Diabetes Genetics & COVID-19 Severity

COVID

Clinical experience suggested that patients with preexisting diabetes and concomitant cardiometabolic comorbidities are more likely to have poor clinical outcomes from COVID-19. This research examined diabetes-related complications in acute COVID-19 illness, including new and persistent hyperglycemia, diabetic ketoacidosis, and severe insulin resistance.

Study Design

Aims & Outcomes

Aims

Evaluate causal associations of cardiometabolic diseases and traits with COVID-19 severity.
Examine whether global genetic risk, variation in candidate cardiometabolic genes, and molecular targets of diabetes drugs are associated with diabetes-related complications in acute COVID-19 illness.
Test for mediation and interaction with prior diabetes diagnosis, prior A1C, obesity, diabetes drug exposures, and circulating ACE2, among other cardiometabolic biomarkers.

Outcomes

Results support the conclusion that higher BMI is a causal risk factor for both COVID-19 susceptibility and severity.

Published Research

From “which risk factors are causal” to “which patients need watching.”

These two papers answer two different but connected questions: which cardiometabolic conditions actually cause worse COVID-19 outcomes (rather than just correlating with them), and once someone is hospitalized, which blood biomarkers flag who’s about to get sicker.

PLoS Medicine · 2021

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

Leong A, Cole JB, Brenner LN, Meigs JB, Florez JC, Mercader JM. PLoS Medicine. 2021;18(3):e1003553. doi:10.1371/journal.pmed.1003553

Early in the pandemic, obesity, diabetes, and other cardiometabolic conditions were all correlated with worse COVID-19 outcomes — but correlation isn’t causation, since sicker patients often have more comorbidities for unrelated reasons. Using two-sample Mendelian randomization — a method that uses genetic variation to approximate a randomized experiment — this study tested 17 cardiometabolic traits and found that body mass index, and only body mass index, showed evidence of a truly causal relationship with both COVID-19 susceptibility and severity, with the effect potentially working through type 2 diabetes.

Illustrative summary of the Mendelian randomization result — only BMI’s confidence interval clears the “no effect” line. Point positions and interval widths are schematic, not the paper’s exact estimates; 13 additional traits tested are omitted here for space. See the paper for full results.

Cardiovascular Diabetology · 2022

Proteomic Analysis of Cardiometabolic Biomarkers and Predictive Modeling of Severe Outcomes in Patients Hospitalized with COVID-19

Schroeder PH, Brenner LN, Kaur V, Cromer SJ, Armstrong K, LaRocque RC, Ryan ET, Meigs JB, Florez JC, Charles RC, Mercader JM, Leong A. Cardiovascular Diabetology. 2022;21:136. doi:10.1186/s12933-022-01569-7

If cardiometabolic disease worsens COVID-19 outcomes, the team reasoned, the blood might show early signs of it. Measuring 92 circulating protein biomarkers previously linked to cardiometabolic disease in 343 patients hospitalized during the first pandemic wave, the team identified seven biomarkers that predicted admission to the ICU or death within 28 days — two (ADAMTS13 and VEGFD) associated with lower risk, the rest with higher risk — and the resulting model held up when tested against a separate group of 194 patients hospitalized later in the same surge.

Co-authored by former team member Philip Schroeder, MS; current team member Vicky Kaur (listed as Varinderpal Kaur); and collaborator Josep Mercader, PhD.

Illustrative summary of the seven-biomarker signature’s direction of effect — bar lengths are schematic, not the paper’s actual effect sizes. See the paper for full statistics on all seven biomarkers.