Gender and genetic factors impacting COVID-19 severity.

COVID-19 pandemic is a cause of global concern and is impacting lives and economy globally. Infection due to SARS-CoV-2 leads to varied clinical manifestations, which can vary from asymptomatic to severe acute respiratory syndrome and death. The clinical features are proposed to depend upon various host factors, namely, gender and genetic factors. The significantly high mortality among males has revealed the role of gender, androgens, age, genetics, and risk factors in determining the severity of COVID-19 among the population. The interplay of various host factors and their association with clinically severe infections is crucial for our understanding of COVID-19 pathogenesis. A PubMed and Google scholar search was made using keywords such as "COVID-19 + sex differences," "COVID-19 + androgens," "COVID-19 + ACE2 receptor," and "COVID-19 + smoking alcoholism pregnancy." The articles which highlight the association of gender and genetic factors to COVID-19 were selected and included in our study. It is mainly the primary care or family physicians who act as the first contact of COVID-19 patients. With the recent increase in SARS-CoV-2 infections in the Indian subcontinent and probability of upcoming surges, it has become imperative to understand its interaction with the various gender and genetic factors to devise effective triage and management protocols. Our review highlights the possible mechanisms by which these factors impact the severity of COVID-19. A better understanding of these factors will be of immense help to primary care physicians.

An Evolutionary Insight Into the Heterogeneous Severity Pattern of the SARS-CoV-2 Infection.

The ongoing pandemic of COVID-19 has elaborated an idiosyncratic pattern of SARS-CoV-2-induced symptoms in the human host. Some populations have succumbed to the SARS-CoV-2 infection in large numbers during this pandemic, whereas others have shown a resilient side by manifesting only milder or no symptoms at all. This observation has relayed the onus of the heterogeneous pattern of SARS-CoV-2-induced critical illness among different populations to the host genetic factors. Here, the evolutionary route was explored and three genetic loci, i.e., rs10735079, rs2109069, and rs2236757, associated with COVID-19 were analyzed. Among the three, the risk allele A at genetic locus rs2236757 residing in the IFNAR2 gene was observed to have undergone recent positive selection in the African population.

Genetic and epigenetic factors associated with increased severity of Covid-19.

Since December 2019, a new form of severe acute respiratory syndrome (SARS) from a novel strain of coronavirus (SARS coronavirus 2 [SARS-CoV-2]) has been spreading worldwide. The disease caused by SARS-CoV-2 was named Covid-19 and declared as a pandemic by the World Health Organization in March 2020. Clinical symptoms of Covid-19 range from common cold to more severe disease defined as pneumonia, hypoxia, and severe respiratory distress. In the next stage, disease can become more critical with respiratory failure, sepsis, septic shock, and/or multiorgan failure. Outcomes of Covid-19 indicate large gaps between the male-female and the young-elder groups. Several theories have been proposed to explain variations, such as gender, age, comorbidity, and genetic factors. It is likely that mixture of genetic and nongenetic factors interplays between virus and host genetics and determines the severity of disease outcome. In this review, we aimed to summarize current literature in terms of potential host genetic and epigenetic factors that associated with increased severity of Covid-19. Several studies indicated that the genetic variants of the SARS-CoV-2 entry mechanism-related (angiotensin-converting enzymes, transmembrane serine protease-2, furin) and host innate immune response-related genes (interferons [IFNs], interleukins, toll-like receptors), and human leukocyte antigen, ABO, 3p21.31, and 9q34.2 loci are critical host determinants related to Covid-19 severity. Epigenetic mechanisms also affect Covid-19 outcomes by regulating IFN signaling, angiotensin-converting enzyme-2, and immunity-related genes that particularly escape from X chromosome inactivation. Enhanced understanding of host genetic and epigenetic factors and viral interactions of SARS-CoV-2 is critical for improved prognostic tools and innovative therapeutics.

Genetic variants are identified to increase risk of COVID-19 related mortality from UK Biobank data.

BACKGROUND: The severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly heterogeneous. Studies have reported that males and some ethnic groups are at increased risk of death from COVID-19, which implies that individual risk of death might be influenced by host genetic factors. METHODS: In this project, we consider the mortality as the trait of interest and perform a genome-wide association study (GWAS) of data for 1778 infected cases (445 deaths, 25.03%) distributed by the UK Biobank. Traditional GWAS fails to identify any genome-wide significant genetic variants from this dataset. To enhance the power of GWAS and account for possible multi-loci interactions, we adopt the concept of super variant for the detection of genetic factors. A discovery-validation procedure is used for verifying the potential associations. RESULTS: We find 8 super variants that are consistently identified across multiple replications as susceptibility loci for COVID-19 mortality. The identified risk factors on chromosomes 2, 6, 7, 8, 10, 16, and 17 contain genetic variants and genes related to cilia dysfunctions (DNAH7 and CLUAP1), cardiovascular diseases (DES and SPEG), thromboembolic disease (STXBP5), mitochondrial dysfunctions (TOMM7), and innate immune system (WSB1). It is noteworthy that DNAH7 has been reported recently as the most downregulated gene after infecting human bronchial epithelial cells with SARS-CoV-2. CONCLUSIONS: Eight genetic variants are identified to significantly increase the risk of COVID-19 mortality among the patients with white British ancestry. These findings may provide timely clues and potential directions for better understanding the molecular pathogenesis of COVID-19 and the genetic basis of heterogeneous susceptibility, with potential impact on new therapeutic options.

The Role of Host Genetic Factors in Coronavirus Susceptibility: Review of Animal and Systematic Review of Human Literature.

The SARS-CoV-2 pandemic raises many scientific and clinical questions. These include how host genetic factors affect disease susceptibility and pathogenesis. New work is emerging related to SARS-CoV-2; previous work has been conducted on other coronaviruses that affect different species. We reviewed the literature on host genetic factors related to coronaviruses, systematically focusing on human studies. We identified 1,832 articles of potential relevance. Seventy-five involved human host genetic factors, 36 of which involved analysis of specific genes or loci; aside from one meta-analysis, all were candidate-driven studies, typically investigating small numbers of research subjects and loci. Three additional case reports were described. Multiple significant loci were identified, including 16 related to susceptibility (seven of which identified protective alleles) and 16 related to outcomes (three of which identified protective alleles). The types of cases and controls used varied considerably; four studies used traditional replication/validation cohorts. Among other studies, 30 involved both human and non-human host genetic factors related to coronavirus, 178 involved study of non-human (animal) host genetic factors related to coronavirus, and 984 involved study of non-genetic host factors related to coronavirus, including involving immunopathogenesis. Previous human studies have been limited by issues that may be less impactful now, including low numbers of eligible participants and limited availability of advanced genomic methods; however, these may raise additional considerations. We outline key genes and loci from animal and human host genetic studies that may bear investigation in the study of COVID-19. We also discuss how previous studies may direct current lines of inquiry.