Healthy lifestyle for the prevention of post-COVID-19 multisystem sequelae, hospitalization, and death: a prospective cohort study (preprint)

Abstract Background Post-COVID complications are emerging as a global public health crisis. Effective prevention strategies are needed to inform patients, clinicians and policy makers, and to reduce their cumulative burden. We aimed to investigate whether a habitual healthy lifestyle predated pandemic is associated with lower risks of multisystem sequelae and other adverse outcomes of COVID-19, and whether the potential protective effects are independent of pre-existing comorbidities. Methods The prospective population-based cohort study enrolled participants with SARS-CoV-2 infection confirmed by a positive polymerase chain reaction test result between March 1, 2020, and March 1, 2022. Participants with no history of the related outcome one year before infection were included and followed up for 210 days. Exposures included ten modifiable healthy lifestyle factors including past or never smoking, moderate alcohol intake ([≤]4 times week), body mass index <30 kg/m2, at least 150 minutes of moderate or 75 minutes of vigorous physical activity per week, less sedentary time (<4 hours per day), healthy sleep duration (7-9 hours per day), adequate intake of fruit and vegetables ([≥]400 g/day), adequate oily fish intake ([≥]1 portion/week), moderate intake of red meat ([≤]4 portions week) and processed meat ([≤]4 portions week). Outcomes included multisystem COVID-19 sequelae (consisting of 75 diseases/symptoms in 10 organ systems), death, and hospital admission following SARS-CoV-2 infection, confirmed by hospital inpatient and death records. Risk was reported in relative scale (hazard ratio [HR]) and absolute scale (absolute risk reduction [ARR]) during both the acute (the first 30 days) and post-acute (30-210 days) phases of infection using Cox models. Findings A total of 68,896 participants (mean [SD] age, 66.6 [8.4]; 32,098 women [46.6%]) with COVID-19 were included. A favorable lifestyle (6-10 healthy lifestyle factors; 46.4%) was associated with a 36% lower risk of multisystem sequelae of COVID-19 (HR, 0.64; 95% CI, 0.58-0.69; ARR, 7.08%; 95% CI, 5.98-8.09), compared with unfavorable lifestyle (0-4 factors; 12.3%). Risk reductions were observed across all 10 prespecified organ systems including cardiovascular, coagulation, metabolic and endocrine, gastrointestinal, kidney, mental health, musculoskeletal, neurologic, and respiratory disorders, and general symptoms of fatigue and malaise. This beneficial effect was largely attributable to direct effects of healthy lifestyle, with mediation proportion ranging from 44% to 93% across organ systems. A favorable lifestyle was also associated with lower risk of post-COVID death (HR, 0.59; 95% CI, 0.52-0.66; ARR, 1.99%; 95% CI, 1.61-2.32) and hospitalization (HR, 0.78; 95% CI, 0.73-0.84; ARR, 6.14%; 95% CI, 4.48-7.68). These associations were observed after accounting for potential misclassification of lifestyle factors, and during acute and post-acute infection, in those tested positive in the hospital and community setting, and independent of vaccination status or SARS-CoV-2 variant. Interpretation Adherence to a healthy lifestyle predated pandemic was associated with substantially lower risk of complications across organ systems, death, and hospitalization following COVID-19, regardless of phases of infection, vaccination status, test setting, and SARS-CoV-2 variants, and independent of comorbidities. These findings illustrate the benefits of adhering to a healthy lifestyle to reduce the long-term adverse health consequences following SARS-CoV-2 infection.

HLA Alleles, COVID-19 Vaccine Antibody Response and Real-World Breakthrough Outcomes (preprint)

The rapid development, approval, and global distribution of COVID-19 vaccines represent an unprecedented intervention in public health history, with over 13 billion doses administered worldwide in two years. However, our understanding of the HLA genetic underpinnings of COVID-19 vaccine-induced antibody responses and their clinical implications for breakthrough outcomes remain limited. To bridge this knowledge gap, we designed and performed a series of genetic and epidemiological analyses among 368,098 vaccinated individuals, and a subset of 194,371 participants who had antibody serology tests. Firstly, we corroborated earlier findings that SNPs associated with antibody response were predominantly located in Major Histocompatibility Complex region, and that the expansive HLA-DQB1*06 allele family was linked to better antibody responses. However, our findings contest the claim that DQB1*06 alleles alone significantly impact breakthrough risks. Additionally, our results suggest that the specific DQB1*06:04 subtype could be the true causal allele, as opposed to the previously reported DQB1*06:02. Secondly, we identified and validated six new functional HLA alleles that independently contribute to vaccine-induced antibody responses. Moreover, we unravelled additive effects of variations across multiple HLA genes that, concurrently, change the risk of clinically relevant breakthrough COVID-19 outcomes. Finally, we detangled the overall vaccine effectiveness and showed that antibody positivity accounts for approximately 20% protection against breakthrough infection and 50% against severe outcomes. These novel findings provide robust population evidence demonstrating how variations within HLA genes strongly, collectively, and causally influence vaccine-induced antibody responses, and the risk of COVID-19 breakthrough infection and related outcomes, with implications for subsequent functional research and personalised vaccination.

