Another and somewhat remarkable gene difference which has been found in man is related to the blood groups but is not, in itself, a blood-grouping factor. This is the secreting gene.
It was discovered fairly early that the blood group antigens A and B were generally present in the saliva and (as we know now) in almost all of the body tissues of an individual if they were present in his red blood cells (i.e., a group B individual would have the B substance in his saliva and gastric juice, a group A person would have A, an AB both, and a group O person neither). The use of proper reagents enabled the rule to be extended to the group O substance also. But in some cases the group substance could not be demonstrated in saliva or body fluids, or was present in very small amounts, and Schiff suggested that the presence or absence of the blood group substance in the saliva was determined by a special gene, which he designated as Se (for secretor) ; the non-secreting gene was designated as se, and Se was supposed to be the dominant member of the pair.
It was first shown by Lehrs in 1930 that some people do and others do not secrete into their saliva antigens corresponding to their ABO blood group. This ability to secrete blood type antigens behaved as a simple Mendelian function dominant to non-secretion. Group A, B, and AB persons who are secretors secrete the antigens corresponding to their blood groups. Group O persons secrete the H substance, as do all other secretors; to a somewhat less extent. The secretor gene is identified as Se to distinguish it from the Ss blood group.
The term "ABH secretor," as used in blood banking, refers to secretion of ABO blood group antigens in fluids such as saliva, sweat, tears, semen, and serum. A person who is an ABH secretor will secrete antigens according to their blood group; for example, a group O individual will secrete H antigen, a group A individual will secrete A and H antigens, etc. Soluble (secreted) antigens are called substances. To test for secretor status, an inhibition or neutralization test is done using saliva. The principle of the test is that if ABH antigens are present in a soluble form in a fluid (e.g., saliva) the antigens will neutralize their corresponding antibodies, and the antibodies will no longer be able to agglutinate red cells possessing the same antigens.
One of the primary differences in physiology between secretors and non-secretors involves qualitative and quantitative differences in components of their saliva, mucus, and other bodily secretions. ABH secretion is controlled by two alleles, Se and se. Se is dominant and se is recessive (or amorphic). Approximately 80 percent of people are secretors (SeSe or Sese).
People who do not secrete their blood type antigen into their secretions are termed 'non-secretors'. About 15% of the population are non-secretors. Several correlations to disease (including rheumatic heart disease and alcoholism) have been linked to non-secretor status.
In general being a non-secretor results in several disadvantages with regard to metabolism and immune function.
Data suggest the non-secretor type is associated with insulin resistance syndrome or "Syndrome X". The data was especially significant with men, including a tendency to a ‘prothrombic’ metabolism and higher levels of triglycerides and fasting levels of serum insulin and plasma glucose. While also positive, these same relationships are not as strong for women. This link to a metabolic function associated with carbohydrate intolerance is especially interesting in light of several well-conducted studies linking non-secretor status with alcoholism. Certain immune functions in diabetic non-secretors are also known to be depressed when compared with secretors and findings suggest that an increased proportion of non-secretors are found among patients with diabetes, particularly of the insulin-dependent diabetes type.
The activity of intestinal and serum alkaline phosphatase is strongly correlated with secretor phenotypes. Non-secretors, independent of their ABO blood groups (as your remember type O's have the highest alkaline phosphatase activity and type A's the least), have lower alkaline phosphatase activity. Intestinal alkaline phosphatase is associated with the breakdown of certain types of dietary fat and the ability to assimilate calcium. It has been estimated that the serum alkaline phosphatase activity of non-secretors is only about 20% of the activity in the secretor groups.
All individuals have in their intestine an enzyme which breaks down organic phosphates—alkaline phosphatase. This particular phosphatase can be recognized by its chemical properties and its speed of electrophoresis, and it has thus been found that some people do and others do not have intestinal alkaline phosphatase in their plasma. Tranfer of this phosphatase from the intestine to the plasma is controlled by the ABO blood group and the secretor systems—it is promoted by the secretor factor and suppressed by the A antigen, whether as group A or AB. This suggests that peptic ulceration is related to the ability or non-ability of the intestinal membrane to let the phosphatase pass into the plasma.
Serum levels of intestinal alkaline phosphatase (IAP), a protein implicated in transcellular transport of chylomicrons, vary among ABO blood groups. Results indicate that IAP is strongly involved in chylomicron formation and fatty acid metabolism might change among ABO blood type. In addition, ABO blood type classification in apoB-48 measurement would improve the diagnostic value in the evaluation of metabolic syndrome. ()
Evidence suggests that non-secretors have lower levels of the antibodies IgG and IgA. The lower levels of IgA are especially significant and may help explain why non-secretors tend to have more frequent problems with heart valve disturbance thought to be the result of infection of the bloodstream due to dental work. One of the innate defenses against superficial infections by Candida species appears to be the ability of an individual to secrete the water-soluble form of his ABO blood group antigens into body fluids. Since they cannot do this, it is not surprising to find that non-secretors also carry more Candida organisms in their mouth and digestive tract than secretors. Non-secretors appear to have an increase in the prevalence of a variety of autoimmune diseases including ankylosing spondylitis, reactive arthritis, psoriatic arthropathy, Sjogren’s syndrome, multiple sclerosis, and Grave’s disease. Non-secretors appear to be at extra risk for recurrent urinary tract infections.
