Association of Glucose-6-Phosphate Dehydrogenase Deficiency With Outcomes in US Veterans With COVID-19.

Importance: The underlying biological risk factors for severe outcome due to SAR-CoV-2 infection are not well defined. Objective: To determine the association between glucose-6-phosphate dehydrogenase (G6PD) deficiency and severity of COVID-19. Design, Setting, and Participants: This retrospective cohort study included analysis of 24 700 veterans with G6PD enzyme testing prior to January 1, 2020, obtained through the US Veterans Health Administration national databases. These veterans were cross-referenced with the Veterans Administration COVID-19 Shared Data Resource for SARS-CoV-2 testing from February 15, 2020, to January 1, 2021. The final study population consisted of 4811 veterans who tested positive for SARS-CoV-2. Statistical analysis was performed from June to December 2021. Exposures: G6PD deficiency. Main Outcomes and Measures: COVID-19 severe illness, as defined by the Centers for Disease Control and Prevention: hospitalization, need for mechanical ventilation and/or intensive care unit admission, or in-hospital mortality after a positive SARS-CoV-2 test. Results: Among 4811 veterans in the Veterans Health Administration who had historical G6PD enzyme activity test results and SARS-CoV-2 positivity included in this study, 3868 (80.4%) were male, 1553 (32.3%) were Black, and 1855 (39%) were White; 1228 (25.5%) were 65 years or older and 3583 (74.5%) were younger than 65 years. There were no significant differences in age, body mass index, or Charlson Comorbidity Index were present between the veterans with G6PD deficiency and without G6PD deficiency. Among these veterans with SARS-CoV-2 infection, G6PD deficiency was more prevalent in Black male veterans (309 of 454 [68.1%]) compared with other racial and ethnic groups. Black male veterans less than 65 years of age with G6PD deficiency had approximately 1.5-fold increased likelihood of developing severe outcomes from SARS-CoV-2 infection compared with Black male veterans without G6PD deficiency (OR, 1.47; 95% CI, 1.03-2.09). In the small subset of White male veterans with G6PD deficiency, we observed an approximately 3.6-fold increased likelihood of developing severe outcomes from SARS-CoV-2 infection compared with White male veterans aged 65 years or older without G6PD deficiency (OR, 3.58; 95% CI, 1.64-7.80). This difference between veterans with and without G6PD deficiency was not observed in younger White male veterans or older Black male veterans, nor in smaller subsets of other male veterans or in female veterans of any age. Conclusions and Relevance: In this cohort study of COVID-19-positive veterans, Black male veterans less than 65 years of age and White male veterans 65 years of age or older with G6PD deficiency had an increased likelihood of developing severe COVID-19 compared with veterans without G6PD deficiency. These data indicate a need to consider the potential for G6PD deficiency prior to treatment of patients with SARS-CoV-2 infection as part of clinical strategies to mitigate severe outcomes.

Impact of COVID-19 on the incidence of localized and metastatic prostate cancer among White and Black Veterans.

The COVID-19 pandemic disrupted prostate-specific antigen (PSA) screening and prostate biopsy procedures. We sought to determine whether delayed screening and diagnostic workup of prostate cancer (PCa) was associated with increased subsequent rates of incident PCa and advanced PCa and whether the rates differed by race. We analyzed data from the Veterans Health Administration to assess the changes in the rates of PSA screening, prostate biopsy procedure, incident PCa, PCa with high-grade Gleason score, and incident metastatic prostate cancer (mPCa) before and after January 2020. While the late pandemic mPCa rate among White Veterans was comparable to the pre-pandemic rate (5.4 pre-pandemic vs 5.2 late-pandemic, p = 0.67), we observed a significant increase in incident mPCa cases among Black Veterans in the late pandemic period (8.1 pre-pandemic vs 11.3 late-pandemic, p < 0.001). Further investigation is warranted to fully understand the impact of the COVID-19 pandemic on the diagnosis of advanced prostate cancer.

A MUC5B Gene Polymorphism, rs35705950-T, Confers Protective Effects Against COVID-19 Hospitalization but Not Severe Disease or Mortality.

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in severe acute respiratory syndrome coronavirus 2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with coronavirus disease (COVID-19) infection among participants in the Million Veteran Program (MVP). Methods: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by transancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (body mass index, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease, and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects. Measurements and Main Results: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations in transancestry meta-analyses within the MVP (Ncases = 4,325; Ncontrols = 507,640; OR = 0.89 [0.82-0.97]; P = 6.86 × 10-3) and joint meta-analyses with the HGI (Ncases = 13,320; Ncontrols = 1,508,841; OR, 0.90 [0.86-0.95]; P = 8.99 × 10-5). The rs35705950-T allele was not associated with reduced COVID-19 positivity in transancestry meta-analysis within the MVP (Ncases = 19,168/Ncontrols = 492,854; OR, 0.98 [0.95-1.01]; P = 0.06) but was nominally significant (P < 0.05) in the joint meta-analysis with the HGI (Ncases = 44,820; Ncontrols = 1,775,827; OR, 0.97 [0.95-1.00]; P = 0.03). Associations were not observed with severe outcomes or mortality. Among individuals of European ancestry in the MVP, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR, 0.82 [0.72-0.93]; P = 0.001). Conclusions: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations.

