Lyle G. Best, Esther Erdei, Karin Haack, Jack W. Kent Jr, Kimberly M. Malloy, Deborah E. Newman, Marcia O’Leary, Rae A. O'Leary, Quan Sun, Ana Navas-Acien, Nora Franceschini, Shelley A. Cole
Abstract
Background
Although COVID-19 infection has been associated with a number of clinical and environmental risk factors, host genetic variation has also been associated with the incidence and morbidity of infection. The CRP gene codes for a critical component of the innate immune system and CRP variants have been reported associated with infectious disease and vaccination outcomes. We investigated possible associations between COVID-19 outcome and a limited number of candidate gene variants including rs1205.
Introduction
The ongoing pandemic of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections has taken a devastating toll on American Indian, Alaskan Native (AI/AN) populations, with hospitalization and death rate ratios for COVID-19 (compared with White ethnicity) reported as 2.5 fold; and 2.1 fold, respectively [1]. A number of demographic and clinical characteristics, such as male gender, socio-economic deprivation, diabetes, cardiovascular disease and obesity, have been identified as risk factors for COVID-19 associated morbidity and mortality [2]. The hypothesis that this increased burden of COVID-19 morbidity and mortality among ethnic minorities is due to the increased prevalence of these co-morbidities in many populations, has been considered; but the proportion of effect attributable to clinical co-morbidities may be small [2]. In spite of considerable interest in possible host genetic factors that influence the severity of COVID-19 among all patients, there have been few reliably replicating studies in specific racial/ethnic groups [3].
Materials and methods
Participants and cohorts
The SHS/SHFS methodology and design has been described previously [4,5]. While SHS/SHFS medical record surveillance of participants originally focused on ascertainment of outcome events related to CVD, in early 2020 ascertainment for COVID-19 was begun, with the recognition of a bidirectional relationship between CVD and COVID-19 infection.
Inclusion criteria:
* All SHS/SHFS participants alive and under surveillance for CVD events between 2/1/20 and 3/1/23
* Any death or hospitalization wherein the physician reviewer identified COVID-19 infection as a defining or contributing factor was considered a COVID-19 outcome
Results
Table 1 shows the genotyped variants selected, their associated genes and allele frequencies in the SHFS or SHS cohorts. The characteristics of both the SHS and SHFS cohorts are summarized in Table 2. Unadjusted results limited to the primary variant of interest from the SHFS, the SHS cohort or combined SHFS/SHS cohorts, using additive and dominant models based on risk or non-risk alleles are shown in Table 3. Results for the remaining variants are found in Supplemental S1 Table. For variants with low frequency, logistic models were often unstable and not reported. Analyses in the SHFS cohort showed nominally significant associations for the rs1205 T allele dominant (T-Dom) genotype in the combined SHFS/SHS cohort and both additive and T-Dom models in the SHFS cohort).
Discussion
We present previously unreported evidence of association between a common human variant (rs1205) and the clinical impact of the SARS-CoV-2 virus causing COVID-19. While our study has a modest number of cases, these results derive from a large cohort of American Indian individuals who are being followed longitudinally using standardized, physician review of medical records [4] The rs1205 variant has been recognized as functionally affecting serum levels of CRP, [25,28,29] in several populations and, in the present SHFS population as well [50]. CRP is an important component of the innate immune system, thus supporting a role of the gene and this variant’s potential effects on the pathophysiology of COVID-19. A genome-wide association meta-analysis has reported an intron variant (rs67579710) associated with COVID-19 hospitalization among 24,741cases and 2,835,201controls [42]. This variant is 4.5Mb from rs1205 [57] and within the thrombospondin3 gene, thus it may play a role in the thrombosis associated with COVID-19, rather than inflammatory pathways.
Acknowledgments
We thank the study participants, Indian Health Service facilities, and participating Tribal communities for their extraordinary cooperation and involvement, which has been critical to the success of the Strong Heart Study since 1988.
Citation: Best LG, Erdei E, Haack K, Kent JW Jr, Malloy KM, Newman DE, et al. (2024) Genetic variant rs1205 is associated with COVID-19 outcomes: The Strong Heart Study and Strong Heart Family Study. PLoS ONE 19(4): e0302464. https://doi.org/10.1371/journal.pone.0302464
Editor: Linglin Xie, Texas A&M University College Station, UNITED STATES
Received: October 24, 2023; Accepted: April 3, 2024; Published: April 25, 2024
Copyright: © 2024 Best et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The data underlying the results of this study are owned and controlled by the Tribal entities that approved its collection. This fact is clearly stated in the Tribal resolutions authorizing the research; and it must be recognized that these Tribal communities are an independent, sovereign governments, in control over research activities within their borders. Access to data and materials can be accomplished by application to Mr. Guthrie Ducheneaux, IT director, Missouri Breaks Research Inc, 505 S Willow St, Eagle Butte, SD 57625, 605-964-3419, email: [email protected], who will arrange for further consultation with the appropriate Tribal partners. Approximately 2 to 3 months may be required. The authors received special access privileges to the data due to their relationship with the Tribal Governments, however, interested researchers who apply for data access will be able to access the same data as the authors.
Funding: LGB, MO, RO: National Heart, Lung and Blood Institute contract: 75N92019D00029, https://www.nhlbi.nih.gov/ NF, SQ: National Institute on Minority Health and Disparities: R01-MD012765, https://www.nimhd.nih.gov/ ANA: National Institute of Diabetes and Digestive and Kidney Diseases: R01-DK117445, https://www.niddk.nih.gov/ EE: National Institute of Environmental Health Science: R21ES033119, https://www.niehs.nih.gov/ ANA: National Institute of Environmental Health Science: R01ES021367, https://www.niehs.nih.gov/ ANA: National Institute of Environmental Health Science: P42ES033719, https://www.niehs.nih.gov/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0302464#abstract0