Non-secretors are reported to have shorter bleeding times (thicker blood) and a tendency towards higher factor VIII. Data allows the conclusion that non-secretors are at a higher risk for myocardial infarction and even more so among men than women. Of surprising interest is the trend towards a protective effect of alcohol in reducing the risk of heart disease among certain elements of the non-secretor population.
In all blood groups, the average amount of cavities is lower for secretors than for non-secretors. This difference is most significant for smooth surface areas of the teeth. And, secretors of blood group mucin A had the lowest numbers of cavities. A higher intensity of oral disease is found among non-secretors. So it is not surprising that when it comes to precancerous, or cancerous changes to tissue of the mouth and esophagus, non-secretors seem to fair worse than secretors. This oral disease susceptibility is reflected in the occurrence of epithelial dysplasia (pre-malignant changes) which is found almost exclusively in the non-secretor group. Being a non-secretor also offers a slight increase risk for having a problem with habitual snoring.
Duodenal ulcer patients are more likely to be non-secretors, and being a non-secretor acts to multiply the activity of a separate gene for the excessive production of the enzyme pepsin. Thus non-secretors have a harder time turning off many of their digestive enzymes and because of this have a higher risk of duodenal ulcer. If you are a non-secretor, your immune response against H. pylori appears to be lower and H. pylori appears to attach with higher aggressiveness and cause more inflammation. If you are a non-secretor and have a duodenal ulcer the odds are very high (maybe even 100%) that it is associated with an H.pylori infection. In the intestines, non-secretors are at an increased risk for development of coeliac disease Since your secretor status dictates the presence of A, B, and H blood group antigens in the gut the inability of non-secretors to secrete their blood type antigens into the mucus in the intestines impacts how some of the bacteria that are capable of taking up local residence.
The non-secretor state is significantly associated with coeliac disease, suggesting that genes on chromosome 19 may directly or indirectly participate in conferring susceptibility. ()
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 the fucose 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, much like a surveyor will proceed a road construction crew.
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.()
Frequency of secretors and non-secretors in various racial groups
From: Genetics And The Races of Man, William C. Boyd. Little Brown and Company, Boston (1950)
|Series, Place||Reference||Number Tested||% Secretor||% Non-secretor||Frequency S||Frequency s|
|'Whites', New York||()||74||82.4||17.6||0.58||0.42|
|American, Indians,New Mexico||()||69||98.5||1.5||0.88||0.12|
|American, Indians, Utah||()||79||100.0||0||1.00||0|
The most important group of diseases so associated is that of the peptic ulcers—gastric and duodenal—which are markedly associated with non-secretion and diabetes mellitus, associated with secretion. The association of O blood groups with the same diseases is partly at least a statistical accident, since an important part of it really is due to the association of hemorrhage with group. It is the hemorrhage which so often brings the patient into hospital and into the scope of blood-group surveys. However, the association with non-secretion is intrinsic to this class of diseases and is independent of hemorrhage.
Carriers of haemolytic streptococcus show a fairly consistent deficiency of secretors, as does rheumatic fever which is also a sequel to streptococcal infection. Much more attention should be given to the combined effects of blood group and secretor state on susceptibility to bacterial infections.
The tendency towards carcinoma of the stomach, markedly associated with group A, may also be affected by these membrane properties, though there seems to be no association between this form of carcinoma and secretion. The subject is however one that demands further research. By analogy with the selective favouring of group 0 through the elimination of A and B offspring of group 0 mothers, there is probably also a selective elimination of secretor fetuses (of groups A and B) of group O (but not necessarily non-secretor) mothers. This results from the fact that fetuses which provoke the immunization of such mothers more frequently secretors than are members of the general population.
It may thus be that there is a constant selection against the secretor gene as a result of ABO hemolytic disease of the newborn, and that the persistence of the secretor gene at varying levels in different populations is the result of environmental conditions which in varying degree favour secretors, and so more or less counterbalance the selection by hemolytic disease. The situation is by no means as clear-cut as the selection against A and B but merits both studies of cases of ABO hemolytic disease of the newborn, and population studies of the distribution of secretors and non-secretors, as well as further research on possible disease associations of the secretor and non-secretor types.()