A systematic study of single‐nucleotide polymorphisms in the <scp>A</scp>4<scp>GALT</scp> gene suggests a molecular genetic basis for the <scp>P</scp>1/<scp>P</scp>2 blood groups

Lai, Yung-Chih; Wu, Wan-Yi; Yang, Chih‐Hsiang; Yang, Lirong; Chu, Chen-Chung; Chan, Yuan-Li; Lin, Marie C.; Yu, Lung‐Chih

doi:10.1111/trf.12771

Cited by 20 publications

(36 citation statements)

References 29 publications

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“…Although the combined frequency and serologic approach for P1 expression identified four NT changes, this could simply be due to linkage disequilibrium, which, in theory, could be addressed with a larger sample size. Indeed, a recent publication identified these same four NT changes associated with P1, but one (rs66781836) was later excluded in an uncommon sample with haplotype recombination between the possible NT changes . To optimize exclusion among strongly linked SNPs, mining of large‐scale genomic data sources for examples where one or more of the linked NT changes occur independently and performing targeted follow‐up serologic typing could be employed.…”

Section: Discussionmentioning

confidence: 99%

“…In 2001, it was shown that A4GALT encodes a 4‐α‐galactosyltransferase enzyme, which adds α‐galactose to paragloboside to create the P1 antigen . In 2011 and 2014, it was reported that the single‐nucleotide polymorphisms (SNPs) designated rs8138197, rs2143918, and rs5751348 correlated with P1+/P1– expression, but the mechanism remained unknown. There was uncertainty as to the actual SNP responsible, but recently Westman et al showed that SNP rs5751348 (NT G > T) is located in a RUNX1 transcription factor binding region that controls the expression of P1 with chromosomal location chr22:43,113,793G associated with the P1+ phenotype and chr22:43,113,793 T with P1–.…”

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confidence: 99%

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A whole genome approach for discovering the genetic basis of blood group antigens: independent confirmation for P1 and Xg^a

et al. 2018

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BACKGROUND Although P1 and Xga are known to be associated with the A4GALT and XG genes, respectively, the genetic basis of antigen expression has been elusive. Recent reports link both P1 and Xga expression with nucleotide changes in the promotor regions and with antigen‐negative phenotypes due to disruption of transcription factor binding. STUDY DESIGN AND METHODS Whole genome sequencing was performed on 113 individuals as part of the MedSeq Project with serologic RBC antigen typing for P1 (n = 77) and Xga (n = 15). Genomic data were analyzed by two approaches, nucleotide frequency correlation and serologic correlation, to find A4GALT and XG changes associated with P1 and Xga expression. RESULTS For P1, the frequency approach identified 29 possible associated nucleotide changes, and the serologic approach revealed four among them correlating with the P1+/P1– phenotype: chr22:43,115,523_43,115,520AAAG/delAAAG (rs66781836); chr 22:43,114,551C/T (rs8138197); chr22:43,114,020 T/G (rs2143918); and chr22:43,113,793G/T (rs5751348). For Xga, the frequency approach identified 82 possible associated nucleotide changes, and among these the serologic approach revealed one correlating with the Xg(a+)/Xg(a–) phenotype: chrX:2,666,384G/C (rs311103). CONCLUSION A bioinformatics analysis pipeline was created to identify genetic changes responsible for RBC antigen expression. This study, in progress before the recently published reports, independently confirms the basis for P1 and Xga. Although this enabled molecular typing of these antigens, the Y chromosome PAR1 region interfered with Xga typing in males. This approach could be used to identify and confirm the genetic basis of antigens, potentially replacing the historical approach using family pedigrees as genomic sequencing becomes commonplace.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

A whole genome approach for discovering the genetic basis of blood group antigens: independent confirmation for P1 and Xg^a

et al. 2018

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“…For each genetic marker, we established PCR-SSP methods according to a standard protocol [23] and with primers listed in table 1. The A4GALT SNP rs2143918 has a 100% correlation with the P 1 /P 2 phenotype in all populations, except for rare individuals of African descent [24]. This SNP was addressed for P genotyping.…”

Section: Methodsmentioning

confidence: 99%

Towards a Regional Registry of Extended Typed Blood Donors: Molecular Typing for Blood Group, Platelet and Granulocyte Antigens

