Loss of Y in leukocytes as a risk factor for critical COVID-19 in men

Abstract

Background The COVID-19 pandemic, which has a prominent social and economic impact worldwide, shows a largely unexplained male bias for the severity and mortality of the disease. Loss of chromosome Y (LOY) is a risk factor candidate in COVID-19 due to its prior association with many chronic age-related diseases, and its impact on immune gene transcription. Methods Publicly available scRNA-seq data of PBMC samples derived from male patients critically ill with COVID-19 were reanalyzed, and LOY status was added to the annotated cells. We further studied LOY in whole blood for 211 COVID-19 patients treated at intensive care units (ICU) from the first and second waves of the pandemic. Of these, 139 patients were subject to cell sorting for LOY analysis in granulocytes, low-density neutrophils (LDNs), monocytes, and PBMCs. Results Reanalysis of available scRNA-seq data revealed LDNs and monocytes as the cell types most affected by LOY. Subsequently, DNA analysis indicated that 46%, 32%, and 29% of critically ill patients showed LOY above 5% cut-off in LDNs, granulocytes, and monocytes, respectively. Hence, the myeloid lineage that is crucial for the development of severe COVID-19 phenotype is affected by LOY. Moreover, LOY correlated with increasing WHO score (median difference 1.59%, 95% HDI 0.46% to 2.71%, p=0.025), death during ICU treatment (median difference 1.46%, 95% HDI 0.47% to 2.43%, p=0.0036), and history of vessel disease (median difference 2.16%, 95% HDI 0.74% to 3.7%, p=0.004), among other variables. In 16 recovered patients, sampled during ICU stay and 93–143 days later, LOY decreased significantly in whole blood and PBMCs. Furthermore, the number of LDNs at the recovery stage decreased dramatically (median difference 76.4 per 10,000 cell sorting events, 95% HDI 55.5 to 104, p=6e−11). Conclusions We present a link between LOY and an acute, life-threatening infectious disease. Furthermore, this study highlights LOY as the most prominent clonal mutation affecting the myeloid cell lineage during emergency myelopoiesis. The correlation between LOY level and COVID-19 severity might suggest that this mutation affects the functions of monocytes and neutrophils, which could have consequences for male innate immunity.

Diabetes as a risk factor of death in hospitalized COVID-19 patients – an analysis of a National Hospitalization Database from Poland, 2020

“…Similar observations were reported for male patients in a recent systematic review, with nearly 50% higher risk of death than in males than in females ( 33 ). These distinctions were previously attributed to differences in the function of the immune system, including counts of selected lymphocytes, lack of some regulatory genes that are located on the X chromosome ( 33 ), and age-related mosaic loss of chromosome Y in elderly males ( 35 ). Moreover, a recent study explained these disparities to some extent by social and contextual factors ( 36 ).…”

Loss of chromosome Y in regulatory T cells

“…Previous studies have established that LOY is associated with the distribution of different types of blood cells [10][11][12]14]. Furthermore, it has been shown that the type of leukocyte affected with LOY might be relevant for disease risks, with LOY in specifically CD4 + T lymphocytes being associated with increased risk for prostate cancer [12].…”

Chromosome-Y haplogroups in Asturias (Northern Spain) and their association with severe COVID-19

“…LOY may also be associated to increased genome instability and impaired leucocyte immune responses (Thompson et al 2019 ; Dumanski et al 2021 ). At least one study reported loss of Y in leukocytes as a risk factor for critical COVID-19 in men (Bruhn-Olszewska et al 2022 ).…”