Exploratory analysis of innate immune gene polymorphisms and COVID-19 in-hospital mortality in a large admixed Brazilian cohort

Abstract

COVID-19 in-hospital mortality varies substantially among patients, suggesting a role for host genetic factors beyond established clinical risk predictors. 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. 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. 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.