Biomarker may protect against severe COVID in people with obesity (By: Mary Van Beusekom, MS)
Researchers have identified a protein biomarker that appears to protect against severe COVID-19 in people with obesity.
A team led by Population Health Research Institute researchers in Ontario, Canada, conducted a genetic association study that used two-sample Mendelian randomization (MR) to assess 235 genetically determined circulating biomarkers, cardiometabolic risk factors (eg, obesity, type 2 diabetes [T2D], high blood pressure), and COVID-19 hospitalization in 2022. MR uses genetic associations with a causal factor and outcome to infer causality.
The researchers analyzed blood samples from 22,101 people, including 4,147 with blood-glucose and cardiovascular risk factors participating in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. These conditions are risk factors for severe COVID-19, but the biological mechanisms linking them with infection severity haven’t been completely elucidated, the study authors noted.
The team also obtained genome-wide association study statistics from previous independent plasma proteome studies, genetic consortia for certain cardiometabolic risk factors, and the COVID-19 Host Genetics Initiative.
The study was published today in JAMA Network Open.
Obesity upregulates KIM-1
MR analysis showed that, of the 235 biomarkers, only higher levels of kidney injury molecule-1 (KIM-1) were associated with lower odds of COVID-19 hospitalization (odds ratio [OR] per standard deviation [SD] increase in KIM-1 levels, 0.86).
A meta-analysis validated the protective association, with no observed directional pleiotropy, or bias (OR per SD increase in KIM-1, 0.91). Of all cardiometabolic risk factors, only body mass index (BMI) was linked to KIM-1 levels (BMI; 0.17 SD increase in biomarker per 1 kilogram per square meter [kg/m2]) and COVID-19 hospitalization (OR per 1-SD biomarker level, 1.33).
A multivariable MR analysis also showed that KIM-1 partially mitigated the association of BMI with COVID-19 hospitalization, decreasing it by 10 percentage points (OR adjusted for KIM-1 level per 1 kg/m2, 1.23).
“Individuals with obesity have a 2.1-fold increase in hospitalization, a 1.7-fold increase in admission to the intensive care unit, and a 1.5-fold increase in death as a result of severe COVID-19,” the study authors wrote. “Similar odds were also reported for T2D and hypertension.”
Findings could lead to drug development
KIM-1 (also known as hepatitis A virus cellular receptor 1) is expressed in the kidney, lung, liver, and spleen and helps control viral infection and autoimmunity through multiple mechanisms. It also is a blood and urine marker of acute kidney injury (AKI) and is being studied for the development of drugs to treat kidney disease.
The researchers noted that previous studies have shown that urinary KIM-1 levels were higher than normal in COVID-19 patients, regardless of whether they had AKI.
“Moreover, KIM-1 may act as a receptor for SARS-CoV-2, the virus causing COVID-19, in both lung and kidney epithelia; according to this, the entry and progression of SARS-CoV-2 may be promoted with elevated KIM-1 levels,” the researchers wrote.
While high BMI may chronically boost KIM-1 expression involved in progressive kidney fibrosis and chronic kidney failure, in acute situations such as COVID-19, high KIM-1 levels may downregulate inflammation and immune responses.
“This early KIM-1–mediated mechanism after ischemic or toxic injury has been well described in acute kidney injury and has been reported as a natural defense system against acute tubular injury, facilitating tissue repair,” the researchers wrote.
Evidence of causal and/or protective relationships among cardiometabolic risk factors, biomarkers, and adverse prognoses in patients with COVID-19 could guide therapeutic decisions, improve risk stratification for COVID-19 severity, and identify new therapeutic targets.
The authors noted that KIM-1 has been associated with viruses other than SARS-CoV-2, acting, for instance, as a receptor or cofactor for Zaire Ebola virus and as a facilitator for dengue virus entry into target cells. “Promoting cellular entry may not necessarily promote adverse infection,” they wrote. “For example, although KIM-1 enhances the cellular internalization of HIV, it also helps inhibit the release of viral particles from the cell, thereby ‘trapping’ the virus within the cell.”
The team called for more research into the possible protective effect of KIM-1 in COVID-19 hospitalization among patients with cardiometabolic risk factors for severe illness. “Information regarding the potentially attenuating role of KIM-1 may be of clinical interest not only in the acute phase but also during the post-COVID recovery phase,” they wrote.
“Evidence of causal and/or protective relationships among cardiometabolic risk factors, biomarkers, and adverse prognoses in patients with COVID-19 could guide therapeutic decisions, improve risk stratification for COVID-19 severity, and identify new therapeutic targets,” they concluded.
