Feb 23 2011

On Blood Groups and Heart Disease

Published by at 12:51 pm
Under Blood Groups | Cholesterol | Disease Links | Genetics

A recent Lancet article has resuscitated some interest about the influence of ABO blood groups and one’s chances of developing coronary atherosclerosis. Like a lot of earlier studies that documented the influence of blood group phenotypic influences on disease incidence, the researchers a.) went in looking for one correlation and wound up finding another; and b.) possibly produced an oversimplification in the rationale of the results.

Historical Aspects

There is a clear-cut association with having A and AB phenotype and an increased risk for heart disease. This has been reported continuously in the scientific literature over the last 50 years. Individuals who are blood group A have higher rates of heart attack across all age groups, both the genders, and all ethnic and national groups.

In 1962, the Framingham Heart Study blood grouped the surviving 4125 members of the original study group of 5209 people first examined in 1948-51. The most striking observance was the lower rates of non-fatal heart disease in men ages 39-72 that were blood group O versus blood group A. (1) A 1994 Polish study on by-pass surgery patients with highly advanced arteriosclerosis of the coronary arteries found a significantly higher number of cases with group AB and a deficiency in group O. (2) A 1981 German study of 13,175 patients showed a prevalence of A blood group in all types of heart disease examined. (3)

In a study of 191 coronary artery bypass candidates, investigators paradoxically found an excess of type O over type A. When they examined the data more closely, they concluded that that the tendency of type A to develop blood clots more readily (“thrombotic proneness”) caused a poorer prognosis. In essence, the blood group A subjects were missing from the study because they had already died in greater numbers, leaving a disproportionate excess of type O among the long-term survivors. (4) In a study of male survivors of heart disease, researchers found that there were fewer type A patients before age 55 than otherwise would have been expected. (5)

An Italian study in 1975 of 746 patients with high blood pressure, 3258 with congenital heart disease, 4503 with a history of heart attack, found a significant lack of patients with type O blood, and a significant excess of blood group A in patients with myocardial infarction. The study also showed an excess of blood group A patients with high blood pressure, and a lack of patients who were blood group B. (6)

A study of 255 women published in the Journal of the American Medical Association originally to study the effects of smoking on the rates of heart attack in women also found several other factors significantly associated with heart attacks in this group, including hypertension, angina pectoris, family history, diabetes mellitus and blood group A. (7)

A 1985 study looked at blood group and heart attacks in two different age groups. The patients were divided into two groups: those who were 65 years old or older and younger patients. The predominance of blood group A in patients with cardiac infarction was “highly significant” in both age groups (P less than 0.005). This study was unique in that other risk factors, such as smoking, high blood pressure, diabetes, and high cholesterol levels, were excluded from the study. When the researchers looked specifically at the more elderly population, the predominance of blood group A in the older patients with cardiac infarction was even higher (P less than 0.001). The researchers concluded, “Our investigation strongly suggests the existence of a genetic factor associated with blood group A and independent of the other risk factors, which is also responsible for a greater incidence of cardiac infarction.” (8)

An eight-year study of 7662 men published in the British Medical Journal found blood group A is linked to the incidence of ischemic heart disease, as well as having higher total serum cholesterol concentrations. (9)

Intestinal alkaline phosphatase

Gene products, which may be expressed under plastic conditions, can contribute to further downstream gene expression by ecological elements. Beginning around 1965 researchers began to notice that people had different levels of an enzyme in their intestinal tract called intestinal alkaline phosphatase (IAP) and that the levels of this enzyme varied according to ABO blood group and secretor status. (10) Type A non-secretors have the lowest levels, and type O secretors the highest, with type B’s somewhere in the middle. The activity of intestinal alkaline phosphatase and serum alkaline phosphatase is strongly correlated with ABH secretor phenotypes. Independent of ABO blood group, ABH non-secretors have lower alkaline phosphatase activity than ABH secretors. It has been estimated that the serum alkaline phosphatase activity of non-secretors is only about 20% of the activity in the secretor groups. It appears likely that the ABO and secretor genes influence the rate at which the intestinal phosphatase enters the blood, or its catabolism, rather than its synthesis in the intestine. (11,12)

IAP has several important functions. During fetal development, IAP is the enzyme with the highest blood concentration during the critical period when the gut lining is developing. IAP also helps to split cholesterol and long chain fatty acids from food into smaller fatty acids. Finally, it also enhances the absorption of calcium from food. The concentration of the intestinal phosphatase is lowest in the serum during fasting and rises after ingestion of fat, reaching a peak at about seven to eight hours. The concentration of intestinal alkaline phosphatase in human thoracic-duct lymph rises after a fatty meal; and presumably, most of the intestinal phosphatase enters the blood by way of the lymphatic system.


