Genetic susceptibility to severe COVID-19

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. Clinical manifestations of the disease range from an asymptomatic condition to life-threatening events and death, with more severe courses being associated with age, male sex, and comorbidities. Besides these risk factors, intrinsic characteristics of the virus as well as genetic factors of the host are expected to account for COVID-19 clinical heterogeneity. Genetic studies have long been recognized as fundamental to identify biological mechanisms underlying congenital diseases, to pinpoint genes/proteins responsible for the susceptibility to different inherited conditions, to highlight targets of therapeutic relevance, to suggest drug repurposing, and even to clarify causal relationships that make modifiable some environmental risk factors. Though these studies usually take long time to be concluded and, above all, to translate their discoveries to patients' bedside, the scientific community moved really fast to deliver genetic signals underlying different COVID-19 phenotypes. In this Review, besides a concise description of COVID-19 symptomatology and of SARS-CoV-2 mechanism of infection, we aimed to recapitulate the current literature in terms of host genetic factors that specifically associate with an increased severity of the disease.

Genetic susceptibility to severe COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. Clinical manifestations of the disease range from an asymptomatic condition to life-threatening events and death, with more severe courses being associated with age, male sex, and comorbidities. Besides these risk factors, intrinsic characteristics of the virus as well as genetic factors of the host are expected to account for COVID-19 clinical heterogeneity. Genetic studies have long been recognized as fundamental to identify biological mechanisms underlying congenital diseases, to pinpoint genes/proteins responsible for the susceptibility to different inherited conditions, to highlight targets of therapeutic relevance, to suggest drug repurposing, and even to clarify causal relationships that make modifiable some environmental risk factors. Though these studies usually take long time to be concluded and, above all, to translate their discoveries to patients' bedside, the scientific community moved really fast to deliver genetic signals underlying different COVID-19 phenotypes. In this Review, besides a concise description of COVID-19 symptomatology and of SARS-CoV-2 mechanism of infection, we aimed to recapitulate the current literature in terms of host genetic factors that specifically associate with an increased severity of the disease.

Recognition and inhibition of SARS-CoV-2 by humoral innate immunity pattern recognition molecules.

The humoral arm of innate immunity includes diverse molecules with antibody-like functions, some of which serve as disease severity biomarkers in coronavirus disease 2019 (COVID-19). The present study was designed to conduct a systematic investigation of the interaction of human humoral fluid-phase pattern recognition molecules (PRMs) with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of 12 PRMs tested, the long pentraxin 3 (PTX3) and mannose-binding lectin (MBL) bound the viral nucleocapsid and spike proteins, respectively. MBL bound trimeric spike protein, including that of variants of concern (VoC), in a glycan-dependent manner and inhibited SARS-CoV-2 in three in vitro models. Moreover, after binding to spike protein, MBL activated the lectin pathway of complement activation. Based on retention of glycosylation sites and modeling, MBL was predicted to recognize the Omicron VoC. Genetic polymorphisms at the MBL2 locus were associated with disease severity. These results suggest that selected humoral fluid-phase PRMs can play an important role in resistance to, and pathogenesis of, COVID-19, a finding with translational implications.

