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.

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.

Sexual orientation-related disparities in health conditions that elevate COVID-19 severity.

PURPOSE: The Veterans Health Administration (VA) is the largest single integrated healthcare system in the US and is likely the largest healthcare provider for people with minoritized sexual orientations (e.g., gay, lesbian, bisexual). The purpose of this study was to use electronic health record (EHR) data to replicate self-reported survey findings from the general US population and assess whether sexual orientation is associated with diagnosed physical health conditions that may elevate risk of COVID-19 severity among veterans who utilize the VA. METHODS: A retrospective analysis of VA EHR data from January 10, 1999-January 07, 2019 analyzed in 2021. Veterans with minoritized sexual orientations were included if they had documentation of a minoritized sexual orientation within clinical notes identified via natural language processing. Veterans without minoritized sexual orientation documentation comprised the comparison group. Adjusted prevalence and prevalence ratios (aPR) were calculated overall and by race/ethnicity while accounting for differences in distributions of sex assigned at birth, age, calendar year of first VA visit, volumes of healthcare utilization, and VA priority group. RESULTS: Data from 108,401 veterans with minoritized sexual orientation and 6,511,698 controls were analyzed. After adjustment, veterans with minoritized sexual orientations had a statistically significant elevated prevalence of 10 of the 11 conditions. Amongst the highest disparities observed were COPD (aPR:1.24 [95% confidence interval:1.23-1.26]), asthma (1.22 [1.20-1.24]), and stroke (1.26 [1.24-1.28]). CONCLUSIONS: Findings largely corroborated patterns among the general US population. Further research is needed to determine if these disparities translate to poorer COVID-19 outcomes for individuals with minoritized sexual orientation.

Positive Predictive Value of COVID-19 ICD-10 Diagnosis Codes Across Calendar Time and Clinical Setting.

PURPOSE: To estimate the positive predictive value (PPV) of International Classification of Diseases, Tenth Revision (ICD-10) code U07.1, COVID-19 virus identified, in the Department of Veterans of Affairs (VA). PATIENTS AND METHODS: Records of ICD-10 code U07.1 from inpatient, outpatient, and emergency/urgent care settings were extracted from VA medical record data from 4/01/2020 to 3/31/2021. A weighted, random sample of 1500 records from each quarter of the one-year observation period was reviewed by study personnel to confirm active COVID-19 infection at the time of diagnosis and classify reasons for false positive records. PPV was estimated overall and compared across clinical setting and quarters. RESULTS: We identified 664,406 records of U07.1. Among the 1500 reviewed, 237 were false positives (PPV: 84.2%, 95% CI: 82.4-86.0). PPV ranged from 77.7% in outpatient settings to 93.8% in inpatient settings and was 83.3% in quarter 1, 80.5% in quarter 2, 86.1% in quarter 3, and 83.6% in quarter 4. The most common reasons for false positive records were history of COVID-19 (44.3%) and orders for laboratory tests (21.5%). CONCLUSION: The PPV of ICD-10 code U07.1 is low, especially in outpatient settings. Directed training may improve accuracy of coding to levels that are deemed adequate for future use in surveillance efforts.