ABO and Secretor Blood Group Genetics
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Published: Mon, 04 Jun 2018
The secretor factor (Se) might be considered either a physiologic trait or an honorary blood group. The individual who is a so-called secretor has demonstrable ABH blood group antigen in the saliva and other body fluids; the nonsecretor does not. Secretor is dominant.
Genetically independent of the ABO blood groups is the secretor system which comprises two allelomorphic genes, (Se) which causes secretion in saliva and other fluids of the antigen or antigens corresponding to the individual’s ABO group, and (se) which, in the homozygous condition determines non-secretion. Heterozygotes are secretors. There are wide variations in the frequencies of the two genes, which could therefore be of considerable anthropological value. Also the secretor and non-secretor states have significant associations with certain diseases. Natural selection is therefore thought to be of considerable importance in determining the frequencies of the genes.
The Se and se genes of the ABH secretor system vary widely in frequency in different populations, but our knowledge of their distribution is incomplete and patchy. In particular the Se gene has a very high frequency in American Indians and apparently a low one in southern India. The system shows well-defined associations with certain diseases and there are indications that it is involved in major processes of natural selection.
Secretor function centers around the action of a cluster of genes which control the production of enzymes called ‘fucosyltransferases’. The genes are called ‘FUT’ and are numbered 1-7. The majority of these are on chromosome number 19 (19q13.3). These enzymes help assemble thefucose strings which then become the H antigen, or are further glycosylated to A and/or B antigens.
Chromosome 19 does most of the secretor work. It carries the the code for FUT1 and FUT2(fucosytransferase enzymes) of which the ‘null allele’ on FUT2 codes for ‘non-secretor’ status. FUT2 codes for fucosyltransferase activity in body exocrine (a type of gland) tissues, which then makes you a secretor, since you are pumping blood type antigens into your secretions.
Many of the FUT genes are intimately involved in the development of the embryo, a fact which helps explain why many people feel that the primary function of ABO antigens are to act as a scaffold in our inter-uterine life.
One of the genes, FUT4, is found on chromosome 11. It appears non-lethal as mice bred to not have it appear healthy. It apparently has something to do with the effects of ABO in bone marrow.
Recently, a new fucosyltransferase gen, FUT7, has been linked to 9q34 (the ABO blood type locus). Tissue distribution of FUT7 is very restricted to leukocytes and high endothelial (blood vessel) cells, and plays a critical role in the function of selectins (tissue specific lectins involved in the migration of white blood cells to areas of infection or tissue damage.) Thus the body itself uses ABO and internal lectins to help target the immune system.
Functional and Genetic Factors Involved in ABH Secretion
ABH secretion is controlled by two alleles, Seand se. Se is dominant and se is recessive (or amorphic). Approximately 80% of people are secretors (SeSe or Sese).
In the most rudimentary sense, the secretor gene (FUT2 at 19q13.3) codes for the activity of the glycosyltransferases needed to assemble aspects of both the ABO and Lewis blood groups. This it does in concert with the gene for group O, or H (FUT1). These enzymes are then active in places like goblet and mucous gland cells, resulting in the presence of the corresponding antigens in body fluids.(1)
The H antigens are indirect gene products expressed as fucose-containing glycan units, residing on glycoproteins or glycolipids of erythrocyte membranes or on mucin glycoproteins in secretions and are the fucosylated glycans substrates for glycosyltransferases that give rise to the epitopes for the A , B and Lewis blood group antigens. The major difference between the two genes is in their pattern of expression: the FUT1 (H) gene is expressed predominantly in erythroid tissues giving rise to FUT1 (H enzyme) whose products reside on erythocytes, whereas the FUT2 (Secretor) gene is expressed predominantly in secretory tissues giving rise to FUT2 (Secretor enzyme) and to products that reside on mucins in secretions.
When alleles of both genes fail to express active enzymes, individuals bearing them, in homozygous state, lack the substrates for the A or B glycosyltransferases and do not express the A and B epitopes.
ABO and Secretor Blood group Genetics
Glycosphingolipids carrying A or B oligosaccharides are integral parts of the membranes of RBCs, epithelial and endothelial cells; they are also present in soluble form in plasma. Glycoproteins that carry identical oligosaccharides are responsible for the A and B activity of secreted body fluids such as saliva. A and B oligosaccharides that lack carrier protein or lipid molecules are found in milk and urine.
Genes at three separate loci (ABO, Hh, and Sese) control the occurrence and the location of the A and B antigens. Three common alleles -A, B and O- are located at the ABO locus on chromosome9q34. The A and B genes encode Glycosyltransferases that produce the A and B antigens, respectively. The O gene is considered to be amorphic since no detectable blood group antigen results from its action. The RBCs of group O persons lack A and B, but carry an abundant amount of H antigen because this antigen is the precursor material on which A and B antigens are built.
