Red Blood Cell-Related Phenotype-Genotype Correlations in Chronic and Acute Critical Illnesses (Traumatic Brain Injury Cohort and COVID-19 Cohort).

Changes in red blood cell (RBC)-related parameters and anemia are common in both severe chronic and acute diseases. RBC-related phenotypes have a heritable component. However, it is unclear whether the contribution of genetic variability is pronounced when hematological parameters are affected by physiological stress. In this study, we analyzed RBC-related phenotypes and phenotype-genotype correlations in two exome-sequenced patient cohorts with or at a high risk for a critical illness: chronic TBI patients admitted for rehabilitation and patients with acute COVID-19. In the analysis of exome data, we focused on the cumulative effects of rare high-impact variants (qualifying variants, QVs) in specific gene sets, represented by Notch signaling pathway genes, based on the results of enrichment analysis in anemic TBI patients and three predefined gene sets for phenotypes of interest derived from GO, GWAS, and HPO resources. In both patient cohorts, anemia was associated with the cumulative effects of QVs in the GO (TBI: = 0.0003, OR = 2.47 (1.54-4.88); COVID-19: = 0.0004, OR = 2.12 (1.39-3.25)) and Notch pathway-derived (TBI: = 0.0017, OR = 2.33 (1.35-4.02); COVID-19: = 0.0012, OR =8.00 (1.79-35.74)) gene sets. In the multiple linear regression analysis, genetic variables contributed to RBC indices in patients with TBI. In COVID-19 patients, QVs in Notch pathway genes influenced RBC, HGB, and HCT levels, whereas genes from other sets influenced MCHC levels. Thus, in this exploratory study, exome data analysis yielded similar and different results in the two patient cohorts, supporting the view that genetic factors may contribute to RBC-related phenotypic performance in both severe chronic and acute health conditions.