Although several studies on highly select populations have yielded conflicting results (13,14), the consensus is that blood group A has a significantly higher basal cholesterol level than the other blood groups. The relationship between ABO blood phenotype and total serum cholesterol level was examined in a Japanese population to determine whether elevated cholesterol levels are associated with blood group A. Their results showed that cholesterol levels were very significantly elevated in the blood group A group compared to non-A group (P < 0.00001). (15) In a nationwide sample of more than 6000 black and white adolescents aged 12 to 17 years, ABO blood group and coronary risk factor levels were measured. Blood group A1 was associated with significantly higher serum total cholesterol levels in white females independent of all other risk factors, in white males independent of age and weight, and in southern black females independent of age and weight. (16) A separate study (the Bogalusa Heart Study) looked at 656 white and 371 black adolescents and found the same results with regard to cholesterol (A higher than others) and also showed higher levels of LDL lipoproteins in type A adolescents over the other blood groups. (17) Whether the association between group A and elevated cholesterol levels is through linkage or environmental factors, such as diet, remains to be determined. The aforementioned ABO variations in intestinal alkaline phosphatase levels have been posited as a potential causative factor.

Viscosity and rheological differences

Elevated Factor VIII (FVIII) levels contribute to venous thrombotic risk. FVIII levels are determined largely by levels of von Willebrand factor (VWF), its carrier protein that protects FVIII against proteolysis. (18) ABO polymorphism is one of the best-characterized genetic modifiers of plasma FVIII; it accounts for approximately 30% of the total genetic effect. (19) Subjects with blood group non-O have higher VWF and FVIII levels than do individuals with blood group O. (20)

Rheology is the science of deformation and flow. One common factor between solids, liquids, and all materials whose behavior is intermediate between solids and liquid is that if we apply a stress or load on any of them they will deform or strain. For our purposes, we will use the term to describe the dynamics between blood clotting (moving towards a solid state) and blood thinning (moving towards a liquid state). It might be tempting to substitute the word “viscosity” for rheology when talking about blood groups and clotting; but it does not cover the “dynamics” of how, when, and why blood can change texture; it only distinguishes one texture state form another.

There is evidence that the rheology of blood may play a role in a variety of chronic anxiety states. When compared to normal subjects, chronic depressive and schizoid patients had very significant differences in their blood rheology and in the ability of their red blood cells to aggregate. When patients having schizoid anxiety were compared to those having depressive anxiety, their ratio of albumin to globulin was increased. When patients were divided according to their ABO blood groups, significant differences were found in their albumin to fibrinogen ratio and their blood viscosity. This was particularly true for women who were type A and who suffered from depressive anxiety: their blood tended to be substantially “thicker” and have higher amounts of serum proteins in it than women with similar depression who were blood group O. (21)

Associations between the ABO phenotype and variations in blood rheology have been also reported in high blood pressure, (22) stress, (23) diabetes, (24) heart attack, cancer and thyroid disease, (25) renal failure (26) and malignant melanoma. (26-27)

Soluble adhesion factor E-selectin

Endothelial (E)-selectin (CD62E), formerly known as ELAM-1, is synthesized de novo by endothelial cells in response to IL-1, lipopolysaccharide, TNF-alpha, or G-CSF and is, therefore, detectable either after or concurrently with P-selectin to augment leukocyte recruitment. In humans, E-selectin is encoded by the SELE gene. E-selectin recognizes and binds to sialylated carbohydrates present on the surface proteins of certain leukocytes. These carbohydrates include members of the Lewis X and Lewis A families found on monocytes, granulocytes, and T-lymphocytes.

E-selectin is a heavily glycosylated transmembrane protein. E-selectin, recognizes several diverse and structurally distinct glycoconjugates on various hematopoietic and carcinomatous cells in affinity or binding assays. These ligands may include cutaneous lymphocyte-associated antigen (CLA) a distinct glycoform of P-selectin glycoprotein ligand-1 (PSGL-1), L-selectin, E-selectin ligand-1, CD43, hematopoietic cell E- and L-selectin ligand (a specialized glycoform of CD44), betaa-2 integrins, and glycolipids. (28) Recently, death receptor-3 (DR3) expressed on colon carcinoma cells has been identified as a new E-selectin ligand. (29)

During inflammation, E-selectin plays an important part in recruiting leukocytes to the site of injury. The local release of cytokines IL-1 and TNF by damaged cells induce the over-expression of E-selectin on endothelial cells of nearby blood vessels. Leukocytes in the blood, expressing the correct ligand, will bind with low affinity to E-selectin, causing the leukocytes to “roll” along the internal surface of the blood vessel as temporary interactions are made and broken. As the inflammatory response progresses, chemokines released by injured tissue enter the blood vessels and activate the rolling leukocytes, which are now able to tightly bind to the endothelial surface and begin making their way into the tissue. E-selectin binds sialyl Lewis X (SLeX).