Family studies have shown that the genes at the remaining two loci, Hh and Sese (secretor), are closely linked. The chromosome on which they are located has not yet been identified. It is suggested that one of these loci may have arisen through gene duplication of the other. Two recognized alleles reside at each locus. Of the two alleles at the H locus, one of these, H, produces an enzyme that acts at the cellular level to construct the antigen on which A or B are built. The other allele at this locus, h, is very rare. No antigenic product has been linked to h, so this gene is also considered an amorph. The possibility exists that other alleles occur at the Hh locus that differ from H in that they cause the production of only very small amounts of H antigen.
The Sese gene is directly responsible for the expression of H (and indirectly responsible for the expression of A and B) on the glycoproteins in epithelial secretions such as saliva. Eighty percent of the population are secretors because they have inherited the Se gene and produce H in their secretions that can be converted to A and/or B (depending on the genetic background of thesecretor). The se gene, having no demonstrable product, is an Amorph.
Oligosaccharide chains on which the A and B antigens are built can exist as simple structures of a few sugar molecules linked together in linear fashion. They can also exist as more complex structures that are composed of many sugar residues connected together in branching chains. It has been proposed that the differences in cellular A, B and H activity seen between specimens from infants and adults may be related to the number of branched structures carried on the cellular membranes of each group. The RBCs of infants are thought to carry A, B and H antigens built predominantly on linear oligosaccharides. Linear oligosaccharides have only one terminus to which the H, then A and B, sugars can be added. In contrast, the RBCs of adults appear to carry a high proportion of branched oligosaccharides. Branching creates additional portions on the oligosaccharide that can be converted to H and then to A and B antigens.
A and B genes do not produce antigens directly but instead produce enzymes calledglycosyltransferases that add specific sugars to oligosaccharide chains that have been converted to H by the action of the H gene. H antigens are constructed on precursor oligosaccharide chain endings called Type 1 and Type 2. The number 1 carbon of the terminal 6-carbon sugar b-D-galactose (Gal) is linked to the number 3 carbon of subterminal N-acetyl-glucosamine (GlcNAc) in Type 1 chains and to the number 4 carbon of GlcNAc in Type 2 chains. Blood group-activeglycoproteins present on cell surfaces or in body fluids carry either Type 1 or Type 2 chains.Glycosphingolipids present in the plasma and those on the membranes of most glandular and parenchymal cells also have either Type 1 or Type 2 chain endings. In contrast, the glycolipidantigens produced by the RBCs; appear to be formed exclusively of Type 2 chains. These chains are carried on a class of glycosphingolipids called paraglobosides.
At the cellular level, the H gene transferase produces a Fucosyltransferase? that adds fucose (Fuc) in alpha (1-2) linkage to the terminal Gal of Type 2 chains. The A and B gene transferases can only attach their immunodominant sugars when the Type 2 (or Type 1) chains have been substituted with Fuc (ie, changed to H) thus, the A and B antigens are constructed at the expense of H. The A gene-specified N-acetyl-galactosaminyl-transferase and the B gene-specified galactosaminyl-transferase add GalNAc and Gal respectively in alpha (1-3) linkages to the same Gal acted on by the H gene transferase.
The alleles at the ABO locus that result in subgroups (phenotypes of A and B that differ from each other with respect to the amount of A or B carried on the RBCs) produce transferases that differ from one another in their ability to convert H antigen. The O gene is thought to produce a protein that can be detected immunologically but has no detectable transferase activity. As a consequence, the RBCs of group O persons carry readily detectable, unconverted H antigen. The secretion of Sese persons contain Type I and Type 2 chains with no H, A or B activity. It has been suggested that the H and Se genes each encode a different Fucosyltransferase. The enzyme produced by H acts primarily on Type 2 chains and in RBC membranes. That produced by Se prefers (but does not limit its action to) Type 1 chains and acts primarily in the secretory. Studies performed on the secretions of persons with the rare Oh phenotype support the concept that two types of H antigen exist. Persons of this phenotype, who are genetically Hh and Sese, have no H and therefore, no A or B antigens on their RBCs or in their secretions. However, H, A and B antigens are found in the secretions of genetically hh persons, who, through family studies, appear to possess at least one Se gene.
The ABO gene codes for the glycosyltransferases that transfer specific sugar residues to H substance, resulting in the formation of blood group A and B antigens. This gene maps to chromosome 9, position 9q34.1-q34.2. It consists of 7 exons, ranging in size from 28 to 688 base pairs (bp), and 6 introns with 554 to 12 982 bp (Figure 1).1-3 The last 2 exons (6 and 7), which comprise 823 of 1062 bp of the transcribed mRNA, encode for the catalytic domain of ABO glycosyltransferases.
