Race may modify the association between blood type and COVID‐19 infection

Abstract This study aims to investigate the race/ethnicity‐specific association between blood type and COVID‐19 susceptibility during March, 2020 and December, 2021 using data from the electronic health record at the University of Chicago Medicine. The study population was stratified into four groups: non‐Hispanic White, non‐Hispanic Black, Hispanic, and other. Log‐binomial generalized mixed model was used to estimate the relative risk (RR) and 95% confidence interval (CI). When compared to blood type O, type B was associated with positive COVID‐19 test in Blacks (RR = 1.12, 95% CI: 1.02–1.23), Whites (RR = 1.28, 95% CI: 0.99–1.66), and Hispanic (RR = 1.36, 95% CI: 0.97–1.92).


INTRODUCTION
Understanding the mechanisms behind racial disparities in COVID-19 susceptibility and severity is a key scientific priority given the evidence of disproportionate impact in underrepresented communities in the United States, especially for African Americans [1]. While social and economic factors may explain this disparity [2], it remains unknown whether a physiological basis underlies it as well.
Blood type is an established risk factor for many infectious diseases, as blood group can serve as receptors and co-receptors for pathogens and facilitate intracellular transportation of viral particles [3]. ABO blood type is associated with infection by a variety of viruses including SARS-CoV-1 [4][5][6][7]. Although a large body of litera-

Participants
The study population was restricted to UCM patients aged 18 or older with valid blood type information from March 1, 2020 to December 31, 2021. In total, 31,784 individuals had lab-verified blood type data in the EHR. We also obtained information on demographics, comorbidities, laboratory results, UCM treatment, and outcomes from the EHR for these patients. Patients who tested multiple times were considered never positive if all tests were negative and ever positive if one or more tests were positive. This study was approved by the University of Chicago Biological Sciences Division Institutional Review Board with a waiver of consent for use of identifiable data.

Measurements
All variables were defined based on information from the UCM EHR

Statistical analysis
Log-binomial generalized mixed model was used to evaluate the relative risk (RR) and 95% confidence interval (CI) for different blood types with type O or Rh-negative as the references. A random intercept and slope were set for race/ethnicity to control for varying blood type prevalence across racial groups. Additionally, to investigate the association between blood type and COVID-19 risk among underrepresented groups, we stratified our study population into four racial groups: non-Hispanic Black, non-Hispanic White, Hispanic, and other.
Moreover, to investigate the related temporal variations, we stratified our study population into two time periods: March to December, 2020 and January to December, 2021. Patients who visited UCM in one period were included in the analysis for that specific period. Therefore, patients who visited UCM in multiple periods were counted in multiple stratified analyses. As vaccination may impact the association between blood type and COVID-19 risk, we also identified patients who received vaccination at UCM and ran the analysis among these vaccinated population.
All models were adjusted for age, BMI, sex, smoking history, hypertension, and type 2 diabetes. We added a cross-product term between the racial group and blood type to test the difference between racial groups.
Missing values in the covariates were treated using multiple imputation. A total of 20 complete data sets were generated and used for analyses. Results from the 20 data sets were combined and analyzed [13]. All analyses were performed using R (version 4.1.2).

RESULTS
Blacks were more likely to test positive for COVID-19 compared to their White counterparts (Table 1). Patients with hypertension were more likely to test positive in the first year, but not in the following year. Ever positive patients were more likely to have a history of type 2 diabetes. Compared to the White patients, Black patients had a higher prevalence of blood type B, and lower prevalence of type A and Rh negative ( Table 2).
Overall, the association was significant for blood type B Among the vaccinated population, no association was observed between any blood type and COVID-19 risk (Table 3).

DISCUSSION
In general, COVID-19 susceptibility varied by ABO blood type, especially in 2020. Specifically, type B was associated with increased risk for viral infection among all racial groups; type AB was associated with increased infection risk among Blacks, but not other racial groups. A significant association was also observed for Rh blood type among Whites in 2020.

TA B L E 1
Distribution of COVID-19 tested cohort at UCM by key demographic factors and comorbidities over time  Findings from the study suggested a modifying role of race/ethnicity in COVID-19 [14,15]. Some possible differences were observed in the associations between blood type and COVID-19 risks. For example, the association of blood type B was more pronounced in Whites and Hispanic patients than in Black patients. In addition to currently unknown biological mechanisms, this difference may also be explained by the varying prevalence across racial groups: the prevalence of blood type B was lower in the Black patients in the study population. We also observed suggestive association of blood type A among White patients, but not Black patients. These findings were consistent with an earlier study that reported associations between blood type A and respiratory distress syndrome among White patients, but not in Black patients [15]. However, given the uncertainty, more studies are warranted to investigate the racial differences.
We only observed associations with ABO and Rh blood types in 2020, consistent with early studies from the same period [8][9][10]. Several possible reasons may explain the null association in the later periods. First, the variants evolved, becoming less sensitive to blood types. Second, preventive measures adopted in the later periods mitigated the impact of blood type. Third, the availability of pharmacologic/biologic therapies or vaccines after the early stage of the pandemic protected patients against any adverse association with blood types.
Several limitations should be considered when interpreting our results. First, our results are based on data collected through COVID-19 testing during the pandemic, which may result in selection bias.
However, the distribution of blood types in our sample is similar to the general population, so selection bias should be minimal as related to blood type. Second, we lacked data on behavioral or occupational differences during the pandemic, which all might vary by race/ethnicity.
In conclusion, race/ethnicity may modify the association between blood type and COVID-19 susceptibility. Although types A and B were observed to be associated with COVID-19 susceptibility, these associations were stronger in Whites than in Blacks and the protection was mitigated significantly as the pandemic context evolved. Identifying biologic mechanisms that underlie these results could help uncover strategies to prevent or treat this major disease.