ABO is a major locus for serum soluble E-selectin levels. E-selectin is higher in O/O than O/A heterozygotes, which likewise have higher levels than A/A genotypes. Analysis of subgroups of A alleles reveals heterogeneity in the association, and even after this was accounted for, an intron 1 SNP remained significantly associated. Additional findings indicate that the genetic variants at ABO locus affect plasma soluble E-selectin levels and diabetes risk. (30,31)


The Lancet researchers conclude that the propensity of ABO blood grousp to influence the course of heart disease “was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction.”

This is indeed true. However there are a great many other factors related to ABO phenotype that interact together to produce clinical cardiovascular illness. Soluble adhesion factors like E-selectin best promote arterial inflammation when in the presence of clotting factors such as Factor VIII and even slightly elevated cholesterol.

Both of these factors are also known to be associated with the blood group A phenotype. Blood viscosity is known to alter most prominently in group A when under stress and a variety of health conditions often unrelated to heart disease.

The almost three-fold differences in intestinal alkaline phosphatase between group O and group A individuals and between ABH secretors and non-secretors points to the cardiovascular benefits of a lower protein diet in group A, especially group A individuals of the non-secretor phenotype; and suggests that secretor status should also be included in any analysis of blood group propensities towards cardiovascular disease.

  1. Havlik RJ, et al. Blood groups and coronary heart disease. Lancet. 1969 Aug 2; 2(7614):269-70.
  2. Slipko Z, Latuchowska B, Wojtkowska E. Body structure and ABO and Rh blood groups in patients with advanced coronary heart disease after aortocoronary bypass surgery. Pol Arch Med Wewn. 1994 Jan; 91(1):55-60.
  3. Meshalkin EN, Okuneva GN, Vlasov IuA, Vel’tmander NN. ABO and Rh blood groups in cardiovascular pathology. Kardiologiia. 1981 Apr; 21(4):46-50.
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  12. Mehta NJ, Rege DV, Kulkarni MB. Total serum alkaline phosphatase (SAP) and serum cholesterol in relation to secretor status and blood groups in myocardial infarction patients. Indian Heart J. 1989 Mar;41(2):82-85
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  18. Platt D, Muhlberg W, Kiehl L, Schmitt-Ruth R. ABO blood group system, age, sex, risk factors and cardiac infarction. Arch Gerontol Geriatr. 1985 Oct; 4(3):241-249.
  19. Whincup PH, Cook DG, Phillips AN, Shaper AG. ABO blood group and ischemic heart disease in British men. BMJ. 1990 Jun 30; 300(6741):1679-1682.
  20. Jorgensen G. ABO blood groups in physicians more than 75 years old. On the hypothesis concerning “little more fitness of blood group O” MMW Munch Med Wochenschr. 1974 Mar 29; 116(13):649-52.
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  24. Dintenfass L, et al. Genetic and ethnic influences on blood viscosity and capillaries in diabetes mellitus. Microvasc Res. 1977 Sep; 14(2):161-72.
  25. Dintenfass L, et al. Effect of fibrinogen on aggregation of red cells and on apparent viscosity of artificial thrombi in hemophilia, myocardial infarction, thyroid disease, cancer and control systems: effect of ABO blood groups. Microvasc Res. 1975 Jan; 9(1):107-18.
  26. Dintenfass L, et al. Formation, consistency and degradation of artificial thrombi in severe renal failure. Effect of ABO blood groups. Thromb Diath Haemorrh. 1968 Nov 15; 20(1):267-84.
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  29. Gout S. et al. Death receptor-3, a new E-selectin counter-receptor that confers migration and survival advantages to colon carcinoma cells by triggering p38 and ERK MAPK activation. Cancer Res. 2006; 66(18):9117–9124.
  30. Paterson AD, Lopes-Virella MF, Waggott D, Boright AP, Hosseini SM, Carter RE, Shen E, Mirea L, Bharaj B, Sun L, Bull SB. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Genome-wide association identifies the ABO blood group as a major locus associated with serum levels of soluble E-selectin. Arterioscler Thromb Vasc Biol. 2009 Nov; 29(11):1958-67.
  31. Qi L, Cornelis MC, Kraft P, Jensen M, van Dam RM, Sun Q, Girman CJ, Laurie CC, Mirel DB, Hunter DJ, Rimm E, Hu FB. Genetic variants in ABO blood group region, plasma soluble E-selectin levels and risk of type 2 diabetes. Hum Mol Genet. 2010 May 1; 19(9):1856-62.

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One Response to “On Blood Groups and Heart Disease”

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