Cardiometabolic Risk Factors for COVID-19 Susceptibility and Severity: A Mendelian Randomization Analysis

Abstract

ABSTRACT Importance Early epidemiological studies report associations of diverse cardiometabolic conditions especially body mass index (BMI), with COVID-19 susceptibility and severity, but causality has not been established. Identifying causal risk factors is critical to inform preventive strategies aimed at modifying disease risk. Objective We sought to evaluate the causal associations of cardiometabolic conditions with COVID-19 susceptibility and severity. Design Two-sample Mendelian Randomization (MR) Study. Setting Population-based cohorts that contributed to the genome-wide association study (GWAS) meta-analysis by the COVID-19 Host Genetics Initiative. Participants Patients hospitalized with COVID-19 diagnosed by RNA PCR, serologic testing, or clinician diagnosis. Population controls defined as anyone who was not a case in the cohorts. Exposures Selected genetic variants associated with 17 cardiometabolic diseases, including diabetes, coronary artery disease, stroke, chronic kidney disease, and BMI, at p <5×10 -8 from published largescale GWAS. Main outcomes We performed an inverse-variance weighted averages of variant-specific causal estimates for susceptibility, defined as people who tested positive for COVID-19 vs. population controls, and severity, defined as patients hospitalized with COVID-19 vs. population controls, and repeated the analysis for BMI using effect estimates from UKBB. To estimate direct and indirect causal effects of BMI through obesity-related cardiometabolic diseases, we performed pairwise multivariable MR. We used p <0.05/17 exposure/2 outcomes=0.0015 to declare statistical significance. Results Genetically increased BMI was causally associated with testing positive for COVID-19 [6,696 cases / 1,073,072 controls; p =6.7×10 -4 , odds ratio and 95% confidence interval 1.08 (1.03, 1.13) per kg/m 2 ] and a higher risk of COVID-19 hospitalization [3,199 cases/897,488 controls; p =8.7×10 -4 , 1.12 (1.04, 1.21) per kg/m 2 ]. In the multivariable MR, the direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes but persisted when conditioning on the effects on coronary artery disease, stroke, chronic kidney disease, and c-reactive protein. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Conclusions and Relevance Genetic evidence supports BMI as a causal risk factor for COVID-19 susceptibility and severity. This relationship may be mediated via type 2 diabetes. Obesity may have amplified the disease burden of the COVID-19 pandemic either single-handedly or through its metabolic consequences. KEY POINTS Question Is there a causal association between cardiometabolic conditions and COVID-19 susceptibility or severity? Findings Using two-sample Mendelian randomization of 17 cardiometabolic diseases and traits, only body mass index was found to be causally associated with testing positive for COVID-19 (6,696 cases/ 1,073,072 controls; p =6.7×10 -4 ) and a higher risk of COVID-19 (3,199 cases/897,488 controls; p =8.7×10 -4 ). Meaning Genetic evidence supports BMI as a causal risk factor for COVID-19 susceptibility and severity.