Exploring loss of Y chromosome in white blood cells as a risk-factor of life-threatening COVID-19 in men

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), affects people by different severities. However, the worst-hit are those with bilateral pneumonia that turns into acute respiratory distress syndrome with a staunch reduction in pulmonary function. In which case, they require treatment with non-invasive or invasive mechanical ventilation. Studies have shown neutrophil activation to be a classic indicator of COVID-19 with lymphocytopenia.

Study: Loss of Y in leukocytes as a risk factor for critical COVID-19 in men. Image Credit: vchal/ShutterstockStudy: Loss of Y in leukocytes as a risk factor for critical COVID-19 in men. Image Credit: vchal/Shutterstock

In COVID-19 patients, neutrophils take on a low-density phenotype (LDNs) on activation and are prone to spontaneous release of neutrophil extracellular traps (NETs) in capillaries. Excess accumulation of NETs in blood vessels leads to vascular occlusion, disrupted microcirculation, and organ damage.

Additionally, hyper-coagulation and thromboembolic events also contribute to death from COVID-19. These symptoms highlight a dysfunction in myeloid cell lineages, and growing evidence validates this hypothesis. More men have been critically ill and died from COVID-19, as evident from the Swedish public health database.

Leukocytes from aging males have shown a mosaic loss of chromosome Y (LOY). It is detectable in whole blood DNA from >40% - 57% of the men aged between 70-93 years. Recent single-cell analyses of peripheral blood mononuclear cells (PBMCs) from 29 aging men with a median age of 80 years identified cells with a dynamic LOY in every sample. This made it the most common post-zygotic mutation.

LOY is most common in leukocytes, with the most common risk factors being age, smoking, and germline predisposition. LOY in whole blood has been associated with increased risk for all-cause mortality, blood-based cancers, Alzheimer’s disease, diabetes, and cardiovascular diseases. Hence, carriers of LOY have an increased risk for diseases inside and outside of the hematopoietic system with idiopathic mechanism(s).

Researchers estimated an unknown male-specific risk factor for COVID-19 patients. They published a study in the pre-print server medRxiv* exploring the possibilities of predisposing men for a life-threatening disease course of COVID-19. They hypothesized that LOY in cells from myeloid lineage might be linked to the development of the critical disorder and predominantly studied critically ill COVID-19 males.

Study details

Researchers collected ~16 ml blood from 139 severely ill male COVID-19 patients treated at two ICUs at University Hospitals (Uppsala and Gothenburg) in Sweden. Inclusion criteria were those categorized by World Health Organization (WHO) as grade 6 or higher in severity. The median age was 65 years, ranging between 19 and 86 years. Also, researchers collected data on smoking habits, comorbidity, and numerous clinical and biochemical parameters recorded during ICU treatment.

Researchers used Fluorescence Assisted Cell Sorting to analyze LOY in LDNs, granulocytes, monocytes, PBMCs, and whole blood for all patients. Thirty-eight healthy controls were also included in the cohort, followed by LOY analysis (n=17) and single-cell transcriptome analysis (n=34). The median age of controls was 71 years. Researchers further studied four male subjects with a milder course of COVID-19. They analyzed LOY status for all samples using droplet-digital PCR (ddPCR).

The LDN cell counts in severely ill patients were significantly higher than healthy controls (median 86.8) and milder COVID-19 patients (median 63.1). The highest percentages of cells with LOY per subject in myeloid lineage cells in COVID-19 patients were 85.5% in granulocytes, 85.4% in monocytes, 81.7% in whole blood, 51.5% in whole blood PBMCs, and 36% in LDNs.

Researchers collected follow-up blood samples from 17 severely ill patients who recovered from COVID-19. The median number of days for collection of follow-up specimens (from the first sampling date) was 119 days. The percentage of LOY values in DNA from whole blood (p=0.29) and PBMCs (p=0.25) were seen to reduce significantly in samples taken at the recovery.

These results from comparisons between ICU and recovery samples suggested that the overall reduction of cell numbers was mostly associated with the critical course of COVID-19 (LDNs and monocytes) and the overall reduction in the viral load of cells with LOY.

Analyzing the samples from the critically ill patients, the percentage of LOY in PBMCs was significantly negatively correlated with maximum erythrocyte count (R = -0.25) and hemoglobin measurement, both at day 1 (R=-0.21) and maximum values (-0.23). In contrast, the maximum thrombocyte counts were significantly positively correlated with the percentage of LOY in monocytes (R=0.023), granulocytes (R=0.023), and whole blood (R=0.24). Increased counts of thrombocytes in critically ill patients with higher levels were hypothesized to predispose them to thromboembolic complications during ICU stay.

Further analysis showed the percentage of LOY in LDNs (median 4.9%) and monocytes (median 2.7%) positively correlated with clinically confirmed thromboembolic events during ICU stay. The percentage of LOY in blood was significantly higher in patients treated with invasive mechanical ventilation (median 1.15%) and in monocytes (median 0.99%).

Moreover, sc-RNA-seq analysis of CD14+ monocytes from 30 COVID-19 males and 34 controls revealed pervasive transcriptional downregulation in LOY-cells, especially affecting the Human Leukocyte Antigen (HLA) class I and II genes which are important for antigen presentation.

Implication

The results from this study suggest that the percentage of LOY might be a key indicator for high-risk patients and contribute to the increased severity of COVID-19.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Sreetama Dutt

Written by

Sreetama Dutt

Sreetama Dutt has completed her B.Tech. in Biotechnology from SRM University in Chennai, India and holds an M.Sc. in Medical Microbiology from the University of Manchester, UK. Initially decided upon building her career in laboratory-based research, medical writing and communications happened to catch her when she least expected it. Of course, nothing is a coincidence.

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