Cardiometabolic risk factors for COVID-19 susceptibility and severity: A Mendelian randomization analysis

Abstract

Background Epidemiological studies report associations of diverse cardiometabolic conditions including obesity with COVID-19 illness, but causality has not been established. We sought to evaluate the associations of 17 cardiometabolic traits with COVID-19 susceptibility and severity using 2-sample Mendelian randomization (MR) analyses. Methods and findings We selected genetic variants associated with each exposure, including body mass index (BMI), at p < 5 × 10−8 from genome-wide association studies (GWASs). We then calculated inverse-variance-weighted averages of variant-specific estimates using summary statistics for susceptibility and severity from the COVID-19 Host Genetics Initiative GWAS meta-analyses of population-based cohorts and hospital registries comprising individuals with self-reported or genetically inferred European ancestry. Susceptibility was defined as testing positive for COVID-19 and severity was defined as hospitalization with COVID-19 versus population controls (anyone not a case in contributing cohorts). We repeated the analysis for BMI with effect estimates from the UK Biobank and performed pairwise multivariable MR to estimate the direct effects and indirect effects of BMI through obesity-related cardiometabolic diseases. Using p < 0.05/34 tests = 0.0015 to declare statistical significance, we found a nonsignificant association of genetically higher BMI with testing positive for COVID-19 (14,134 COVID-19 cases/1,284,876 controls, p = 0.002; UK Biobank: odds ratio 1.06 [95% CI 1.02, 1.10] per kg/m2; p = 0.004]) and a statistically significant association with higher risk of COVID-19 hospitalization (6,406 hospitalized COVID-19 cases/902,088 controls, p = 4.3 × 10−5; UK Biobank: odds ratio 1.14 [95% CI 1.07, 1.21] per kg/m2, p = 2.1 × 10−5). The implied direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes, coronary artery disease, stroke, and chronic kidney disease. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Small study samples and weak genetic instruments could have limited the detection of modest associations, and pleiotropy may have biased effect estimates away from the null. Conclusions In this study, we found genetic evidence to support higher BMI as a causal risk factor for COVID-19 susceptibility and severity. These results raise the possibility that obesity could amplify COVID-19 disease burden independently or through its cardiometabolic consequences and suggest that targeting obesity may be a strategy to reduce the risk of severe COVID-19 outcomes.

Reversion of Gut Microbiota during the Recovery Phase in Patients with Asymptomatic or Mild COVID-19: Longitudinal Study

“…However, gut dysbiosis by various factors has deleterious effects on host health, including the gastrointestinal tract [26] and immune system [27], and metabolic diseases [28]. The F/B ratio is known as a hallmark of obesity, and, interestingly, two recent studies have reported strong evidence for a causal impact of obesity on the susceptibility and severity of COVID-19 [29,30]. However, recent studies have reported no association between the F/B ratio and obesity [31].…”

Obesity as a Risk Factor for Severe COVID-19: Summary of the Best Evidence and Implications for Health Care

“…Further work examining whether measures of central adiposity (i.e., waist or waist to hip ratio) give better estimates of risks of excess (regional) adiposity from COVID-19, would also be useful. Additional genetic data to validate early findings from Leong and colleagues [ 9 ••] would also be valuable, including extending results to differing ethnic groups and to genetic variants linked to measures of body fat distribution. With respect to interventions, it is unlikely that a weight loss trial can be adequately powered or sufficiently large enough to prove benefits of intentional weight loss on COVID-19 risks.…”

“…Such methods have been used to support higher BMI as a causal risk factor for multiple cardiovascular outcomes (e.g., coronary heart disease, atrial fibrillation and heart failure) [ 8 •], and many other diseases. Using this MR approach, Leong and colleagues related genetics that underpin 17 cardiometabolic traits to risk for COVID-19 outcomes [ 9 ••]. The only statistically positive association was for genes that predict higher BMI—a 14% (95% CI 7 to 21%) higher risk for COVID-19 hospitalisation per every 1kg/m 2 higher BMI level was noted, a risk around twice seen in observational studies.…”

The effect of obesity-related traits on COVID-19 severe respiratory symptoms is mediated by socioeconomic status: a multivariable Mendelian randomization study

“…The association of obesity-related traits with COVID-19 outcomes has been confirmed by multiple investigations, also including MR analyses that showed putative causal effects of BMI [9,10,11,41,42], WC [9,10], and trunk fat ratio [9]. Some of these previous investigations also have included MVMR analyses that highlighted how the effect of these traits on COVID-19 is independent of several cardiometabolic traits and other known risk factors [43].…”