How are genetics, lifestyles, and cardiovascular and thromboembolic events associated following COVID-19 diagnosis?

A recent study published in Nature Communications evaluated the associations between host genetics, lifestyle factors, and cardiovascular and thromboembolic events (CVEs) after coronavirus disease 2019 (COVID-19).

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide. COVID-19 sequelae and repercussions are expected to further contribute to the increasing CVD burden. Prevention of life-threatening CVEs is crucial during COVID-19 treatment. Nevertheless, it remains a challenge to accurately identify at-risk individuals to warrant targeted prophylaxis or intensive surveillance.

Although prophylactic coagulation is recommended for hospitalized COVID-19 patients, mixed evidence exists for milder ambulatory and more critical COVID-19 patients. Polygenic risk scores (PRSs) have been proposed for early risk stratification and precision medicine. Whether genetic susceptibility to chronic CVD predisposes COVID-19 patients to CVE complications is unknown.

About the study

In the study, researchers assessed the associations between lifestyle factors, host genetics, and the risk of CVEs following COVID-19 diagnosis.

They included a cohort of individuals from the United Kingdom Biobank with a positive COVID-19 test between March 2020 and September 2022. The Biobank released a list of (standard and enhanced) PRSs for 28 diseases in May 2022. Standard PRSs were used for venous thromboembolic disease (VTE), atrial fibrillation (AF), ischemic stroke (ISS), and coronary artery disease (CAD).

Detailed information on lifestyles was obtained through questionnaires. A composite healthy lifestyle score was estimated based on nine lifestyle factors (alcohol intake, time spent watching television, smoking status, sleep duration, physical activity, and intake of fruits, vegetables, oily fish, and red or processed meat). The first infection was defined as the index date, and four CVEs (CAD, ISS, VTE, and AF) were studied during a follow-up of 90 days.

Cox proportional hazard models assessed associations of each PRS for CVE with the corresponding post-COVID-19 complication. The associations were additionally evaluated in sub-groups of age, sex, body mass index (BMI), ethnicity, recent anti-thrombotic medication, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection type (vaccine breakthrough or non-breakthrough).

Numerous sensitivity analyses using enhanced PRSs were performed to test the robustness of the primary findings.

Findings

Overall, the study included 106,005 COVID-19 patients, with an average age of 67.6. Most patients were White (89.4%) and female (54.8%). The prevalence of unhealthy lifestyle factors ranged between 8.7% for smoking and 53% for the intake of red meat. More than half the cohort (54.7%) showed a favorable composite lifestyle, while 7.4% had an unfavorable lifestyle.

In total, 1,397 AF, 244 VTE, 104 ISS, and 733 CAD events were reported during the 90-day follow-up after COVID-19. The incidence rates were 4.14 for ISS, 9.73 for VTE, 29.3 for CAD, and 56.05 for AF per 1000 person-years. The cumulative incidence of most CVEs (CAD, VTE, and AF) increased dramatically within 30 days post-COVID-19 and flattened afterward.

Subjects with a higher genetic risk had a higher incidence of CVEs in a dose-dependent manner than those with a lower genetic risk. Higher genetic risk was linearly associated with increased risks of CVEs. The associations were similarly reproduced across different subgroups. Moreover, genetic risks for CVEs persisted among fully vaccinated individuals with a breakthrough infection.

Further, subjects with healthier lifestyles pre-COVID-19 had significantly lower risks of CVEs than those with less healthy lifestyles. Participants with favorable lifestyles had lower cumulative incidences than those with unfavorable or moderate lifestyles. Notably, the protective associations of healthy lifestyles attenuated during the Omicron period.

Besides, an additive association was identified between lifestyle and genetic factors for CAD and AF post-COVID-19, with the highest cumulative incidence among those with unfavorable lifestyles and high genetic risk and the lowest among those with favorable lifestyles and low genetic risk. Sensitivity analyses produced consistent results. However, the magnitude of genetic associations was notably higher for all outcomes using enhanced PRSs.

Conclusions

Taken together, the study revealed that increased genetic risk was linearly associated with a higher incidence of post-COVID-19 CVEs. Specifically, subjects with the top 20% of PRSs showed 2.6, 2.1, 3.3-, and 3.4-fold excess risks of ISS, VTE, CAD, and AF, respectively, relative to those with the lowest 20%. A compositive favorable lifestyle was associated with lower risks of post-COVID-19 CVEs.

Moreover, an additive association was observed between lifestyle factors and genetic predisposition that was more pronounced for CAD and AF and less substantial for ISS and VTE. Overall, the findings underscore that lifestyles and genetics independently influence the occurrence of post-COVID-19 CVEs that can inform healthy lifestyle interventions to offset the cardiovascular burden.