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The Possible Relationship Between ABO and Rhesus System Phenotypes and SARS-CoV-2 Infection
Marina Nagervadze,1,2,ID Leila Akhvlediani,1,2,ID Teona Phutkaradze,1 Mamuka Sikharulidze,Shorena Gabaidze,1,ID   SophioTskvitinidze,1,2,ID Salome Abuladze,1 Rusudan Khukhunaishvili,1 Marina Koridze,1 Ketevan Dolidze1
Received: 22 Apr 2023; Accepted: 26 Apr 2023; Available online: 27 Apr 2023
Background: Several studies have recently revealed the relationship between blood Rhesus factor and SARS-CoV-2 viral infection; however, the underlying mechanism is still unclear. An intriguing finding was the very low viral infection rate among blood Rhesus-negative people (notably O(I) and Rh-) and the high vulnerability in Rh-positive infected patients.

Objectives: The current study aimed to find a possible relationship between Rh blood groups and susceptibility to the SARS-CoV-2 viral infection. Based on the results of comparing ABO and Rh blood group phenotypes in uninfected (healthy) and post-infection individuals, we were able to identify SARS-CoV-2 susceptible or resistant phenotypes.

Methods: 447 blood samples were examined, including 333 from SARS-CoV-2 post-infection patients and 114 from healthy controls within four months (from January 28, 2021, to April 30, 2021).

Results: The distribution of phenotypic categories for Rhesus positive (Rh+) and Rhesus negative (Rh-) individuals in the control and post-infection groups has been identical. There was no correlation between the Rhesus factor and susceptibility to SARS-CoV-2 virus infection. However, there was a significant correlation between the combination of two variables (the Rh and ABO groups) and SARS-CoV-2 susceptibility. Remarkably, the frequency of the O(I) and Rh- phenotypes was approximately 1.4 times lower in the post-infection period than in controls. In contrast, patients in the post-infection period exhibit the most considerable prevalence of the A(II)Rh+ phenotypic combination.

Conclusions: The SARS-CoV-2 infection susceptibility is low in people with the O(I)Rh- phenotype and high in individuals with the A(II)Rh+ phenotype.

Keywords: COVID-19; Rh blood group; SARS-CoV-2 viral infection.

DOI: 10.52340/GBMN.2023.01.01.24
Blood group antigens are carbohydrates or proteins attached to the surface of red blood cells (RBC). The AB0 blood group antigen chemically belongs to carbohydrates, and their formation requires a series of enzymatic reactions. Rh blood group-specific antigens are proteins. (1) Blood group antigens are evolutionary-established characteristics that determine the adaptation of human beings as biological species (Homo sapiens) to the surrounding environment. (2)

Blood group antigens are ancient biomarkers that have been established evolutionarily. There are several hypotheses describing the development of blood group antigens. (3) One of the most popular hypotheses is that the prototype blood group was AB(IV). A(II), B(III), and the last O(I) blood groups have been formed due to several allele-specific inherited mutations. (2)

The distribution of blood groups varies according to geographic regions and results from the so-called "genogeographic adaptation" of different types of ecosystems. (4,5) Numerous scientific publications show that ABO blood group antigens are associated with pandemics and infectious diseases such as the black plague, cholera, and measles. (1,5,6)

The pandemic SARS-CoV-2 is a respiratory virus that spreads quickly with a high risk of severe complications, including death. (7,8)
Numerous medical and sociodemographic risk factors can affect the incidence of viral infections and are associated with both the onset and severity of COVID-19. (9-15)

Identifying additional risk factors is the most crucial step in prevention. The erythrocyte ABO and Rh blood groups may also play a potential role in the immunopathogenesis of the SARS-CoV-2 viral infection.16 Most recent studies have revealed a higher proportion of blood group A(II) and a lower proportion of blood group O(I) among COVID-19 patients compared to healthy controls. However, group A patients have a higher incidence of significant comorbidities, which is considered one contributor to COVID-19 complications. (17-19)

