key: cord-0890016-ugccpqyw authors: Paim, Adriana Alves Oliveira; Lopes-Ribeiro, Ágata; Daian e Silva, Daniele S.O.; Andrade, Luis Adan F.; Moraes, Thais F. S; Barbosa-Stancioli, Edel F.; da Fonseca, Flávio Guimarães; Coelho-dos-Reis, Jordana G. title: Will a little change do you good? A putative role of polymorphisms in COVID-19 date: 2021-04-24 journal: Immunol Lett DOI: 10.1016/j.imlet.2021.04.005 sha: 6eb6629c72f5dba80a9c7ae5032dc5a74545c7dc doc_id: 890016 cord_uid: ugccpqyw An alarming disease caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) named COVID-19 has emerged as an unprecedented public health problem and ignited a world health crisis. As opposed to what was believed at the beginning of the pandemic, the virus has not only spread but persevere causing secondary waves and challenging the concept of herd immunity against viral infections. While the majority of SARS-CoV-2-infected individuals may remain asymptomatic, a fraction of individuals may develop low to high-grade severity signs and symptoms of COVID-19. The disease is multifactorial and can progress quickly, leading to severe complications and even death in a few days. Therefore, understanding the pre-existing factors for disease development has never been so pressing. In this scenario, the insights on the mechanisms underlying disease allied to the immune response developed during the viral invasion could shed light on novel predictive factors and prognostic tools for COVID-19 management and interventions. A recent genome-wide association study (GWAS) revealed several molecules that significantly impacted critically ill COVID-19 patients, leading to the core mechanisms of Covid-19 pathogenesis. Considering these findings and the fact that ACE-2 polymorphisms alone cannot explain disease progress and severity, this review aims at summarizing the most important and recent findings of the research and expert consensus of possible cytokine-related polymorphisms existing in the differential expression of paramount immune molecules that could be crucial for providing guidelines for decision-making and appropriate clinical management of COVID-19. • An Entangled Truesome: Genetic Polymorphisms, Cytokine Storm And SARS; • Genes related to Innate antiviral immunity are associated with SARS; • interferon receptor IFNAR2 (chr21q22.1; rs2236757) is associated to severe COVID-19; • severe COVID-19 is associated to high expression of TYK2 Janus kinase signaling; An alarming disease caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) named COVID-19 has emerged as an unprecedented public health problem and ignited a world health crisis. As opposed to what was believed at the beginning of the pandemic, the virus has not only spread but persevere causing secondary waves and challenging the concept of herd immunity against viral infections. While the majority of SARS-CoV-2-infected individuals may remain asymptomatic, a fraction of individuals may develop low to high-grade severity signs and symptoms of COVID-19. The disease is multifactorial and can progress quickly, leading to severe complications and even death in a few days. Therefore, understanding the pre-existing factors for disease development has never been so pressing. In this scenario, the insights on the mechanisms underlying disease allied to the immune response developed during the viral invasion could shed light on novel predictive factors and prognostic tools for COVID-19 management and interventions. A recent genome-wide association study (GWAS) revealed several molecules that significantly impacted critically ill COVID-19 patients, leading to the core mechanisms of Covid-19 pathogenesis. Considering these findings and the fact that ACE-2 polymorphisms alone cannot explain disease progress and severity, this review aims at summarizing the most important and recent findings of the research and expert consensus of possible cytokinerelated polymorphisms existing in the differential expression of paramount immune molecules that could be crucial for providing guidelines for decision-making and appropriate clinical management of COVID-19. Keywords: SARS-CoV-2; polymorphism; cytokine storm; SARS. December of 2019 (Lai et al., 2020) and its continued dissemination led WHO to nominate it as a pandemic on 11 March 2020 (WHO, 2020-A). So far, it is estimated that around 134 million people were infected worldwide and about 2,9 million deaths occurred (dated of April 9 th , 2021; Johns Hopkins, 2021) in less than two years from its acknowledged viral circulation. SARS-CoV-2 pandemic was exceedingly uncontrolled and rapid progressive in contrast with other critical pandemics such as HIV, which is comprised of 38 million infected people worldwide accumulated over the last 40 years. The majority of people infected with SARS-CoV-2 may remain asymptomatic and still contribute to viral spread and transmission, which renders the control of viral dissemination complicated. However, a fraction of SARS-CoV-2-infected patients develop COVID-19, which is characterized in mild cases by fever, myalgia or fatigue, cough, shortness of breath, headaches, and diarrhea (Kimball et al., 2020) . Statistically, the risk group is made up of people over 60, with diabetes, high blood pressure, and cardiovascular disease (CDC, 2020). These people are more likely to develop the most severe form of the disease, characterized by complications such as pneumonia followed by severe respiratory distress syndrome (SARS), acute cardiac injury, and elevated levels of some cytokines (Huang et al., 2020; Guan et al., 2020) . Although the increase in inflammatory cytokines and chemokines is expected during infection for the coordinated fight by the immune system, their increase can cause a mismatch leading to a condition described as a cytokine storm. The cytokine storm is characterized by a picture of illness in multiple organs and hyper inflammation. In the context of COVID-19, this would manifest itself mainly, but not exclusively, in the lungs, arising as a result of the excessive release of cytokines and chemokines coming from an uncontrolled immune activation (Henderson et al., 2020; Xu et al., 2020) . In this scenario, key polymorphisms in cytokine and chemokine genes have been described as associated with different pathogenic conditions, with a strong association between the severity of such responses and the level of their expression as illustrated in figure 1. Although the genes encoding cytokines, as well as, their receptors are relatively The progressive increase of cytokines and chemokines in pro-inflammatory status and its association with these polymorphisms needs to be clarified to gain a deeper understanding of disease progression in different parts of the world. In order to map cytokine-related polymorphisms and see any association with the higher number of cases in the Americans, well-stablished polymorphisms on alleles coding for crucial cytokines such as IFNAR2, TNF, INF-a/b, IL-4 and IL-1RN were plotted in a globe map according to their frequency in European, Asian, African and American regions ( Figure 2 ). In acute respiratory infections caused by SARS-CoV-1 and SARS-CoV-2, the first consideration is to assume that polymorphisms associated to the ACE-2, the receptor that The study about the GG genotype of the interleukin IL-10 promoter polymorphism in position -1082G/G has been associated with increased IL-10 production (Gong et al., 2006) . The authors hypothesized that the -1082G/G genotype is associated with the development of SARS outcomes. The -1082G/G genotype was associated with decreased severity of illness on admission, lower daily organ dysfunction scores, and lower 60-day mortality. In conclusion, the high IL-10 producing -1082G/G genotype may be associated with variable odds for SARS development in an age-dependent fashion. Among those with severe acute respiratory distress syndrome, the -1082G/G genotype is associated with lower mortality and The impact of polymorphisms on the differential expression of cytokines, chemokines, and immune molecules in the different clinical manifestations of COVID-19 is currently unknown. It also remains to be understood if the already known SNP polymorphisms to immune molecules could be associated with the exhaustion of the immune system associated with the overexpression or suppression of cytokines discussed here. It is considered that, in the case of SARS-CoV-2, the infection triggers an important imbalance in the eye of the storm, which is composed of immune cells. Innate and adaptive programmed cell subsets are the main sources of cytokines and immune molecules. Monocytes, macrophages, dendritic cells, and T cells are protagonists of the immune system, with close attention to the CD4 + T-lymphocytes that could produce Interferon and TNF abundantly. 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