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

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To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Is the presence of sickle cell trait (SCT) associated with worse outcomes of COVID-19?

Findings  In this genetic association study of 2729 persons with SCT and 129 848 who were SCT negative, individuals with SCT had a number of preexisting kidney conditions that were associated with unfavorable outcomes following COVID-19. The presence of SCT was associated with increased risk of mortality and acute kidney failure following COVID-19.

Meaning  Results strongly support the inclusion of SCT as an adverse prognostic factor for COVID-19.


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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Article Information

Accepted for Publication: April 23, 2022.

Published Online: June 27, 2022. doi:10.1001/jamainternmed.2022.2141

Corresponding Authors: Shiuh-Wen Luoh, MD, PhD, VA Portland Health Care System, 3710 SW US Veterans Hospital Rd, Portland, OR 97239 (shiuh-wen.luoh@va.gov; luohs@ohsu.edu); Sudha K. Iyengar, PhD, Case Western Reserve University, 2103 Cornell Rd, 1315 WRB, 1315 Wolstein Research Bldg, Cleveland, OH 44106 (ski@case.edu).

Author Contributions: Drs Verma, Gao, Iyengar, and Luoh had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Verma, Huffman, and Gao contributed equally to this work. Drs Iyengar and Luoh jointly supervised this work.

Concept and design: Verma, Minnier, Cho, Garcon, Joseph, McGeary, Suzuki, J. Lynch, Meigs, Natarajan, Bonomo, Thompson, Zhou, Chang, Tsao, Sun, Hung, O’Donnell, Gaziano, Iyengar, Luoh.

Acquisition, analysis, or interpretation of data: Verma, Huffman, Gao, Minnier, Wu, Ho, Goman, Pyarajan, Rajeevan, McGeary, Reaven, Wan, J. Lynch, Petersen, Freiberg, Gatsby, K. Lynch, Zekavat, Dalal, Jhala, Arjomandi, Pathak, Zhou, Donskey, Madduri, Wells, Gelernter, Huang, Polimanti, Liao, Tsao, Sun, Wilson, Gaziano, Hauger, Iyengar, Luoh.

Drafting of the manuscript: Verma, Minnier, Garcon, Wan, Arjomandi, Bonomo, Zhou, Madduri, Chang, Liao, Hauger, Iyengar, Luoh.

Critical revision of the manuscript for important intellectual content: Verma, Huffman, Gao, Minnier, Wu, Cho, Ho, Goman, Pyarajan, Rajeevan, Joseph, McGeary, Suzuki, Reaven, Wan, J. Lynch, Petersen, Meigs, Freiberg, Gatsby, K. Lynch, Zekavat, Natarajan, Dalal, Jhala, Thompson, Pathak, Donskey, Wells, Gelernter, Huang, Polimanti, Chang, Liao, Tsao, Sun, Wilson, Hung, O’Donnell, Gaziano, Hauger, Iyengar, Luoh.

Statistical analysis: Verma, Gao, Minnier, Rajeevan, Zekavat, Pathak, Zhou, Polimanti, Iyengar, Luoh.

Obtained funding: J. Lynch, Chang, Tsao, O’Donnell, Gaziano, Iyengar, Luoh.

Administrative, technical, or material support: Wu, Cho, Ho, Goman, Wan, J. Lynch, Gatsby, Bonomo, Thompson, Madduri, Chang, Liao, Tsao, Sun, Wilson, O’Donnell, Gaziano, Luoh.

Supervision: Cho, Pyarajan, Meigs, Natarajan, Iyengar, Luoh.

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.

Funding/Support: This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by the MVP035 award and VA Grant BX 004831 (Drs Wilson and Cho).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: A complete list of investigators and staff in the VA Million Veteran Program COVID-19 Science Initiative is provided in Supplement 3.

Disclaimer: This publication does not represent the views of the Department of Veterans Affairs of the US government.

Additional Contributions: We are grateful to our veterans for their contribution to MVP. Full acknowledgments for the VA Million Veteran Program COVID-19 Science Initiative can be found in the eAppendix in Supplement 1.

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Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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