Despite evidence from several studies demonstrating a correlation between blood Rh factor and SARS-CoV-2 infection, the precise mechanism of this relationship is still unclear. Rhesus-negative individuals (especially O(I) and Rh) showed a relatively low infection rate. (20) The data from New York City suggest that the Rhesus-negative phenotype may also be protective. (21) Individuals with Rh-positive but not Rh-negative blood groups are more vulnerable to the SARS-CoV-2 viral infection. (22) The current study aims to investigate the relationship between blood groups and SARS-CoV-2-infected patients.
447 blood samples in total have been analyzed in the study period from January 28, 2021, to April 30, 2021. 2 ml of whole blood drawn from a peripheral vein in special test tubes of EDTA K3 served as the primary source of the sample after being assigned a unique code for each sample.

The majority of the studied materials (n=333) belonged to SARS-CoV-2 post-infection individuals with (i) verified SARS-CoV-2 viral infection by a rapid (antigen/antibody) or PCR test and (ii) less than one month after the SARS-CoV-2 virus infection.

The control group (n=114) consisted of individuals who (i) were not infected with the SARS-CoV-2 virus during the collection of the study materials and (ii) were not vaccinated (the vaccination process in our country started on March 15, 2021). Written informed consent was received from all participants before study initiation. The study protocol was approved by the School of Medicine and health sciences ethics committee at Batumi International University (BAU). The control group and the post-infection cohort had similar baseline data.

We used direct immuno-serological forward and reversed methods with anti-A, anti-B, anti-AB, anti-C, anti-c, anti-D, anti-E, and anti-e monoclonal antibodies for ABO and Rh blood typing (Bio-Rad, Cypress Diagnostics). The blood type procedures were conducted at the Immunogenetics Laboratory of Batumi Shota Rustaveli State University (BSU, Batumi, Georgia) and the Microbiologic Laboratory of Batumi International University (BAU, Batumi, Georgia).

The differences between the cohort of post-infection patients and the control group were assessed by the Chi-square (χ2) analysis. A statistical significance was taken as a p<0.05.
At the initial stage of our study, we checked the associations between the presence of Rhesus factors (Rhesus-positive and Rhesus-negative) and SARS-CoV-2 susceptibility.

As can be seen from
Figure 1, the distribution of the mentioned phenotypes is almost identical in the control and post-infection groups. The equal distribution of Rhesus phenotypes refuses a possible correlation between the Rhesus factor and SARS-CoV-2 susceptibility (chi-square is 0.2867, a p-value is 592363, the results are unreliable p<0.05).

FIGURE 1. Phenotypic groups of the Rhesus system in the post-infection and control groups
The Possible Relationship Between ABO and Rhesus System Phenotypes and SARS-CoV-2 Infection
Abbreviations: Rh+, Rhesus-positive phenotype; Rh-, Rhesus-negative phenotype.

In the second stage of the current study, we evaluated the correlation between the phenotypic combinations of the Rhesus and ABO blood group systems and SARS-CoV-2 susceptibility. Eight varieties (O(I)Rh-; O(I)Rh+; A(II)Rh-; A(II)Rh+; B(III)Rh-; B(III)Rh+; AB(IV)Rh-; and AB(IV)Rh+) of ABO and Rh systems were studied in post-infection and control groups. Figure 2 depicts the distribution of the combinations mentioned above in both groups.

FIGURE 2. AB0 and Rh system combinations in the post-infection and control groups
The Possible Relationship Between ABO and Rhesus System Phenotypes and SARS-CoV-2 Infection
Abbreviations: Rh+, Rhesus-positive phenotype; Rh-, Rhesus-negative phenotype.

