca-f1ba-4d3c-8f10-2377284eda25,
  abstract     = {{The objectives of the thesis were to seek a better understanding of polymorphic RBC surface molecules in the Thai, and to investigate the role of certain blood groups in malarial invasion. MALDI-TOF MS was employed in Study I as an efficient method for genotyping to establish the common blood group and platelet antigen genotypes of 396 blood donors. Investigation of outliers identified variation among these samples, both expected and novel. The expected high prevalence of the Mi(a+) phenotype was observed, and identified that 2.3% of samples carried FY c.265T, a polymorphism carried on FY*01 instead of FY*02 as found in the Caucasians. Of potential clinical relevance in a region where transfusion-dependent thalassemia is common, we identified two RHCE*02 alleles known to encode an e-variant antigen. Allelic discrimination assays for extended testing of platelet polymorphism predicted the expected antigen distribution for Southeast Asia. <br>
In Study II, homozygosity for a novel nonsense mutation (c.420T&gt;G) in B3GALNT1 (GLOB*01N.13) was identified in two Thai sisters suffering from recurrent spontaneous abortions due to the Pk phenotype, adding to the twelve null alleles already known in the GLOB system. Screening of the blood donor cohort revealed another individual carrying this allele, suggesting regional occurrence of this rare allele.<br>
In Study III, DNA sequencing not only confirmed that GYP*Mur is the most frequent allele of the variant glycophorin genes in Thai blood donors, but also identified a GYP*Bun-like allele (designated GYP*Thai) that was shown to be relatively common (MAF = 0.01) in this group. These hybrid alleles have a previously uncharacterized effect on s antigen expression on RBCs, qualitatively and quantitatively, that has implications for reagent selection in transfusion medicine.<br>
Study IV turned to platelets, which showed an inhibitory effect on RBC invasion by P. falciparum under physiological platelet:RBC ratios (approx. 1:10 - 1:40) in a dose-dependent manner and that was still effective at levels considered to be thrombocytopenic. At higher platelet concentrations, the trend was reversed so that platelets did not increase the inhibitory effect on RBC invasion further. However, platelet-dependent killing, as witnessed by increased extracellular parasites, remained effective.<br>
Despite all we know about blood group polymorphism, much remains to learn. This thesis has explored allelic variation in a region of the world where malaria has long been endemic and the observed blood cell traits highlight our intriguing ability to adapt.}},
  author       = {{Jongruamklang, Philaiphon}},
  isbn         = {{978-91-7619-924-4}},
  issn         = {{1652-8220}},
  keywords     = {{Thai; Blood group polymorphism; Human platelet antigens; Malaria susceptibility; Plasmodium falciparum}},
  language     = {{eng}},
  number       = {{2020:63}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Studies of Thai blood group and platelet polymorphism. Implications for malaria susceptibility.}},
  url          = {{https://lup.lub.lu.se/search/files/78945059/dokumentdatablad_Philaiphon_J.pdf}},
  year         = {{2020}},
}