MEDTEC Students against Coronavirus: Investigating the Role of Hemostatic Genes in the Predisposition to COVID-19 Severity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. Besides virus intrinsic characteristics, the host genetic makeup is predicted to account for the extreme clinical heterogeneity of the disease, which is characterized, among other manifestations, by a derangement of hemostasis associated with thromboembolic events. To date, large-scale studies confirmed that genetic predisposition plays a role in COVID-19 severity, pinpointing several susceptibility genes, often characterized by immunologic functions. With these premises, we performed an association study of common variants in 32 hemostatic genes with COVID-19 severity. We investigated 49,845 single-nucleotide polymorphism in a cohort of 332 Italian severe COVID-19 patients and 1668 controls from the general population. The study was conducted engaging a class of students attending the second year of the MEDTEC school (a six-year program, held in collaboration between Humanitas University and the Politecnico of Milan, allowing students to gain an MD in Medicine and a Bachelor's Degree in Biomedical Engineering). Thanks to their willingness to participate in the fight against the pandemic, we evidenced several suggestive hits (p < 0.001), involving the PROC, MTHFR, MTR, ADAMTS13, and THBS2 genes (top signal in PROC: chr2:127192625:G:A, OR = 2.23, 95%CI = 1.50-3.34, p = 8.77 × 10-5). The top signals in PROC, MTHFR, MTR, ADAMTS13 were instrumental for the construction of a polygenic risk score, whose distribution was significantly different between cases and controls (p = 1.62 × 10-8 for difference in median levels). Finally, a meta-analysis performed using data from the Regeneron database confirmed the contribution of the MTHFR variant chr1:11753033:G:A to the predisposition to severe COVID-19 (pooled OR = 1.21, 95%CI = 1.09-1.33, p = 4.34 × 10-14 in the weighted analysis).

ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy Orthopaedic Guidelines for the COVID-19 Post-Outbreak Period: Experience from Wuhan, People's Republic of China

As the outbreak of coronavirus disease 2019 (COVID-19) progresses, prognostic markers for early identification of high-risk individuals are an urgent medical need. Italy has one of the highest numbers of SARS-CoV-2-related deaths and one of the highest mortality rates. Worldwide, a more severe course of COVID-19 is associated with older age, comorbidities, and male sex. Hence, we searched for possible genetic components of COVID-19 severity among Italians by looking at expression levels and variants in ACE2 and TMPRSS2 genes, crucial for viral infection.Exome and SNP-array data from a large Italian cohort were used to compare the rare-variants burden and polymorphisms frequency with Europeans and East Asians. Moreover, we looked into gene expression databases to check for sex-unbalanced expression.While we found no significant evidence that ACE2 is associated with disease severity/sex bias, TMPRSS2 levels and genetic variants proved to be possible candidate disease modulators, prompting for rapid experimental validations on large patient cohorts. Currently, the coronavirus disease 2019 (COVID-19) crisis has rapidly spread worldwide. As the earliest outbreak area of the pandemic, Wuhan, People's Republic of China, is gradually recovering to its normal state under the effective control of government authorities. Outpatient services in major hospitals are now being restored. An accumulation of asymptomatic infections is a potential risk for medical personnel, especially when there is crowding in hospitals. As the biggest center for orthopaedic patients in Wuhan, our orthopaedic outpatient department admits >300 patients per day. Optimal guidelines on how to handle this huge number of patients during the post-outbreak stage of the COVID-19 pandemic, particularly with regard to potential asymptomatic infection, are urgently needed for orthopaedic surgeons. We have developed and proposed applicable guidelines to fill this knowledge gap, including the necessary protective strategies for medical personnel in orthopaedic outpatient and inpatient wards as well as during surgery. We also have provided mental health recommendations for health-care workers. To the best of our knowledge, these guidelines are the first of their kind for orthopaedic surgeons who are slowly reestablishing medical activity following the pandemic.

ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy.

As the outbreak of coronavirus disease 2019 (COVID-19) progresses, prognostic markers for early identification of high-risk individuals are an urgent medical need. Italy has one of the highest numbers of SARS-CoV-2-related deaths and one of the highest mortality rates. Worldwide, a more severe course of COVID-19 is associated with older age, comorbidities, and male sex. Hence, we searched for possible genetic components of COVID-19 severity among Italians by looking at expression levels and variants in ACE2 and TMPRSS2 genes, crucial for viral infection.Exome and SNP-array data from a large Italian cohort were used to compare the rare-variants burden and polymorphisms frequency with Europeans and East Asians. Moreover, we looked into gene expression databases to check for sex-unbalanced expression.While we found no significant evidence that ACE2 is associated with disease severity/sex bias, TMPRSS2 levels and genetic variants proved to be possible candidate disease modulators, prompting for rapid experimental validations on large patient cohorts.