ABO blood group antigen determinants (ie, A, B, and H) are located not only on red blood cells but also on the surfaces of a range of other cells and tissues, including the epithelium, platelets, vascular endothelium, and neurons. Consequently, their interactions extend beyond transfusion and to other types of disease, including the development of heart disease and cancers. To date, genome-wide association studies have confirmed a link between blood group and pancreatic cancer, coronary heart disease, venous thromboembolism, and more.
The following is a closer look at the molecular basis of blood groups and five diseases linked to blood type.
How blood groups work
ABO blood groups are carbohydrate moieties found on the surface of red blood cells. They are attached to the H antigen, which constitutes a protein backbone. The three variant alleles A, B, and O located on the ABO gene of chromosomes 9q34 determine blood type by coding for three glycosyltransferases with distinct substrate specificities.
Taken together, these glycosyltransferases trigger the transfer of sugar moieties from activated donor molecules to specific acceptor molecules like the H antigen.
The A and B alleles differ in eight nucleotides which result in four amino acid substitutions and altered enzyme specificity for the substrate. The A glycosyltransferase binds N-acetylgalactosamine and the B glycosyltransferase binds D-galactose. On the other hand, the O allele transcribes a nonfunctional glucosyltransferase, leaving the H antigen unmodified.
Metabolic disease in the form of type 2 diabetes may be linked to blood type, per the results of a study published in Diabetologia.
In the study, researchers assessed the relationship between ABO-blood type (A, B, AB, and O), as well as Rhesus factor and a blood-type/Rhesus factor combination, with risk for type 2 diabetes in a cohort of 82,104 women followed from 1990-2008.
When compared with the O group, participants with A or B type blood had higher odds of developing diabetes, with hazard ratios of 1.10 and 1.21, respectively. They observed no difference in type 2 diabetes risk due to Rhesus positive or negative groupings.
Compared with universal donors (O−), the team observed increased risk of diabetes in A+, A−, AB+, and B+ groups, with HRs of 1.17, 1.22, 1.26, and 1.35, respectively. Associations remained unchanged after accounting for potential confounders, including fasting blood sugar levels and lipid concentrations.
The authors suggested reasons for possibly explaining the associations.
They wrote: “The mechanisms underlying the observed association are unknown. It has been suggested that the human ABO locus might influence endothelial or inflammation markers, such as the factor VIII–von Willebrand factor (vWF) complex, which is present in higher levels in non-O individuals. In addition, the ABO blood groups have been associated with plasma soluble intercellular adhesion molecule 1 (ICAM-1) and TNF receptor 2 (TNF-R2) levels. These markers have both been associated with an increased type 2 diabetes risk, thus providing a potential explanation for the observed relationships. Finally, a recent paper suggested that the ABO blood group is one of the genetically determined host factors that modulate the composition of the intestinal microbiota, which participates in metabolism by affecting the energy balance, glucose metabolism and low-grade inflammation,” they concluded.
Importantly, although the study population was female, associations should also hold for men, too. According to the authors: “To our knowledge, no biological mechanisms are likely to explain a sex-dependent association. Information on the participants was self-reported but this is unlikely to substantially affect the results.”
Only 4% of the US population has the AB blood group. Per the results of a study published in Neurology, people with this blood type are at an 82% higher risk of developing cognitive and memory problems that lead to dementia. In fact, those with blood type O may have lower risks of stroke and heart attack, which can lead to cognitive impairment.
Specifically, during a mean of 3.4 years of follow-up, those with blood group AB and higher Factor VIII levels exhibited a respective odds ratio of 1.82 for cognitive impairment after adjusting for confounding variables. Of note, average FVIII levels were higher in those with blood type AB (142 IU/dL; 95% CI 119–165) vs. blood type O (104 IU/dL; 95% CI 101–107), with FVIII responsible for 18% of the association between AB group and incident cognitive impairment.
The authors suggested that cardiovascular risk may play a role in cognitive decline, with ABO blood group acting as a bridge.
