Genetic characterization of the ABO blood group in Neandertals

Background  

The high polymorphism rate in the human ABO blood group gene seems to be related to susceptibility to different pathogens. It has been estimated that all genetic variation underlying the human ABO alleles appeared along the human lineage, after the divergence from the chimpanzee lineage. A paleogenetic analysis of the ABO blood group gene in Neandertals allows us to directly test for the presence of the ABO alleles in these extinct humans.     

ABO blood group system

The accuracy of regular serum methods to detect ABO blood groups can be negatively affected by some factors, such as irregular antibodies, autoantibodies or effects of diseases leading to false or weak agglutination. This study aimed to accurately identify ambiguous ABO blood groups by serological and gene detection methods. The samples were collected in the First Affiliated Hospital of Nanjing Medical University from December 2018 to December 2019. ABO genotyping was performed by polymerase chain reaction-sequence specific primer (PCR-SSP) method in 20 samples, and ABO exons 6 and 7 or FUT1 and FUT2 genes were sequenced in 5 samples. The genes detected in the 21 specimens included 4 cases of A/B, 2 cases of A205/O01, 3 cases of A/O01, 3 cases of A/O02, 1 case of O01/O01, 1 case of O01/O02, 1 case of B/O01, 1 case of B/O02, 1 case of Bel/O01, 1 case of Cisab01/O01, 1 case of rare B/O04, 1 case of Bombay-like Bmh, 1 case of new gene showing c.261del G of exon 6, c.579 T > C of exon 7 and B new/O01. This study suggests that ABO blood group genotyping technology combined with serological typing can be used for accurately typing ambiguous blood groups.     

ABO blood group system

The ABO blood group system in humans has three different carbohydrate antigens named A, B, and O. The A antigen sequence is terminal trisaccharide N-acetylgalactosamine (GalNAc)α1-3[Fucα1-2]Galβ-, B is terminal trisaccharide Galα1-3[Fucα1-2]Galβ-, and O is terminal disaccharide Fucα1-2Galβ-. The single ABO gene locus has three alleles types A, B and O. The A and B genes code A and B glycosyltransferases respectively and O encodes an inactive enzyme. A large allelic diversity has been found for A and B transferases resulting in the genetic subgrouping of each ABO blood type. Genes for both transferases have been cloned and the 3D structure of enzymes with and without substrate has been revealed by NMR and X ray crystallography. The ABO blood group system plays a vital role in transfusion, organ and tissue transplantation, as well as in cellular or molecular therapies.     

ABO blood group system

The ABO blood group system in humans has three different carbohydrate antigens named A, B, and O. The A antigen sequence is terminal trisaccharide N-acetylgalactosamine (GalNAc)α1-3[Fucα1-2]Galβ-, B is terminal trisaccharide Galα1-3[Fucα1-2]Galβ-, and O is terminal disaccharide Fucα1-2Galβ-. The single ABO gene locus has three alleles types A, B and O. The A and B genes code A and B glycosyltransferases respectively and O encodes an inactive enzyme. A large allelic diversity has been found for A and B transferases resulting in the genetic subgrouping of each ABO blood type. Genes for both transferases have been cloned and the 3D structure of enzymes with and without substrate has been revealed by NMR and X ray crystallography. The ABO blood group system plays a vital role in transfusion, organ and tissue transplantation, as well as in cellular or molecular therapies.     

Incidence of ABO(H) blood group variants among the Bulgarian population.

The result of a screening of ABO (Hh) variants after investigating the blood group of 106,980 persons are presented. The Ax variant is registered most frequently among the Bulgarian population. As a whole the frequencies of ABO blood group variants Ax, Ael, A3, Aend and Am among the Bulgarian population are similar to that established by other authors among the French population and nearly twice as high as among the population of Bombay. The group of H-deficient phenotypes includes AA1Xh, AHm, OHm variants. Their frequency is significantly lower when compared with the frequency of AHm and OHm variants among the population of Thailand. Variants A1 and Aint with unusually high H-content are classified as A1H, A1Hint, Aint H and integrated as a category of H-excess phenotypes. Their incidence among the Bulgarian population is significantly lower than that registered among Maharastrian, South African Bantu and Indian.     

