In this study, we found a significantly lower incidence of MEFV gene mutation carriage rate among patients with COVID-19 infection in comparison to the normal population in the region which was in line with our primary hypothesis. The idea of MEFV gene mutations protective role against infectious diseases or other environment factors is been proposed previously due to the preserved status of high MEFV gene mutations throughout centuries. For example it's suggested that heterozygote carriers may have a higher resistance against tuberculosis and brucellosis (13, 14), however these hypotheses are not proved due to lack of adequate studies.
Many COVID 19 exposed people clear the virus without presenting any symptoms. This fact suggests that the immune system may have the capability to defeat the virus (15). Although this capability includes whole immune systems, innate immunity as a potential part of inflammation has been emphasized in COVID 19 immune-pathogenesis and it’s cytokines storm.
Tissue-resident macrophages are one of the first main leukocytes in the process of triggering the acute inflammation in response to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) during early pulmonary viral infections including COVID 19 (5, 16). There are remarkable evidence of innate immune hyperactivity in driving the acute lung injury that defines patients with requirement of hospitalization (5). These macrophages initiate an inflammatory cascade resulting in release of several cytokines including IL-1 which enhances the endothelial activation and continuation of acute inflammatory response and recruitment of neutrophils and cytotoxic T cells (5, 17).
IL-6 is another key cytokine, released from macrophages as a key cell in innate immunity and increased population of monocytes, partly in response to the priory secreted IL-1 (18, 19). IL-6 results in an increase of the inflammation by subsequent release of various immune mediators (20). This response may cause a hyperactive state as evidence suggest IL-6 levels correlate with severity of the disease and its mortality (20).
Considering the role of IL-1 in triggering such a state, the preliminary events leading to the secretion of IL-1 may influence the noted cascade. Pyrin is considered to be one of the precedential agents (21). Pyrin (also known as marenostrin) is encoded by MEFV gene (8). It plays a key role in apoptotic and inflammatory signaling pathways. Pyrin modulates caspase-1 and IL-1β activation exerting both pro-inflammatory (21–23) or anti-inflammatory mechanisms (8, 24). There are several evidence suggesting a pro-inflammatory function for Pyrin as well as its anti-inflammatory functions depending on the experiment. For example, Stimulation of monocytes with pro-inflammatory agents such as bacterial lipopolysaccharide (LPS), interferon-γ and tumor necrosis factor-α (TNF-α) induces the expression of MEFV, suggesting a role in the inflammatory signal cascades (25). Due to its role in inducing IL-1β, alteration in Pyrin function through MEFV gene mutations may influence the upcoming events in the clinical response to the viral infections, particularly, COVID 19 infection. This hypothesis is strengthened while looking at the recent findings in clinical trials which suggest that the non-selective NLRP3 inhibition by colchicine may enhance the clinical presentation of COVID 19 infection, considering the role of NLRP3 in formation of IL-1β from pro-IL-1β (26).
Meanwhile, the worldwide distribution shows that the prevalence of COVID 19 infection per one million individuals is relatively lower in the Caucasians and population of eastern Mediterranean region (www.news.google.com/covid19/map). Although this epidemiologic perspective is under several influential factors such as different screening methods, the genetic basis of MEFV gene expression may also have a key role in the epidemiologic aspects of the disease.
Considering that ethnic differences of populations affect the presentation of infection diseases (27), there are some similarities among the Mediterranean populations. These regions have a relatively high prevalence of MEFV gene mutations and consequently, FMF disease. For example a mutant allele frequency up to 15.6% and a carrier rate up to 20–25% is reported among normal population of different Mediterranean people (12, 28–30). Interestingly, in our sample of hospitalized COVID 19 infected patients, the mutant MEFV allele frequency was only 6% with no homozygote and compound heterozygous form and a carrier rate of 12%. This prevalence seem to be significantly lower than the normal population of the region (12), suggesting a probable protective role of MEFV gene mutations in COVID 19 infection. The idea of its protective role has been raised not only by this study, but also other report in the region (31).
Interestingly, none of the patients who had a mutant variant of MEFV gene died in the course of COVID 19 infection. Although due to small sample it was not statistically meaningful, this difference was clinically significant and requires further studies with a larger sample size. These mutations may affect the mortality of COVID 19 patients and it may explain the high mortality rate among Hispanic, western European, black Americans, and British COVID 19 patients (www.news.google.com/covid19/map) in whom, the prevalence of MEFV gene mutations are lower than the normal population of eastern Mediterranean region (32–34). Although we think this finding as a first study in COVID disease is very interesting, however, the limitation of small size of patients necessitates its rework in a larger sample sizes and different ethnic groups.