How A Common Gene Variant Influences Your Risk of Severe Illness From COVID-19

A new study led by Yale researchers has found that a common genetic variant that occurs in nearly 20% of individuals influences both susceptibility to COVID-19 and the development of severe disease.

“Knowledge of this gene variation can identify patients who need to be monitored and treated more aggressively to prevent severe illness,” said the study’s lead author Jenny Shin, MD, PhD, assistant professor of medicine in the Section of Rheumatology, Allergy & Immunology in the internal medicine department of Yale School of Medicine.

Variant forms of the gene are also associated with complications of different infectious and autoimmune disorders, said Richard Bucala, MD, PhD, Waldemar Von Zedtwitz Professor of Medicine (rheumatology), professor of pathology and of epidemiology (microbial diseases), and the study’s organizer. “The new findings validate the importance of natural variation in our genes in different stages of COVID-19 infection,” Bucala said.

The authors relate their findings in the article, “MIF is a Common Genetic Determinant of COVID-19 Symptomatic Infection and Severity,” published in QJM: An International Journal of Medicine.

The findings are the culmination of a multinational, retrospective case control study of 1,177 patients from three tertiary medical centers in the United States and Europe that examined if common genetic variants in the immune cytokine macrophage migration inhibitory factor (MIF) were associated with COVID-19.

The authors first assessed susceptibility to infection by comparing MIF gene frequencies in COVID-19 patients with a pre-pandemic control group of 637 healthy subjects. Those with a high inflammatory variant of the MIF gene were found to be less likely to be diagnosed with COVID-19. Among all subjects with COVID-19, however, those with the high inflammatory MIF variant were nearly 3-fold more likely to require hospitalization, indicating an underlying role for inflammation in the progression to severe COVID-19 illness.

“This genetic predisposition to severe COVID-19 occurs in 19% of individuals, and the 2.9 fold higher risk of hospitalization after diagnosis occurs independently of age, sex, or other factors,” said Shin. “Knowledge of the gene variant could identify patients who need to be monitored or treated more aggressively to prevent severe illness and hospitalization. The genetic information also could benefit the prioritization of health resources in different parts of the world in future pandemics.”

Yale clinicians had suspected a role for MIF in severe COVID-19 at the outset of the pandemic. Maor Sauler, MD, associate professor of medicine and Geoffrey Chupp, MD, professor of medicine in the Section of Pulmonary, Critical Care & Sleep Medicine, had initiated a clinical phase II trial for severe COVID-19 of a MIF antagonist discovered by Yale pharmacologists before the genetic results were known.

Partnering institutions were Trinity College in Ireland, the University of Pécs and Semmelweis University in Hungary, and the University of Valladolid in Spain. In addition to Shin and Bucala, the authors included Wei Fan, Jennefer Par-Young, Marta Piecychna, Lin Leng, Kavita Israni-Winger, Hua Qing, Jianlei Gu, Hongyu Zhao, Wade L. Schulz, Serhan Unlu, John Kuster, Grant Young, Jian Liu, Albert I Ko, Alvaro Baeza Garcia, Maor Sauler, Adam V. Wisnewski, Lawrence Young, Antonio Orduña, Andrew Wang, Ocskay Klementina, Antonio Blesa Garcia, Peter Hegyi, Michelle E Armstrong, Patrick Mitchell, David Bernardo Ordiz, András Garami, and Insoo Kang.

The Section of Rheumatology, Allergy and Immunology is dedicated to providing care for patients with rheumatic, allergic and immunologic disorders; educating future generations of thought leaders in the field; and conducting research into fundamental questions of autoimmunity and immunology. To learn more about their work, visit Rheumatology, Allergy & Immunology.