Portegys

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Bloos

et al. 2018

Transfus Med Hemother

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Background: The provision of compatible blood products to patients is the most essential task of transfusion medicine. Besides ABO and Rh, a number of additional blood group antigens often have to be considered for the blood supply of immunized or chronically transfused patients. It also applies for platelet antigens (HPA) and neutrophil antigens (HNA) for patients receiving platelet or granulocyte concentrates. Here, we describe the molecular screening for a number of blood group, HPA, and HNA alleles. Based on the screening results we are building up a regional blood donor registry to provide extended matched blood products on demand. Methods: We developed and validated TaqMan™ PCR and PCR-SSP methods for genetic markers defining 37 clinically relevant blood group antigens (beyond ABO and Rh), 10 HPA, and 11 HNA. Furthermore, we describe a feasible method for fast molecular screening of the HNA-2^null phenotype. All data were statistically evaluated regarding genotype distribution. Allele frequencies were compared to ExAC data from non-Finnish Europeans. Results: Up to now more than 2,000 non-selected regular blood donors in south-west Germany have been screened for blood group, HPA, and HNA alleles. The screening results were confirmed by serology and PCR-SSP methods for selected numbers of samples. The allele frequencies were similar to non-finnish Europeans in the ExAC database except for the alleles encoding the S, HPA-3b and HNA-4b antigens, with significantly lower prevalence in our cohort, as well as the LU14 and the HNA-3b antigens, with a higher frequency compared to the ExAC data. We identified 71 donors with rare blood groups such as Lu(a+b-), Kp(a+b-), Fy(a-b-) and Vel-, and 169 donors with less prevalent HPA or HNA types. Conclusion: Molecular screening for blood group alleles by using TaqMan™ PCR is an effective and reliable high-throughput method for establishing a rare donor registry.

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“…Despite several attempts, the molecular background of the P1PK blood group system is still not fully elucidated. Several authors have shown that the expression levels of A4GALT mRNA is higher in P 1 than in P 2 , and there is a general agreement that the upregulated transcript may cause increased production of Gb3/CD77 synthase [18–20]. However, despite finding several SNPs associated with P 1 /P 2 status, no credible mechanism for allelic variation in A4GALT gene expression has been proposed.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of an amino acid residue critical for the specificity and activity of human Gb3/CD77 synthase

et al. 2016

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Human Gb3/CD77 synthase (α1,4-galactosyltransferase) is the only known glycosyltransferase that changes acceptor specificity because of a point mutation. The enzyme, encoded by A4GALT locus, is responsible for biosynthesis of Gal(α1–4)Gal moiety in Gb3 (CD77, Pk antigen) and P1 glycosphingolipids. We showed before that a single nucleotide substitution c.631C > G in the open reading frame of A4GALT, resulting in replacement of glutamine with glutamic acid at position 211 (substitution p. Q211E), broadens the enzyme acceptor specificity, so it can not only attach galactose to another galactose but also to N-acetylgalactosamine. The latter reaction leads to synthesis of NOR antigens, which are glycosphingolipids with terminal Gal(α1–4)GalNAc sequence, never before described in mammals. Because of the apparent importance of position 211 for enzyme activity, we stably transfected the 2102Ep cells with vectors encoding Gb3/CD77 synthase with glutamine substituted by aspartic acid or asparagine, and evaluated the cells by quantitative flow cytometry, high-performance thin-layer chromatography and real-time PCR. We found that cells transfected with vectors encoding Gb3/CD77 synthase with substitutions p. Q211D or p. Q211N did not express Pk, P1 and NOR antigens, suggesting complete loss of enzymatic activity. Thus, amino acid residue at position 211 of Gb3/CD77 synthase is critical for specificity and activity of the enzyme involved in formation of Pk, P1 and NOR antigens. Altogether, this approach affords a new insight into the mechanism of action of the human Gb3/CD77 synthase.

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A systematic study of single‐nucleotide polymorphisms in the A4GALT gene suggests a molecular genetic basis for the P₁/P₂ blood groups

Abstract: The results of this investigation demonstrate a consistent association of A4GALT SNPs rs2143918 and rs5751348 with the P1/P2 phenotypes and suggest that SNP rs5751348 may lead to allelic variations in A4GALT gene expression and consequently leads to the formation of the P1/P2 phenotypes.

Cited by 20 publications

References 29 publications

A whole genome approach for discovering the genetic basis of blood group antigens: independent confirmation for P1 and Xg^a

A whole genome approach for discovering the genetic basis of blood group antigens: independent confirmation for P1 and Xg^a

Towards a Regional Registry of Extended Typed Blood Donors: Molecular Typing for Blood Group, Platelet and Granulocyte Antigens

Evaluation of an amino acid residue critical for the specificity and activity of human Gb3/CD77 synthase

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A systematic study of single‐nucleotide polymorphisms in the A4GALT gene suggests a molecular genetic basis for the P1/P2 blood groups

Abstract: The results of this investigation demonstrate a consistent association of A4GALT SNPs rs2143918 and rs5751348 with the P1/P2 phenotypes and suggest that SNP rs5751348 may lead to allelic variations in A4GALT gene expression and consequently leads to the formation of the P1/P2 phenotypes.

Cited by 20 publications

References 29 publications

A whole genome approach for discovering the genetic basis of blood group antigens: independent confirmation for P1 and Xga

A whole genome approach for discovering the genetic basis of blood group antigens: independent confirmation for P1 and Xga

Towards a Regional Registry of Extended Typed Blood Donors: Molecular Typing for Blood Group, Platelet and Granulocyte Antigens

Evaluation of an amino acid residue critical for the specificity and activity of human Gb3/CD77 synthase

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A systematic study of single‐nucleotide polymorphisms in the A4GALT gene suggests a molecular genetic basis for the P₁/P₂ blood groups

A whole genome approach for discovering the genetic basis of blood group antigens: independent confirmation for P1 and Xg^a

A whole genome approach for discovering the genetic basis of blood group antigens: independent confirmation for P1 and Xg^a