COVID-19 Is a Coronary Artery Disease Risk Equivalent and Exhibits a Genetic Interaction With ABO Blood Type

Abstract

Background: COVID-19 is associated with acute risk of major adverse cardiac events (MACE), including myocardial infarction, stroke, and mortality (all-cause). However, the duration and underlying determinants of heightened risk of cardiovascular disease and MACE post-COVID-19 are not known.

Methods: Data from the UK Biobank was used to identify COVID-19 cases (n=10 005) who were positive for polymerase chain reaction (PCR⁺)-based tests for SARS-CoV-2 infection (n=8062) or received hospital-based International Classification of Diseases version-10 (ICD-10) codes for COVID-19 (n=1943) between February 1, 2020 and December 31, 2020. Population controls (n=217 730) and propensity score-matched controls (n=38 860) were also drawn from the UK Biobank during the same period. Proportional hazard models were used to evaluate COVID-19 for association with long-term (>1000 days) risk of MACE and as a coronary artery disease risk equivalent. Additional analyses examined whether COVID-19 interacted with genetic determinants to affect the risk of MACE and its components.

Results: The risk of MACE was elevated in COVID-19 cases at all levels of severity (HR, 2.09 [95% CI, 1.94-2.25]; P<0.0005) and to a greater extent in cases hospitalized for COVID-19 (HR, 3.85 [95% CI, 3.51-4.24]; P<0.0005). Hospitalization for COVID-19 represented a coronary artery disease risk equivalent since incident MACE risk among cases without history of cardiovascular disease was even higher than that observed in patients with cardiovascular disease without COVID-19 (HR, 1.21 [95% CI, 1.08-1.37]; P<0.005). A significant genetic interaction was observed between the ABO locus and hospitalization for COVID-19 (P_interaction=0.01), with risk of thrombotic events being increased in subjects with non-O blood types (HR, 1.65 [95% CI, 1.29-2.09]; P=4.8×10^-5) to a greater extent than subjects with blood type O (HR, 0.96 [95% CI, 0.66-1.39]; P=0.82).

Conclusions: Hospitalization for COVID-19 represents a coronary artery disease risk equivalent, with post-acute myocardial infarction and stroke risk particularly heightened in non-O blood types. These results may have important clinical implications and represent, to our knowledge, one of the first examples of a gene-pathogen exposure interaction for thrombotic events.

Keywords: COVID-19; SARS-CoV-2; genetics; major adverse cardiac events; myocardial infarction; stroke; thrombosis.

Figure 1.

Overview of clinical and genetic analyses. A study was designed with 416 588 UK Biobank subjects who had hospital in-patient data and were alive on February 1, 2020 (pink box). COVID-19 cases at all levels of severity were defined as subjects who had either a positive polymerase chain reaction (PCR) test for SARS-CoV-2 infection or received a hospital-based International Classification of Diseases version-10 (ICD-10) code for COVID-19 through October 31, 2022 (light green box). Severe cases were defined as the subset of subjects who were hospitalized for COVID-19 (dark green inset box). Population controls were defined as subjects alive on February 1, 2020 and who did not have a positive PCR test for SARS-CoV-2 infection or who had ever been assigned a hospital-based ICD-10 code for COVID-19 through December 31, 2020 (yellow box). Controls were then randomly assigned an enrollment date based on the start dates of all COVID-19 case and matched to cases at a ratio of 20:1. After exclusion of subjects with thrombotic events or death within 30 days of the date of entry into analysis (gray box), 10 005 COVID-19 cases and 217 730 population controls (green and yellow boxes) were used to evaluate association of COVID-19 with major adverse cardiac events (MACE), defined as myocardial infarction (MI), stroke, or all-cause mortality, up until October 31, 2022 (orange box). Gene-pathogen exposure interactions on the risk of thrombotic events were performed with previously identified genetic variants (blue box).

Figure 2.

Hospitalization for COVID-19 is associated with an increased risk of major adverse cardiac event (MACE). A, Among hospitalized cases and all population controls, COVID-19 increased cumulative incidence of MACE (MI, stroke, or all-cause mortality) in both subjects with and without cardiovascular disease (CVD). B, COVID-19 similarly increased cumulative incidence of MACE when comparing hospitalized cases to propensity score–matched population controls.

Figure 3.

COVID-19 Represents a CAD (CVD) Risk Equivalent. Cumulative incidence of MACE in hospitalized COVID-19 cases without CVD (red line) was equivalent to that observed in all population controls with CVD (purple line) or PAD (pink line), and even greater than in population controls with diabetes (green line). Incidence of MACE was highest among hospitalized COVID-19 cases with CVD (blue line).

Figure 4.

Hospitalization for COVID-19 increases risk of thrombotic events through a genetic interaction with ABO blood group. COVID-19 increased cumulative incidence of myocardial infarction and stroke to a greater extent among hospitalized cases with non-O blood types than blood type O, leading to a significant gene-pathogen exposure interaction (P_interaction=0.01). No differences in rate of thrombotic events was observed as a function of ABO blood type among all population controls.