A genetic predisposition for Cytokine Storm in life-threatening COVID-19 infection

The COVID-19 pandemic is a cause of serious morbidity and mortality and is placing a significant burden on healthcare systems globally. The clinical manifestations of COVID-19 disease form a wide spectrum, from mild symptoms to life threatening disease. A small subset of patients develop Cytokine Release Syndrome (CRS)/Cytokine Storm (CS) that results in hyper inflammation, clinical deterioration and multi-organ failure. There is growing evidence that Interleukin-6 (IL-6) is a central mediator of CS. Evidence of an inflammatory Kawasaki-like syndrome in children with severe COVID-19 is also emerging. Familial Mediterranean Fever (FMF) and Glucose-6-phosphate Dehydrogenase (G6PD) deficiency are 2 common gene polymorphisms that predispose to hyper inflammatory states. Countries with high mortality rates for COVID-19 deaths (such as Spain, Italy and France) or the Middle East (Iran) also have a high number of carriers of mutations in the Mediterranean Fever gene (MEFV), which causes Familial Mediterranean Fever (FMF). G6PD deficiency, a common enzymopathy caused by X-linked gene polymorphisms that reduce the ability of cells to deal with oxidant stress also has a global distribution affecting Black, Asian and Minority Ethnic (BAME) groups. In combination with acquired causes of inflammation such as obesity, these genetic variations may predispose to increased risk of severe COVID-19. Mendelian randomisation studies are needed to establish if there is a contribution to higher mortality rates in certain populations due to genetic factors such as MEFV or G6PD mutations and related genes and if these may represent predictive and prognostic biomarkers.