“The results of our study support the hypothesis that ABO blood group represents a link between cardiovascular risk and cognitive function. Blood group AB and higher FVIII were associated with cognitive decline in a large cohort of both black and white Americans, and while higher FVIII levels were seen in those with type AB, mediation of the group AB–cognitive decline association by FVIII was nonsignificant. This indicates that the effect may be the result of other pathways influenced by the ABO glycosyltransferase,” they concluded.
In a study published in Atherosclerosis, Thrombosis, and Vascular Biology, He and co-authors prospectively analyzed the link between blood groups and coronary heart disease risk in the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). They also combined this data with findings from previously published prospective studies in the form of meta-analysis.
After adjusting for cardiovascular confounders, in a combined analysis, the team found that participants with A, B, or AB blood types were more prone to developing coronary heart disease, with adjusted hazard ratios for incident coronary heart disease 1.06 [0.99–1.15], 1.15 [1.04–1.26], and 1.23 [1.11–1.36], respectively. In total, 6.27% of cases of coronary heart disease were due to inheritance of a non-O blood type, with a relative risk of CHD being 1.11 in these participants vs. O blood group, per the results of the meta-analysis.
For some time, experts have hypothesized that ABO blood type could influence heart disease risk factors. In those without O-blood type, for instance, plasma levels of factor VIII–von Willebrand factor (vWF) are about 25% higher than those of people with group-O blood type. Of note, higher levels of factor VIII-vWF can result in coronary heart disease. Results from genome-wide association studies have indicated that ABO blood group may also moderate plasma lipid levels and inflammatory marker levels.
“The vWf has an important role in hemostasis and thrombosis by mediating platelet adhesion to the vascular wall, especially under high shear stress conditions,” the authors wrote.
“Along with fibrinogen, vWF also participates in platelet aggregation and plays a role in the development of atherosclerosis. ABO blood group has been associated with plasma lipid levels; in particular, the A blood group has been noted to have higher levels of serum total cholesterol and low-density lipoprotein cholesterol,” they added.
In a study published in the International Journal of Molecular Sciences, Chinese researchers combined results from a case-control study involving 1,045 cases of gastric cancer and 53,026 healthy controls with additional meta-analysis of extant research to determine the relationship between blood type and gastric cancer.
They found that there was a slightly increased chance of gastric cancer in those with blood type A, with these people more likely to be infected with H. pylori compared with blood type O patients. Of note, H. Pylori plays an important role in the development of stomach cancer. On the other hand, those with blood type O had a decreased risk of gastric cancer.
The researchers suggested certain explanations for the association. For instance, those with blood type A may be more likely to develop pernicious anemia, which is linked to gastric cancer. Additionally, those with blood group A may have decreased immune reactions to tumors compared with those who don’t harbor A-type blood.
Per the results of a study analyzing two large, independent, prospective cohort studies—the Nurses’ Health Study and Health Professionals Follow-up Study—researchers observed an association between blood type and incident rates of pancreatic cancer.
Specifically, compared with the O-blood type, those with the A-blood type exhibited an adjusted HR of 1.32; those with AB, 1.51; and those with B, 1.72. In total, they found that 17% of pancreatic cancer cases in the population were due to non-O blood type.
The researchers suggested several mechanisms underlying the observed association.
“In addition to their expression on the surface of red blood cells, the ABO antigens are highly expressed on the surface of epithelial cells of the gastrointestinal, bronchopulmonary, and urogenital tracts,” they wrote.
“Pathology studies have demonstrated the deletion and the novel expression of A, B, and H antigens on the surface of pancreatic cancer cells compared with surrounding normal ductal cells, suggesting that alterations in glycosyltransferase specificity may occur during pancreatic tumorigenesis. Glycosyltransferase specificity has broad implications, beyond defining ABO blood type,” they continued.
“Glycoconjugates are important mediators of intercellular adhesion and membrane signaling, two processes integral to malignant progression and spread. In addition, these surface molecules are recognized by the host immune response and may have a role in facilitating immunosurveillance for malignant cells,” they added.
Other mechanisms they proposed included changes in inflammatory status due to blood type that could contribute to pancreatic cancers. Additionally, H. pylori binding could differ based on blood type, and as with gastric cancer, this pathogen could contribute to pancreatic cancer.