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. 2022 Aug 1;182(8):796-804.
doi: 10.1001/jamainternmed.2022.2141.

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

Anurag Verma  1   2 , Jennifer E Huffman  3 , Lina Gao  4   5 , Jessica Minnier  5   6   4 , Wen-Chih Wu  7   8 , Kelly Cho  3   9 , Yuk-Lam Ho  3 , Bryan R Gorman  10 , Saiju Pyarajan  10   11 , Nallakkandi Rajeevan  12   13 , Helene Garcon  3 , Jacob Joseph  14   15 , John E McGeary  16   17 , Ayako Suzuki  18   19 , Peter D Reaven  20   21 , Emily S Wan  22   23 , Julie A Lynch  24 , Jeffrey M Petersen  25   26 , James B Meigs  27 , Matthew S Freiberg  28 , Elise Gatsby  29 , Kristine E Lynch  29   30 , Seyedeh Maryam Zekavat  31   32 , Pradeep Natarajan  32   33   11   34 , Sharvari Dalal  26   35 , Darshana N Jhala  26   35 , Mehrdad Arjomandi  36   37 , Robert A Bonomo  38   39 , Trevor K Thompson  40 , Gita A Pathak  41   42 , Jin J Zhou  43   44 , Curtis J Donskey  45   46 , Ravi K Madduri  47 , Quinn S Wells  48 , Joel Gelernter  42   49 , Rose D L Huang  17 , Renato Polimanti  48   49 , Kyong-Mi Chang  1   26 , Katherine P Liao  50   51   52 , Philip S Tsao  53 , Yan V Sun  54   55 , Peter W F Wilson  55   56 , Christopher J O'Donnell  57 , Adriana M Hung  28   58 , J Michael Gaziano  59   60 , Richard L Hauger  61   62 , Sudha K Iyengar  63   64 , Shiuh-Wen Luoh  5   65 ; VA Million Veteran Program COVID-19 Science Initiative
Collaborators, Affiliations

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

Anurag Verma et al. JAMA Intern Med. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Suzuki reports other (consulting) from Pfizer unrelated to COVID-19 outside the submitted work. Dr Lynch reports grants from Janssen Pharmaceuticals Inc outside the submitted work. Dr Natarajan reports grant support from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis; personal fees from Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech/Roche, Novartis, and TenSixteen Bio; holding equity in TenSixteen Bio and Genexwell; and spousal employment at Vertex; all outside the submitted work. Dr Arjomandi reports salary support from US Department of Veterans Affairs during the conduct of the study; and grants from the Departments of Defense (W81XWH-20-1-0158) and Veterans Affairs (CXV-00125), the Flight Attendant Medical Research Institute (012500WG and CIA190001), and the California Tobacco-related Disease Research Program (T29IR0715) during the conduct of the study; and received research support from Guardant Health and Genentech. Mr Thompson reports grants from Vanderbilt University Medical Center Vanderbilt Medical Scholar during the conduct of the study. Dr O’Donnell is an employee of Novartis Institute for Biomedical Research. Dr Hung reports grants from Veterans Health Administration (CSR&D MVP Merit 5I01CX001897 Genetics of CKD and Hypertension—Risk Prediction and Drug Response in the MVP) and grants from MVP COVID-19 Science Program (MVP035) during the conduct of the study; and grants from Vertex to Vanderbilt University Medical Center outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flowchart With the Number of Individuals Selected for the Association Study
Left, phenome-wide association study (PheWAS) and laboratory-wide association study (LabWAS) analysis; middle, outcome severity; right, association study with clinical outcomes that occurred within 60 days of COVID-19 testing/diagnosis. Individuals tested within the Department of Veterans Affairs (VA) who had nonmissing genotyping and ethnic information were included. Phecodes that showed association with sickle cell trait (SCT) were tested for their association with COVID-19–related death in individuals of African ancestry (left lower); SCT-related conditions post–COVID-19 were tested for their mediation of SCT-related death in COVID-19 (right lower). AKF indicates acute kidney failure; Hb, hemoglobin; ICD-9/ICD-10, International Classification of Diseases, Ninth Revision/Tenth Revision; MVP, Million Veteran Program.
Figure 2.
Figure 2.. Association Study of rs334-T With Prepandemic Comorbidities in the Million Veteran Program (MVP)
A, Plot showing associations of rs334-T and clinical conditions derived from the electronic health records data prior to COVID-19 in MVP participants of African ancestry. The clinical conditions are shown on the y-axis and organized by broader disease categories. The P value (−log10) of each association is shown on the x-axis. The direction of each triangle represents the direction of effect of the associations, with the upward triangle representing increased risk and the downward represents reduced risk. The red line indicates the significance threshold based on the Bonferroni correction (P < 1 × 10−5). B, The plot shows the odds ratio and 95% CI of the Bonferroni significant associations of rs334-T in participants of African ancestry. CKD indicates chronic kidney disease.
See this image and copyright information in PMC

References

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