NEW YORK (Reuters Health) – Epigenetic biomarkers could help identify COVID-19-positive individuals who are at high risk for severe disease despite a lack of comorbidities and other known risk factors, researchers suggest.

Epigenetic changes are heritable but do not involve changes to the underlying DNA sequences of genes; however, they do affect how those genes are expressed. DNA methylation (i.e., addition of methyl groups to a DNA molecule) is one way that epigenetic changes affect gene expression.

“We have found a molecular signature in the genome of healthy people that predicts those who are going to experience severe disease versus those who will be fine,” Dr. Manel Esteller of the Josep Carreras Leukaemia Research Institute in Barcelona told Reuters Health by email.

“Those with worse outcomes are born with an epigenomic profile that makes them very prone to exaggerated immune and inflammatory responses, and have a higher tendency to develop metabolic disorders such as diabetes,” he said.

“The idea is that a blood test (or even eventually a saliva sample) will give the health professional a likelihood/probability of that person developing high-risk COVID-19,” he explained. “Our assay (which provides a result within three days) can be combined with clinical, epidemiological and other laboratory data to indicate the high-risk group of people who, when infected, will show a bad clinical course.”

“In the future,” he added, “we can think about drugs that remove these aberrant chemical marks in new treatments of the disease. Some of these epigenetics compounds are now given in the context of cancer, particularly in leukemia, lymphoma and sarcoma.”

As reported in EBioMedicine, Dr. Esteller and colleagues performed an epigenome-wide association study to identify candidate loci that could be involved in the onset of COVID-19 in patients without comorbidities.

They analyzed peripheral blood samples from 407 confirmed COVID-19 patients without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) who had a severe clinical course that required respiratory support.

Participants were divided into discovery and validation cohorts, balanced for age and sex. The mean age was 42 and a little more than half (54.5%) were women.

Analyses of 850,000 CpG sites (DNA regions where a cytosine nucleotide is followed by a guanine nucleotide) in these patients revealed that the DNA methylation status of 44 CpG sites was associated with COVID-19 severity.

Of these 44, 23 (52.3%) were located in 20 coding genes. These genes – such as the inflammasome component Absent in Melanoma 2 and the Major Histocompatibility Complex, class I C candidates – were mainly involved in the response of interferon to viral infection.

Overall, after adjustment for sex and age, of the 44 CpGs in which DNA methylation status differed significantly between asymptomatic/paucisymptomatic and severe COVID-19 patients, 37 (84.1%) were also significantly associated with worse clinical outcomes in the validation cohort.

The predictive value of the CpG sites in which DNA methylation status was associated with COVID-19 severity in the discovery cohort was confirmed in the validation cohort.

The findings were used to establish a DNA methylation signature, which the team calls EPICOVID, that is associated with the severity of the disease.

The authors state, “Our findings demonstrate the existence of differential DNA methylation sites that distinguish COVID-19 patients with paucisymptomatic clinical status from those who will require hospitalized oxygen therapy, including mechanical ventilation and additional organ support measures. The epigenetic loci identified were mostly located within genes associated with the interferon response pathway.”

Infectious diseases specialist Dr. Matthew Robinson, a member of the Advisory Team for the Johns Hopkins Precision Medicine Center of Excellence for COVID-19 in Baltimore, commented on the study in an email to Reuters Health. “Despite a year and a half of intensive global research on COVID-19, researchers and clinicians have limited insight into why some patients develop mild disease and others develop severe disease,” he said.

“These findings bring a new discipline – epigenetics – into the effort to explore COVID-19 severity risk,” he added. “However, it is difficult to imagine that this will be used clinically in the short-term, as the lab infrastructure to perform epigenetic profiling is not easily accessible where patients present for COVID-19 care, and the additive benefit for risk prediction using epigenetic profiling beyond simpler measures remains to be proven.”

SOURCE: https://bit.ly/3hUDurV EBioMedicine, online April 15, 2021.

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