Genetic relationships between the HL-A system, the blood group systems (Rh, ABO) and the immune reactivity]

The authors examined in immunized healthy persons the correlations between the ability of immune response, the value of their different immunological parameters, and the HL-A blood-group antigens by computer analysis. Immune reactivity showed mosaic-like correlation against the HL-A system. The most definite negative correlation was noticed between the HL-A 3 and 7 antigens and the cytotoxic activity of lymphocytes. Remarkable and definite correlation was found between the Rh system and immune reactivity. The level of the natural antibodies, the immunoglobulins and the functions of lymphocytes were generally decreased in males in comparison to females.     

The structural basis for specificity in human ABO(H) blood group biosynthesis

The human ABO(H) blood group antigens are produced by specific glycosyltransferase enzymes. An N-acetylgalactosaminyltransferase (GTA) uses a UDP-GalNAc donor to convert the H-antigen acceptor to the A antigen, whereas a galactosyltransferase (GTB) uses a UDP-galactose donor to convert the H-antigen acceptor to the B antigen. GTA and GTB differ only in the identity of four critical amino acid residues. Crystal structures at 1.8-1.32 A resolution of the GTA and GTB enzymes both free and in complex with disaccharide H-antigen acceptor and UDP reveal the basis for donor and acceptor specificity and show that only two of the critical amino acid residues are positioned to contact donor or acceptor substrates. Given the need for stringent stereo- and regioselectivity in this biosynthesis, these structures further demonstrate that the ability of the two enzymes to distinguish between the A and B donors is largely determined by a single amino acid residue.     

ABO(H) blood group A and B glycosyltransferases recognize substrate via specific conformational changes

The final step in the enzymatic synthesis of the ABO(H) blood group A and B antigens is catalyzed by two closely related glycosyltransferases, an alpha-(1-->3)-N-acetylgalactosaminyltransferase (GTA) and an alpha-(1-->3)-galactosyltransferase (GTB). Of their 354 amino acid residues, GTA and GTB differ by only four "critical" residues. High resolution structures for GTB and the GTA/GTB chimeric enzymes GTB/G176R and GTB/G176R/G235S bound to a panel of donor and acceptor analog substrates reveal "open," "semi-closed," and "closed" conformations as the enzymes go from the unliganded to the liganded states. In the open form the internal polypeptide loop (amino acid residues 177-195) adjacent to the active site in the unliganded or H antigen-bound enzymes is composed of two alpha-helices spanning Arg(180)-Met(186) and Arg(188)-Asp(194), respectively. The semi-closed and closed forms of the enzymes are generated by binding of UDP or of UDP and H antigen analogs, respectively, and show that these helices merge to form a single distorted helical structure with alternating alpha-3(10)-alpha character that partially occludes the active site. The closed form is distinguished from the semi-closed form by the ordering of the final nine C-terminal residues through the formation of hydrogen bonds to both UDP and H antigen analogs. The semi-closed forms for various mutants generally show significantly more disorder than the open forms, whereas the closed forms display little or no disorder depending strongly on the identity of residue 176. Finally, the use of synthetic analogs reveals how H antigen acceptor binding can be critical in stabilizing the closed conformation. These structures demonstrate a delicately balanced substrate recognition mechanism and give insight on critical aspects of donor and acceptor specificity, on the order of substrate binding, and on the requirements for catalysis.     

ABO blood group and risk of renal cell cancer

Background: The genetic determinants of sporadic renal cell cancer (RCC) are largely unknown. Previous studies have suggested associations between ABO blood group and risk of various cancers. However, its relationship to RCC remains unclear and no prospective data are available. Methods: We prospectively followed up 77,242 women in the Nurses’ Health Study and 30,071 men in the Health Professionals Follow-Up Study from 1996 to 2008. The information on the ABO blood group was collected from participants’ self-reports in 1996. Incidence of pathology-confirmed RCC was compared using hazard ratios (HRs) and 95% confidence intervals (CIs) derived from Cox proportional hazards models. Results: During 12 years of follow-up, 163 cases of incident RCC were documented in women and 88 cases in men. The multivariate HRs between non-O blood group (combined group of A, AB, and B) vs. blood group O were 1.51 (95% CI 1.09–2.09) in women, 1.08 (95% CI 0.70–1.66) in men, and 1.32 (95% CI 0.95–1.82) in the pooled cohorts. The associations between ABO blood group and RCC were consistent across strata of known risk factors for RCC including age, obesity, smoking, and history of hypertension (Pinteraction ≥ 0.32). Conclusions: We found a suggestive non-significant association between non-O blood group and increased risk of RCC in the pooled cohorts of men and women, and this association was significant in women. Our findings need to be replicated by other prospective studies.