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Genetic determinants of severe COVID-19 in young Asian and Middle Eastern patients: a case series.

ABSTRACT: Studies of genetic factors associated with severe COVID-19 in young adults have been limited in non-Caucasian populations. Here, we clinically characterize a case series of patients with COVID-19, who were otherwise healthy, young adults (N = 55; mean age 34.1 ± SD 5.0 years) from 16 Asian, Middle Eastern, and North African countries. Using whole exome sequencing, we identify rare, likely deleterious variants affecting 16 immune-related genes in 17 out of 55 patients (31%), including 7 patients (41% of all carriers or 12.7% of all patients) who harbored multiple such variants mainly in interferon and toll-like receptor genes. Protein network analysis as well as transcriptomic analysis of nasopharyngeal swabs from an independent COVID-19 cohort (N = 50; 42% Asians and 22% Arabs) revealed that most of the altered genes, as identified by whole exome sequencing, and the associated molecular pathways were significantly altered in COVID-19 patients. Genetic variants tended to be associated with mortality, intensive care admission, and ventilation support. Our clinical cases series, genomic and transcriptomic findings suggest a possible role for interferon pathway genes in severe COVID-19 and highlight the importance of extending genetic studies to diverse populations to better understand the human genetics of disease.

SUBMITTER: Badla BA

PROVIDER: S-EPMC10661561 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Genetic determinants of severe COVID-19 in young Asian and Middle Eastern patients: a case series.

Badla Beshr Abdulaziz BA Hanifa Mohamed Samer MS Jain Ruchi R Naofal Maha El ME Halabi Nour N Yaslam Sawsan S Ramaswamy Sathishkumar S Taylor Alan A Alfalasi Roudha R Shenbagam Shruti S Khansaheb Hamda H Al Suwaidi Hanan H Nowotny Norbert N Popatia Rizwana R Al Khayat Abdulla A Alsheikh-Ali Alawi A Loney Tom T AlDabal Laila Mohamed LM Abou Tayoun Ahmad A

Scientific reports 20231120 1

Studies of genetic factors associated with severe COVID-19 in young adults have been limited in non-Caucasian populations. Here, we clinically characterize a case series of patients with COVID-19, who were otherwise healthy, young adults (N = 55; mean age 34.1 ± SD 5.0 years) from 16 Asian, Middle Eastern, and North African countries. Using whole exome sequencing, we identify rare, likely deleterious variants affecting 16 immune-related genes in 17 out of 55 patients (31%), including 7 patients ...[more]

PMID: 37985737

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Project description:BackgroundTo date, more than 105,805,951 cases of COVID-19 have been diagnosed including 2,312,278 deaths. Many patients have cardiovascular risk-factors and/or co-morbidities and a lot of them developed de novo heart conditions during the active or the post-infectious phase of the infection. A number of studies tried to demonstrate an association between poor prognostic outcomes and cardiovascular comorbidities and related damages, but the quality of current evidence is still weak.Patients and methodsThe aim of this single-center report is to describe the prevalence of cardiac injuries among our COVID-19 patients, to explore their association with survival outcomes and to demonstrate the medical care provided in our real-world setting. Our study included 610 COVID-19 patients admitted to the intensive care unit of our university hospital of whom13.77% (n = 84) presented cardiovascular injuries and which we included in this case series.ResultsThe average age of our patients was 65 years (27-90). 60 were men (71.42%) while 24 were women (28.55%). Their average BMI was 29.7 kg/m2. Among them, 50 had a pulmonary embolism (59.52%), 12 patients had a myocardial infarction (14.28%), 10 presented pericarditis (11.9%) and 3 developed myocarditis (3.57%). There were 6 cases of ischemia (7.14%), 2 cases of stroke (2.38%), and 1 case of decompensated heart failure (1.19%). Among our patients, 46.42% had diabetes, 32.14% had a high blood pressure, 13.09% had a chronic renal failure and 14.28% had a history of ischemic heart disease. 14 patients (16.66%) had an elevated troponin with higher levels than 1000 ng/mL. The D-dimer value was high in almost all patients (80.95%). Lung damage from COVID-19 was extensive in 27.38%, severe in 32.14%, and critical in 40.47% of enrolled cases. CT chest angiography, ECG, and cardiac ultrasound were performed to the paraclinical confirmatory exploration of cardiac damages of these patients. Medical care was based on isolation, azithromycin, vitamin C, zinc, vitamin D, salicylic acid, dexamethasone followed with methylprednisolone, and anticoagulation for all hospitalized patients. Tocilizumab was indicated for 17 patients with hyperferritinemia (20.23% of patients). The initial respiratory care of our patients required oxygen therapy using nasal cannula (7.14%) high concentration masks (33.33%), high flow nasal cannula treatment (11.9%), non-invasive ventilation (NIV) (5.95%), and mechanical ventilation (41.66%). Thrombolysis was performed in three subjects with myocardial infarction and 2 underwent angioplasty with placement of an active stent at the proximal interventricular anterior artery, which all were successful. Three massive pulmonary embolisms died despite adequate treatment. Colchicine and salicylic acid were administered for pericarditis cases. Thromboprophylaxis was indicated for all patients and was reinforced if a venous thrombotic episode was confirmed. Patients with limb ischemia underwent surgical treatment. Among the 84 patients included in our cohort, 34 (40.47%) died in intensive care unit and 50 (59.52%) had a favorable evolution.ConclusionCardiovascular involvement during COVID-19 should not be neglected and are associated with severe outcomes.

Project description:ImportanceSevere coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).ObjectiveTo explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19.Design, setting, and participantsCase series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments.ExposureSevere COVID-19.Main outcome and measuresResults of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects.ResultsThe 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod.Conclusions and relevanceIn this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.

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Genetic determinants of severe COVID-19 in young Asian and Middle Eastern patients: a case series.

Publications

Genetic determinants of severe COVID-19 in young Asian and Middle Eastern patients: a case series.

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