Figure 1. Schematic representation of the genomic organization of the ABO gene. The exons (black squares) and regulatory regions (clear squares) are drawn to scale, as are the intervening introns, although the scale of the latter is 10 times smaller. The calculated numbers of nucleotides (nts) in the exons and introns are shown. The upstream regulatory region, which includes a CBF/NF-Y binding motif, is located around nt -3800 and, depending on the ABOhaplotype, 215 or 344 base pairs (bp) in size; the regulatory region in the 5′ untranslated region (UTR) is located from nt -118 to -1.
The 6 common ABO alleles in white individuals are ABO*A101 (A1), ABO*A201 (A2), ABO*B101 (B1), ABO*O01 (O1), ABO*O02 (O1v), and ABO*O03 (O2). In exons 6 and 7 they differ by only a few base positions. ABO*A201, which is responsible for blood group A2, is identical to ABO*A101 apart from a nonsynonymous substitution at nucleotide (nt) position 467 and a single deletion (1060delC) in exon 7. This deletion results in disruption of the stop codon and an A-transferase product with an extra 21 amino acid (AA) residue at the C-terminus. ABO*B101 is distinguishable from ABO*A101 at 7 nt positions: 3 synonymous mutations at positions 297, 657, and 930; and 4 nonsynonymous mutations at positions 526, 703, 796, and 803. The nt sequence of ABO*O01 differs from that of ABO*A101 by a single base deletion at position 261 in exon 6; this deletion shifts the reading frame, thus generating a premature stop codon. ABO*O01 is thought to be either silent or translated into a truncated and catalytically inactive peptide. In contrast, the ABO*O03 allele lacks the 216delG polymorphism but possesses nonsynonymous mutations that may abolish the protein’s enzyme activity by altering the nt sugar binding site.
Eighty-three ABO alleles discriminated at 52 polymorphic sites within the coding region of the ABO gene have been reported in the literature so far. In most cases the investigators analyzed only exons 6 and 7. The number of described ABO alleles increases to 88 when nt differences within intron 6 are also considered. It has been shown that studies of the nt sequence of intron 6 are crucial for elucidation of the origin of some novel haplotypes. To our knowledge, there is no information available on sequence variation of the noncoding regions upstream from exon 6 and little data on mutations within the first 5 exons of the ABO gene and their relevance for the ABO phenotypes.14 In the present study, we therefore examined the complete exon/intron sequences (except for the huge intron 1 comprising 12 982 bp) and 2 regulatory regions of common and rare ABO alleles to evaluate the genetic diversity and diversification at the ABO locus. The genomic sequence data were first correlated with the associated ABO phenotypes then used for lineage definition.
The presence of a large number of recurrent mutations is characteristic for the considerable diversity of the ABO gene. Phenotype-genotype correlation revealed that an extensive heterogeneity underlies the molecular basis of various alleles that generate serologic ABO subgroups. ABO sequence variations also include phenotypically relevant replacement mutations in exons 2 to 5. Thus, ABO genotyping strategies would have to consider all variations distributed across the entire coding region to achieve safe phenotype prediction. Therefore, ABO genotyping remains mainly reserved as a complement to serology for determination of inherited ABO subgroups and exclusion of ABO*B allele markers in the acquired B phenotype. The data on highly conserved and lineage-specific intron sequence motifs provide a powerful base for elucidating the origin of variant ABO alleles and may prove valuable for anthropologic studies on the origins and movements of populations.
In a cohort of asthmatic children, we have recently shown that the ABO-secretor genetic complex influences susceptibility to asthma in children. Since previous studies have shown an association of asthma with adenosine deaminase (ADA) genotype 2, we have searched for possible interactions between the two systems concerning their effects on susceptibility to asthma in children. The sample study has been described in a previous paper 1 and was composed of 165 children, 109 males and 56 females, aged from 1 month-15â€…yrs. The criterion for inclusion in the study was the occurrence of two or more episodes of wheezing in the last 6 months, irrespective of aetiology/pathogenesis of the attack.
A consecutive series of 362 newborn infants from the same Caucasian population in Rome, Italy, was used as the control sample.
The proportion of nonsecretor/O subjects with the ADA*1/*1 genotype was much higher in asthmatic children than in controls. On the contrary, the proportion of subjects with other phenotypes of secretor-ABO complex carrying the ADA*2 allele was much lower in asthmatic children than in controls. The other two phenotypic categories showed a similar proportion in asthmatic children and controls.
The lack of three-way interaction among secretor/ABO complex, ADA and disease (tableâ€…2⇓), suggests that ADA does not influence the effect of the secretor-ABO complex and vice versa, thus indicating that there was not an epistatic effect. On the contrary, the analysis suggests a cooperative effect of the genetic factors on susceptibility to asthma.