A translational genomics approach identifies IL10RB as the top candidate gene target for COVID-19 susceptibility.

Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes that reduce COVID-19 host susceptibility is a critical next step. Using a translational genomics approach that integrates COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX), and perturbagen signatures, we identified IL10RB as the top candidate gene target for COVID-19 host susceptibility. In a series of validation steps, we show that predicted GReX upregulation of IL10RB and higher IL10RB expression in COVID-19 patient blood is associated with worse COVID-19 outcomes and that in vitro IL10RB overexpression is associated with increased viral load and activation of disease-relevant molecular pathways.

Association of Kidney Comorbidities and Acute Kidney Failure With Unfavorable Outcomes After COVID-19 in Individuals With the Sickle Cell Trait.

Importance: Sickle cell trait (SCT), defined as the presence of 1 hemoglobin beta sickle allele (rs334-T) and 1 normal beta allele, is prevalent in millions of people in the US, particularly in individuals of African and Hispanic ancestry. However, the association of SCT with COVID-19 is unclear. Objective: To assess the association of SCT with the prepandemic health conditions in participants of the Million Veteran Program (MVP) and to assess the severity and sequelae of COVID-19. Design, Setting, and Participants: COVID-19 clinical data include 2729 persons with SCT, of whom 353 had COVID-19, and 129 848 SCT-negative individuals, of whom 13 488 had COVID-19. Associations between SCT and COVID-19 outcomes were examined using firth regression. Analyses were performed by ancestry and adjusted for sex, age, age squared, and ancestral principal components to account for population stratification. Data for the study were collected between March 2020 and February 2021. Exposures: The hemoglobin beta S (HbS) allele (rs334-T). Main Outcomes and Measures: This study evaluated 4 COVID-19 outcomes derived from the World Health Organization severity scale and phenotypes derived from International Classification of Diseases codes in the electronic health records. Results: Of the 132 577 MVP participants with COVID-19 data, mean (SD) age at the index date was 64.8 (13.1) years. Sickle cell trait was present in 7.8% of individuals of African ancestry and associated with a history of chronic kidney disease, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease. Among the 4 clinical outcomes of COVID-19, SCT was associated with an increased COVID-19 mortality in individuals of African ancestry (n = 3749; odds ratio, 1.77; 95% CI, 1.13 to 2.77; P = .01). In the 60 days following COVID-19, SCT was associated with an increased incidence of acute kidney failure. A counterfactual mediation framework estimated that on average, 20.7% (95% CI, -3.8% to 56.0%) of the total effect of SCT on COVID-19 fatalities was due to acute kidney failure. Conclusions and Relevance: In this genetic association study, SCT was associated with preexisting kidney comorbidities, increased COVID-19 mortality, and kidney morbidity.

A Population-Level Analysis of the Protective Effects of Androgen Deprivation Therapy Against COVID-19 Disease Incidence and Severity.

Background: The incidence and severity of coronavirus disease 19 (COVID-19) is substantially higher in men. Sex hormones may be a potential mechanism for differences in COVID-19 outcome in men and women. We hypothesized that men treated with androgen deprivation therapy (ADT) have lower incidence and severity of COVID-19. Methods: We conducted an observational study of male Veterans treated in the Veterans Health Administration from February 15th to July 15th, 2020. We developed a propensity score model to predict the likelihood to undergo Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) testing. We performed multivariable logistic regression modeling adjusted with inverse probability weighting to examine the relationship between ADT and COVID-19 incidence. We conducted logistic regression analysis among COVID-19 patients to test the association between ADT and COVID-19 severity. Results: We identified a large cohort of 246,087 VA male patients who had been tested for SARS-CoV-2, of whom 3,057 men were exposed to ADT, and 36,096 men with cancer without ADT. Of these, 295 ADT patients and 2,427 cancer patients not on ADT had severe COVID-19 illness. In the primary, propensity-weighted comparison of ADT patients to cancer patients not on ADT, ADT was associated with decreased likelihood of testing positive for SARS-CoV-2 (adjusted OR, 0.88 [95% CI, 0.81-0.95]; p = 0.001). Furthermore, ADT was associated with fewer severe COVID-19 outcomes (OR 0.72 [95% CI 0.53-0.96]; p = 0.03). Conclusion: ADT is associated with reduced incidence and severity of COVID-19 amongst male Veterans. Testosterone and androgen receptor signaling may confer increased risk for SARS-CoV-2 infection and contribute to severe COVID-19 pathophysiology in men.