Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread, over 390 million cases have been infected worldwide, including 6 million reported deaths (https://covid19.who.int/). Significant efforts have been made to cognize the Coronavirus Disease-2019 (COVID-19) infection mechanism, but its physiopathology is not fully clarified. However, it is well-known that the cytokine storm is primarily responsible for an increased rate of hospitalization, intensive care admission, and mortality in a fraction of COVID-19 patients who develop the most critical form of the disease [1], [2], [3].

As an acute hyper inflammation reaction, the cytokine storm is associated with higher serum levels of several pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-17A, IL-4, IL-1, IL-6, and interferon-γ (IFN-γ) [4], [5], [6], [7], [8]. The manifest of such phenomenon in COVID-19 patients is mainly, but not exclusively, in the lungs as acute respiratory distress syndrome (ARDS) [9], [10], [11]. Although several risk factors, including age, body mass index (BMI), and presence of comorbidities, are associated with the severity of SARS-CoV-2 infection, disease severity can develop in patients even in the absence of obvious risk factors. Therefore, other factors such as heterogeneous genetic makeup may contribute to the disease severity [12]. Identifying the impact of single nucleotide polymorphisms (SNPs) located in cytokine and chemokine genes, which have been linked to the remodeling of the immunological response upon COVID-19 infection, may help elucidate the hyper inflammation status recognized by the cytokine storm in COVID-19 [13]. In this context, several polymorphisms in immune-related genes have been linked to severe COVID-19 infection [12], [13], [14], [15], [16].

Since the start of the pandemic, increased serum concentrations of IL-6 have been frequently reported as a hallmark in severely ill patients with COVID-19 [17]. As a cytokine with pleiotropic effects, many cell types secret IL-6, including macrophages, B and T lymphocytes, and dendritic cells. The elevated level of IL-6 has been associated with hyper inflammation status and the progression of ARDS, a primary cause of death of coronavirus-related infections, including COVID-19, SARS, and MERS [18], [19], [20], [21]. As a result, monitoring serum concentrations of IL-6 has been used as a predictor of COVID-19 severity and mortality [22], [23], [24], [25]. Also, considering the importance of IL-6 as part of the ill-regulated immune response to SARS-CoV-2, several clinical trials have been developed to target this cytokine [26], [27], [28]. Given the vital role of IL-6 in regulating CD4+ T cells, exploring its related polymorphism may shed light on the molecular aspects of COVID-19. Rs1800795 lays on the IL-6 promoter, which is reported to be associated with IL-6 expression level. The rs1800795 GG genotype is protective against pneumococcal pneumonia and pneumonia-induced sepsis, while G alleles are related to a worse outcome of HCV infection [29], [30], [31]. A meta-analysis by Ulhaq & Soraya also found that rs1800795 carrier status is linked to elevated IL-6 production and pneumonia severity [32].

Several reports also highlighted that increased Th17 lymphocytes and serum IL-17A are linked to the clinical severity and progression of SARS-CoV-2 infection [33], [34]. IL-17A is a non-canonical pro-inflammatory cytokine that induces pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α, which can play a significant role in the cytokine storm. [35]. In addition, the decrease in the lymphocytic population identified in COVID-19 patients, with the increase in Th17 lymphocytes fraction and Th17-produced cytokines, support the involvement of IL-17A in immunological response driving hyper inflammation [36]. Several IL-17 SNPs have been examined and are linked to asthma and infectious lung diseases, indicating susceptibility to disease progression. [37]. In line with this, a retrospective study of IL-17A gene SNPs (low production of IL-17A level) indicated that patients with ARDS had an enhanced 30-day survival rate [38]. In a meta-analysis, the polymorphism rs2275913, located in the regulatory sequence of the IL-17A gene, also was related to disease prevalence and mortality rate among COVID-19 patients in different countries [39].

Given the significance of IL-6 and IL-17A in controlling the immune response to COVID-19 infection and cytokine storm, identifying genetic variations in these genes may help to explain, at least in part, the observed wide range of COVID-19 symptoms. As a result, we investigated the two common SNPs, rs1800795 and rs2275913, in Iranian patients with COVID-19 to explore their association with disease severity, mortality, and cytokine storm.