Contribution of genetics and lifestyle to the risk of major cardiovascular and thromboembolic complications following COVID-19 (preprint)

Clinical determinants for cardiovascular and thromboembolic (CVE) complications of COVID-19 are well-understood, but the roles of genetics and lifestyle remain unknown. We performed a prospective cohort study using UK Biobank, including 25,335 participants with confirmed SARS-CoV-2 infection between March 1, 2020, and September 3, 2021. Outcomes were hospital-diagnosed atrial fibrillation (AF), coronary artery disease (CAD), ischemic stroke (ISS), and venous thromboembolism (VTE) within 90 days post-infection. Heritable risk was represented by validated polygenic risk scores (PRSs). Lifestyle was defined by a composite of nine variables. We estimated adjusted hazard ratios (aHR) and confidence intervals (CI) using Cox proportional hazards models. In the COVID-19 acute phase, PRSs linearly predicted a higher risk of AF (aHR 1.52 per standard deviation increase, 95% CI 1.39 to 1.67), CAD (1.59, 1.40 to 1.81), and VTE (1.30, 1.11 to 1.53), but not ISS (0.92, 0.64 to 1.33). A healthy lifestyle was associated with a substantially lower risk of post-COVID-19 AF (0.70, 0.53 to 0.92), CAD (0.64, 0.44 to 0.91), and ISS (0.28, 0.12 to0.64), but not VTE (0.82, 0.48 to 1.39), compared with an unhealthy lifestyle. No evidence for interactions between genetics and lifestyle was found. Our results demonstrated that population genetics and lifestyle considerably influence cardiovascular complications following COVID-19, with implications for future personalised thromboprophylaxis and healthy lifestyle campaigns to offset the elevated cardiovascular disease burden imposed by the ongoing pandemic.

Contribution of genetics and lifestyle to the risk of major cardiovascular and thromboembolic complications following COVID-19 (preprint)

Clinical determinants for cardiovascular and thromboembolic (CVE) complications of COVID-19 are well-understood, but the roles of genetics and lifestyle remain unknown. We performed a prospective cohort study using UK Biobank, including 25,335 participants with confirmed SARS-CoV-2 infection between March 1, 2020, and September 3, 2021. Outcomes were hospital-diagnosed atrial fibrillation (AF), coronary artery disease (CAD), ischemic stroke (ISS), and venous thromboembolism (VTE) within 90 days post-infection. Heritable risk was represented by validated polygenic risk scores (PRSs). Lifestyle was defined by a composite of nine variables. We estimated adjusted hazard ratios (aHR) and confidence intervals (CI) using Cox proportional hazards models. In the COVID-19 acute phase, PRSs linearly predicted a higher risk of AF (aHR 1.52 per standard deviation increase, 95% CI 1.39 to 1.67), CAD (1.59, 1.40 to 1.81), and VTE (1.30, 1.11 to 1.53), but not ISS (0.92, 0.64 to 1.33). A healthy lifestyle was associated with a substantially lower risk of post-COVID-19 AF (0.70, 0.53 to 0.92), CAD (0.64, 0.44 to 0.91), and ISS (0.28, 0.12 to0.64), but not VTE (0.82, 0.48 to 1.39), compared with an unhealthy lifestyle. No evidence for interactions between genetics and lifestyle was found. Our results demonstrated that population genetics and lifestyle considerably influence cardiovascular complications following COVID-19, with implications for future personalised thromboprophylaxis and healthy lifestyle campaigns to offset the elevated cardiovascular disease burden imposed by the ongoing pandemic.

The prevalent RNA modification on SARS-CoV-2 RNAs may confound the SNP profile and evolutionary patterns revealed by previous studies (preprint)

Background The recent outbreak of SARS-CoV-2 has caused severe damage to the world. The concomitant papers on the evolutionary patterns of SARS-CoV-2 is continuously emerging. Studies has utilized the publically available RNA-seq data to find out the so-called SNPs in the virus genome and analyzed their selection patterns.Methods We downloaded a set of RNA-seq data and performed a well-established but modified variant calling pipeline to allow the identification of multiple clustered mutations.Results We found prevalent “putative” but reliably detected A-to-G RNA modifications in the RNA-seq data of SARS-CoV-2 with high signal to noise ratios, presumably caused by the host’s deamination enzymes. Importantly, since SARS-CoV-2 is an RNA virus, it is technically impossible to truly distinguish SNPs and RNA modifications from the RNA-seq data alone.Conclusions The technically indistinguishable RNA modifications and SNPs of SARS-CoV-2 have complicated the situation where many researchers intend to unveil the evolutionary patterns behind the mutation spectrum. This is not a problem for DNA organisms but should be seriously considered when we are investigating the RNA viruses.