The secretor gene (FUT2) and the ABO system act in concert to build up oligosaccharide structures in exocrine secretions, including secretions in the respiratory tract. Specific oligosaccharide epitopes are necessary for recognition and adherence of microorganisms to the cell membrane, suggesting that genetic variation in these systems may influence susceptibility to viral and bacterial respiratory infections.
Based on the different roles of the ABO-secretor complex and ADA in the functional integrity of the respiratory tract, it is likely that the effects of the two systems on susceptibility to asthma follow different pathways: the ABO-secretor complex acting on the bacterial-viral infective component and ADA on the cellular reactivity component.
FUT2:fucosyltransferase 2 (secretor status included) Chromosomal Location: 19q13.3
The fusion allele of the FUT2 (secretor type alpha(1,2)-fucosyltransferase) gene at a high frequency and a new se385 allele in a Korean population
Ann Hematol. 2005 Oct ;84:656-60 Kyoung Un Park, Junghan Song, Kyou Sup Han, Jin Q Kim
The fusion gene (se(fus)), a nonfunctional allele of the FUT2 [secretor type alpha(1,2)-fucosyltransferase] gene, was found in Japanese populations with high frequencies (4.8-7.9%). In a study on a Korean population, se(fus) was found at a very low frequency (0.6%), but it has not yet been revealed in any other ethnic population. The aim of the present study was to investigate FUT2 gene polymorphisms in a Korean population and to evaluate their implications in secretor expression in saliva. From a total of 696 alleles examined, the frequency of the se(fus) allele in the Korean population was 10.8%. In addition, the new se385 allele was found in about 7.2% of the subjects, an unusually frequent occurrence compared to any other population investigated so far. The null alleles of the FUT2 gene are another example of rare alleles occurring with unexpectedly high frequencies in distinct geographic regions or populations.
ABO genes consist of at least 7 exons, and the coding sequence in the seven coding exons spans over 18kb of genomic DNA. The single nucleotide deletion, found in a large number (but not all) of O alleles and responsible for the loss of the activity of the enzyme, is located in exon 6. The first of the seven nucleotide substitutions which distinguish the A and B transferases, resides in coding exon 6; exon 7, the largest of all, contains the other six nucleotide substitutions which result in four amino acid substitutions that differentiate the A and B transferases. Among those, substitutions responsible for alterations at two sites (residues 266 and 268) determine the A or B specificity of the enzyme (Yamamoto and Hakamori). In addition to four common alleles (A1, A2, B and O), numerous alleles which encode glycosyltransferases with changes in activity and/or specificity have been identified.
The primary gene products of functional alleles are glycosyltransferases. The A alleles encode UDP-GalNAc: Fuc alpha1->2 Gal alpha1->3 N-acetyl-D-galactosaminyltransferase (alpha 1->3 GalNAc transferase or histo-blood group A transferase). The B alleles encode UDP-Gal: Fuc alpha1->2 Gal alpha 1->3 galactosyltransferase (alpha 1->3 galactosyltransferase or histo-blood group B transferase). O alleles encode proteins without glycosyltransferase function. The function of ABH antigens remains unknown.
Location of the FUT2 gene, which codes for secretor status.
Secretion of ABH antigens is under control of two linked genes on gene locus 19q13, another Haplotype: a mutation (SNP variant) in one always goes with a mutation in the other. Presence of the secretor gene adds the H antigen (fucose) to red blood cells and body secretions. If this genetic code for secreting H is absent in the genetic material inherited from both parents, the individual will not secrete their red blood cell antigens into their body tissues, which is what we know as ABH non-secretors. If they inherit the secretor gene from one parent only, they may still have some of the characteristics of a non-secretor: even though they secrete their ABH antigens, it was postulated that they may have some of the metabolic disease associations connected with being a non-secretor (but not necessarily the cell surface antigen-related ones). 19q13 has 288 verified genes related to this locus, even more than the ABO locus. Chromosome 19 has the highest gene density of all human chromosomes, and many of these relate to how the immune system works, which explains the difference between immune response of secretors and non-secretors: the humoral vs. the cellular response (TH1 and TH2). Other potentially genes on this chromosome relate to insulin-dependent diabetes, familial hypercholesterolaemia, and repair of other genes relating to repairing DNA damage from exposure to radiation and to other environmental pollutants.
The probability of having a particular combination of two specific alleles at a given locus can be calculated using a mathematical formula, which suggests that 2/3 of the general population will be heterozygous for secretor status (i.e. having both secretor and non-secretor genes), which may have a significance in itself when compared with homozygote secretors and non-secretors.
9q34 is the location, or locus of the ABO gene, which codes for the ABO blood group. It is also the location of many other genes that may be associated with the ABO blood group of an individual through genetic linkage.
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