- Cardiometabolic diseases have been implicated as risk factors for COVID-19 in numerous epidemiologic studies, but these risk factors may be only correlated, not causal
- Using two-sample Mendelian randomization, a method used in statistical genetics for causal inference, researchers at Massachusetts General Hospital found that genetically increased body mass index (BMI) was a causal risk factor for COVID-19 susceptibility and severity severity
- The direct effects of BMI on these outcomes were abolished when the researchers accounted for the genetic effects of type 2 diabetes, suggesting that type 2 diabetes may mediate the causal association of BMI and COVID-19 illness
- 16 other cardiometabolic diseases and traits tested were not causally related to COVID-19
Epidemiologic studies across the world—large and small, prospective and retrospective—have identified cardiometabolic diseases as risk factors for COVID-19. Observational studies can't show, however, whether a cardiometabolic risk factor is causally related to COVID-19.
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To compensate, researchers at Massachusetts General Hospital used an analytic method called Mendelian randomization, which relies on measuring the variation in genes of known function to examine the causal effect of a modifiable risk factor on disease. The team found that body mass index (BMI), but no other cardiometabolic disease or trait, is a causal risk factor for COVID-19 susceptibility and severity.
The results of research led by Aaron Leong, MD, an endocrinologist in the Diabetes Unit at Massachusetts General Hospital and researcher in the Center for Genomic Medicine, and Josep M. Mercader, PhD, research-scientist of the Diabetes Unit and Center for Genomic Medicine, were published on medRxiv, a preprint server. Preprints are not peer-reviewed.
Using statistics from large-scale published genome-wide association studies (GWAS), the team generated genetic datasets for 17 cardiometabolic diseases and traits:
- Type 1 and type 2 diabetes
- Hemoglobin A1c
- Fasting glucose and fasting insulin adjusted for BMI
- Waist–hip ratio
- Triglycerides and low- and high-density lipoprotein cholesterol
- Systolic and diastolic blood pressure
- Creatinine-based estimated glomerular filtration rate
- Chronic kidney disease (CKD)
- Coronary artery disease (CAD)
- C-reactive protein (CRP, can be elevated in people with high cardiometabolic risk)
They tested the datasets against information on two COVID-19 outcomes provided by the international COVID-19 Host Genetics Initiative:
- Susceptibility—6,696 people who tested positive for COVID-19 or were diagnosed by a physician were compared with 1,073,072 population controls
- Severity—3,199 people who were hospitalized with COVID-19 were compared with 897,488 population controls
Genetically increased BMI was causally associated with a higher risk of:
- COVID-19 diagnosis (P = 6.7×10−4)
- COVID-19 hospitalization (P = 8.7×10−4)
To obtain effect sizes, the analysis was repeated using BMI data from the UK Biobank:
- COVID-19 diagnosis: OR, 1.08 per kg/m2 increase in BMI
- COVID-19 hospitalization: OR, 1.12 per kg/m2 increase in BMI
The direct effects of BMI on these outcomes were abolished when the team accounted for the genetic effects of type 2 diabetes, suggesting that type 2 diabetes may mediate the causal association of BMI and COVID-19 illness. Adjusting for the genetic effects of CKD, CAD, stroke and CRP did not attenuate the direct effect of BMI.
Implications for Public Health
Measures designed to diminish the burden of obesity on individuals and communities should be part of strategies to prevent COVID-19 and limit its severity. Conversely, government regulations that increase the risk of obesity (e.g., preventing access to open spaces for exercise) should be reconsidered.
Most of the GWAS consulted had subjects of European ancestry, so the results of this analysis are not necessarily generalizable to people of all races/ethnicities.
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Learn more about the Diabetes Unit at Mass General