There were only two statistically significant differences between the post-infection cohort and the control group: the high prevalence of the A(II)Rh- phenotype in the cohort of patients and the O(I)Rh+ phenotype in the control group (41.4% vs. 29.8% and 33% vs. 42.9%, respectively).
Most blood group antigens are found on red blood cells, thrombocytes, leukocytes, plasma proteins, and some epithelial tissues. (1)

The Rhesus (Rh) blood group system is one of our body's most complex, polymorphic, and immunogenic systems and consists of approximately 45 independent antigens. (23)

The ABO and Rh blood group systems, are linked with infection, malignancy, and coagulation. Rhesus-negative subjects were reported to have more frequent allergic, digestive, cardiovascular, hematological, immune, mental health, and neurological problems. (24)

Several studies have been conducted in the past two years, investigating possible relationships between blood types, SARS-CoV-2 susceptibility, and the severity of COVID-19 disease.

According to the results of the current study, Rh+ and Rh- phenotypes were equally distributed in the control and post-infection groups (chi-square is 0.2867, the p-value is 592363, and the results are unreliable p<0.05). Particularly in the control group, the prevalence rate of the Rh-positive phenotype was 78.9%, and the Rh-negative phenotype was 21.1%. In contrast, in the post-infection group, the prevalence rates of the Rh+ and Rh-phenotypes were 81.7% and 18.8%, respectively. These results allowed us to conclude that there is no correlation between the Rhesus factor and SARS-CoV-2 susceptibility.

Our previous work demonstrated an association between ABO blood types and SARS-CoV-2 infection.25 Evaluating the relationship between combined ABO and Rhesus phenotypes and SARS-CoV-2 susceptibility, we found some statistically significant correlations. Particularly, the O(I)Rh-phenotypic group was presented at approximately 1.4 times lower frequency in post-infection individuals than the controls. This fact gives the O(I)Rh- group the status of a relatively resistant phenotype to the SARS-CoV-2 infection. Conversely, the prevalence of the A(II)Rh+ phenotypic combination was higher in the group of post-infection patients than in the controls. This indicates that this phenotype is more susceptible to SARS-CoV-2 virus infection.

Our findings are consistent with those of other authors. In a single-center, retrospective investigation, Rana and colleagues
(26) hypothesized that blood groups O, AB, and Rh-negative are less likely to be infected with SARS-CoV-2 infection than blood groups A, B, and Rh+. The cited authors found no association between blood types and COVID-19 disease severity or mortality.

Zeits and coauthors suggested that blood type is essential for the risk of infection, intubation, and death.
(21) They predict that all three outcomes are less likely for Rh-negative individuals. They also suggested a protective relationship between Rh-negative blood types and SARS-CoV-2 infection, intubation, and death.

Several hypotheses explain why Rh-negative individuals are more resistant to viral infections. One of the most well-known is that Rh-negative patients are more likely to develop various cardiac and respiratory conditions and some immunological and autoimmune disorders, like rheumatoid arthritis. According to the global population pattern, Rh-negative people may struggle with autoimmunity, may be more resistant to viral infections, and, conversely, maybe less resistant to illnesses of bacterial origin. (24)

There are alternative suggestions by several authors. (26) Laurys and coauthors found no relationship between blood group and infection rate.
Large sample sizes or meta-analyses are required to estimate these effects more clearly. We hope that our findings will be used in meta-analyses.
According to the present study's findings, there was no correlation between the Rhesus blood group and SARS-CoV-2 susceptibility. On the other hand, the highest prevalence of the A(II)Rh+ and lowest O(I)Rh- phenotypic combinations are found among patients in the post-infection period. Due to this, the O(I)Rh- the group might be classified as relatively resistant to SARS-CoV-2 infection. On the other hand, SARS-CoV-2 virus infection is more likely to affect the O(I)Rh- phenotype.

1 Faculty of Natural Sciences and Health Care of Batumi Shota Rustaveli State University, Batumi, Georgia

2 School of Medicine and Health Sciences of Batumi International University (BAU), Batumi, Georgia

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