Exploratory analysis of innate immune gene polymorphisms and COVID-19 in-hospital mortality in a large admixed Brazilian cohort.
4 affiliations
- 1Faculty of Medicine, Institute of Tropical Medicine, University of São Paulo, São Paulo, Brazil.
- 2Department of Obstetrics and Gynecology, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
- 3Faculty of Medicine, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil.
- 4Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, United States.
Abstract
Introduction
COVID-19 in-hospital mortality varies substantially among patients, suggesting a role for host genetic factors beyond established clinical risk predictors.Methods
This case-control study investigated the association of the candidate SNPs rs2241880 (ATG16L1), rs1800450 (MBL2), rs10754558 (NLRP3), and rs12252 (IFITM3), alongside clinical variables, with in-hospital mortality in consecutive hospitalized patients including 505 non-survivors and 535 survivors of acute COVID-19 treated at a public hospital in São Paulo, Brazil, between March and August 2020. Baseline demographic, clinical, and genetic characteristics were compared between groups, and independent predictors of mortality were identified using multivariate logistic regression with Firth's penalized likelihood as the primary model to address quasi-complete separation.Results
Deceased patients were significantly older, more frequently male, and had a higher comorbidity burden. In the Firth penalized model, male sex [exp(β) = 2.30; 95% CI: 1.33-4.02; p = 0.003], immunodeficiency [exp(β) = 5.06; 95% CI: 1.28-24.6; p = 0.019], and mechanical ventilation [exp(β) = 136; p < 0.001] were independent clinical predictors of mortality. Nominally significant exploratory associations were observed for the rs2241880 G/G genotype [ATG16L1; exp(β) = 2.27; 95% CI: 1.09-4.87; p = 0.028] and the rs12252 G/G genotype [IFITM3; exp(β) = 5.83; 95% CI: 1.02-45.7; p = 0.047] with increased mortality risk, and for the rs1800450 T/T genotype [MBL2; exp(β) = 0.03; 95% CI: 0.00-0.94; p = 0.047] with reduced mortality risk; however, none of these associations survived correction for multiple testing. No association was observed for rs10754558 (NLRP3). Variant allele frequencies differed significantly across ethnic groups, particularly for rs12252, whose G allele was more frequent in Black (21.6%) than in White (13.9%) patients (p < 0.001), and a sensitivity analysis adjusting for self-reported ethnicity confirmed the directional consistency of genetic associations with marginally attenuated effect sizes.Discussion
These exploratory findings suggest that innate immune pathways, including autophagy, antiviral restriction, and complement activation, may contribute to COVID-19 mortality risk in the highly admixed Brazilian population and underscore the importance of conducting genetic studies in populations currently underrepresented in global genomic databases. Replication in larger, multi-ancestry cohorts with matched clinical endpoints is warranted to confirm or refute these signals.
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BibTeX
@article{amorim2026exploratory,
title = {{Exploratory analysis of innate immune gene polymorphisms and COVID-19 in-hospital mortality in a large admixed Brazilian cohort.}},
author = {Mariene Ribeiro Amorim and Tania Regina Tozetto-Mendoza and Mariane Pereira Brito and Vanessa Cássia Raymundi and Rafaella Medina-Neves and Iara Moreno Linhares and Alvina Clara Felix and Layla Honorato and Noely Ferreira and Laura Sampaio Azevedo and Carlos R R Carvalho and Emanuelle Leonília Marques and Antonio Charlys Da-Costa and Maria Cassia Mendes Correa and Steven S Witkin},
journal = {Frontiers in medicine},
year = {2026},
month = oct,
doi = {10.3389/fmed.2026.1919908},
url = {https://europepmc.org/article/MED/42908632},
note = {CC BY},
}
RIS
TY - JOUR
TI - Exploratory analysis of innate immune gene polymorphisms and COVID-19 in-hospital mortality in a large admixed Brazilian cohort.
AU - Mariene Ribeiro Amorim
AU - Tania Regina Tozetto-Mendoza
AU - Mariane Pereira Brito
AU - Vanessa Cássia Raymundi
AU - Rafaella Medina-Neves
AU - Iara Moreno Linhares
AU - Alvina Clara Felix
AU - Layla Honorato
AU - Noely Ferreira
AU - Laura Sampaio Azevedo
AU - Carlos R R Carvalho
AU - Emanuelle Leonília Marques
AU - Antonio Charlys Da-Costa
AU - Maria Cassia Mendes Correa
AU - Steven S Witkin
PY - 2026
DA - 2026/10/07
JO - Frontiers in medicine
DO - 10.3389/fmed.2026.1919908
UR - https://europepmc.org/article/MED/42908632
AB - Introduction COVID-19 in-hospital mortality varies substantially among patients, suggesting a role for host genetic factors beyond established clinical risk predictors.Methods This case-control study investigated the association of the candidate SNPs rs2241880 (ATG16L1), rs1800450 (MBL2), rs10754558 (NLRP3), and rs12252 (IFITM3), alongside clinical variables, with in-hospital mortality in consecutive hospitalized patients including 505 non-survivors and 535 survivors of acute COVID-19 treated at a public hospital in São Paulo, Brazil, between March and August 2020. Baseline demographic, clinical, and genetic characteristics were compared between groups, and independent predictors of mortality were identified using multivariate logistic regression with Firth's penalized likelihood as the primary model to address quasi-complete separation.Results Deceased patients were significantly older, more frequently male, and had a higher comorbidity burden. In the Firth penalized model, male sex [exp(β) = 2.30; 95% CI: 1.33-4.02; p = 0.003], immunodeficiency [exp(β) = 5.06; 95% CI: 1.28-24.6; p = 0.019], and mechanical ventilation [exp(β) = 136; p < 0.001] were independent clinical predictors of mortality. Nominally significant exploratory associations were observed for the rs2241880 G/G genotype [ATG16L1; exp(β) = 2.27; 95% CI: 1.09-4.87; p = 0.028] and the rs12252 G/G genotype [IFITM3; exp(β) = 5.83; 95% CI: 1.02-45.7; p = 0.047] with increased mortality risk, and for the rs1800450 T/T genotype [MBL2; exp(β) = 0.03; 95% CI: 0.00-0.94; p = 0.047] with reduced mortality risk; however, none of these associations survived correction for multiple testing. No association was observed for rs10754558 (NLRP3). Variant allele frequencies differed significantly across ethnic groups, particularly for rs12252, whose G allele was more frequent in Black (21.6%) than in White (13.9%) patients (p < 0.001), and a sensitivity analysis adjusting for self-reported ethnicity confirmed the directional consistency of genetic associations with marginally attenuated effect sizes.Discussion These exploratory findings suggest that innate immune pathways, including autophagy, antiviral restriction, and complement activation, may contribute to COVID-19 mortality risk in the highly admixed Brazilian population and underscore the importance of conducting genetic studies in populations currently underrepresented in global genomic databases. Replication in larger, multi-ancestry cohorts with matched clinical endpoints is warranted to confirm or refute these signals.
SN - 2296-858X
ER -