Allelic Variants Within the ABO Blood Group Phenotype Confer Protection Against Critical COVID-19 Hospital Presentation

Abstract

Introduction: Coronavirus disease 2019 (COVID-19) disease severity differs widely due to numerous factors including ABO gene-derived susceptibility or resistance. The objective of this study was to investigate the association of the ABO blood group and genetic variations of the ABO gene with COVID-19 severity in a heterogeneous hospital population sample from the United Arab Emirates, with the use of an epidemiological and candidate gene approach from a genome-wide association study (GWAS).Methods: In this cross-sectional study, a total of 646 participants who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were recruited from multiple hospitals and population-based (quarantine camps) recruitment sites from March 2020 to February 2021. The participants were divided into two groups based on the severity of COVID-19: noncritical (n = 453) and critical [intensive care unit (ICU) patients] (n = 193), as per the COVID-19 Reporting and Data System (CO-RADS) classification. The multivariate logistic regression analysis demonstrated the association of ABO blood type as well as circulating anti-A antibodies and anti-B antibodies as well as A and B antigens, in association with critical COVID-19 hospital presentation. A candidate gene analysis approach was conducted from a GWAS where we examined 240 single nucleotide polymorphisms (SNPs) (position in chr9: 136125788-136150617) in the ABO gene, in association with critical COVID-19 hospital presentation.Results: Patients with blood group O [odds ratio (OR): 0.51 (0.33, 0.79); p = 0.003] were less likely to develop critical COVID-19 symptoms. Eight alleles have been identified to be associated with a protective effect of blood group O in ABO 3'untranslated region (UTR): rs199969472 (p = 0.0052), rs34266669 (p = 0.0052), rs76700116 (p = 0.0052), rs7849280 (p = 0.0052), rs34039247 (p = 0.0104), rs10901251 (p = 0.0165), rs9411475 (p = 0.0377), and rs13291798 (p = 0.0377).Conclusion: Our findings suggest that there are novel allelic variants that link genetic variants of the ABO gene and ABO blood groups contributing to the reduced risk of critical COVID-19 disease. This study is the first study to combine genetic and serological evidence of the involvement of the ABO blood groups and the ABO gene allelic associations with COVID-19 severity within the Middle Eastern population.

The association of COVID-19 severity and susceptibility and genetic risk factors: A systematic review of the literature

“…Other SNPs located on the ABO locus were also found to protect the risk of critical illness from COVID-19 infection. These include rs199969472, rs34266669, rs76700116, rs7849280, rs34039247, rs10901251, rs9411475, and rs13291798 ( Jelinek et al, 2022 ) .…”

“…The lower susceptibility associated with blood group O was supported by a recent meta-analysis of 30 studies (Gutiérrez‐Valencia et al, 2022). Additionally, a recent cross-sectional study showed that blood group O offered a protective effect against developing critical COVID-19 ( Jelinek et al, 2022 ). This could arise since human anti-A antibodies, found in patients with blood group O, are hypothesized to bind to the S protein of SARS-CoV-2, thereby hindering its attachment to the ACE2 receptor and preventing its invasion of lung tissue (R. Goel et al, 2021 ).…”

ABO blood group and link to COVID-19: A comprehensive review of the reported associations and their possible underlying mechanisms

“…Nonetheless, blood type A has been the most associated with severe outcomes, while blood type O frequently appears as a protective factor against the disease progression [ 17 , 18 , 69 , 70 , 77 , [83] , [84] , [85] , [86] , [87] , [88] ]. For instance, although failing to describe a significant difference in ABO phenotype distribution between hospitalized COVID-19 patients and the control group, Muñiz-Diaz et al described a significant positive association between blood type A and mortality, and a significant negative association for blood type O [ 18 ].…”

“…In contrast, after finding significantly lower levels of blood type O among critical COVID-19 patients (vs. non-critical patients), Jelinek et al performed a candidate gene approach based on previous GWAS data and examined 240 SNPs in the ABO gene for association with critical COVID-19 presentation. 8 SNPs located at the ABO 3'untranslated region were significantly associated with disease severity, with significantly lower frequencies of the risk alleles in non-critical patients with blood type O [ 83 ].…”

“… 6.492 patients vs. rs505922 Susceptibility, hospitalization and severity. 1.012.809 controls Pathak et al [ 103 ] International COVID-19 hospitalized patients vs. 7.885 cases vs. 961.804 controls – Severity controls CHGI [ 92 ] International (multiethnic) COVID-19 patients vs. matched controls 49.562 cases vs. 2.000.000 controls rs91280525 Susceptibility and severity Shelton et al [ 91 ] US/UK SARS-CoV-2 positive vs. controls 12.972 cases vs. 101.268 controls rs9411378 Susceptibility Vargas-Alarcón et al [ 94 ] Mexico COVID-19 patients vs. healthy hospital staff members 415 cases vs. 288 controls rs8176740 and rs512770 Susceptibility and platelets concentration Jelinek et al [ 83 ] United Arab Emirates Critical vs. non-critical COVID-19 patients 193 cases vs. 453 controls rs199969472, rs34266669, rs76700116, rs7849280, rs34039247, rs10901251, rs9411475, and rs13291798 Severity Nishida et al [ 97 ] Japan COVID-19 patients vs. healthy controls 461 cases vs. 1.193 controls rs8176719 and rs8176747 (ABO) and rs1047781 (FUT2) Susceptibility Palmos et al [ 99 ] International Mendelian Randomiation ...…”