Rare genetic variants and severe COVID-19 in previously healthy admixed Latin American adults.
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Rocha Gabriela Dias, Oliveira Pablo Rafael Silveira, de Oliveira Sá Marcus Villander Barros, de Lima Campos Túlio, Galdino Galisa Steffany Larissa, Silva Andreia Soares, Moura Patricia, de São Pedro Raquel Bispo, Tavares Natália Machado, Boaventura Viviane Sampaio, Nunes Sara, Bonyek-Silva Icaro, Caldas Juliana Ribeiro, Roma Eric Henrique, Almeida Jorge Reis, Silva Andrea Alice, Baccin Tatiana, de Castro Andrea Cauduro, Vallinoto Antônio Carlos Rosario, da Silva Rosilene, Dos Santos Eduardo José Melo, Garcia Cristiana Couto, Slhessarenko Renata Dezengrini, da Costa Armstrong Anderson, do Carmo Rodrigo Feliciano, Vasconcelos Luydson Richardson Silva
Аннотация
Rare genetic variants that affect host defense against SARS-CoV-2 may contribute to COVID-19 progression, helping to explain severe or fatal cases in young and middle-aged patients. This study aimed to identify rare genetic variants potentially implicated in life-threatening COVID-19 in a cohort of Brazilian patients aged 18 to 60, with no prior history of health issues, who required intensive care unit admission (n = 161). Whole genome sequencing was performed, followed by a prioritization approach for rare variants in loci previously associated with severe COVID-19. A total of 104 rare and potentially deleterious variants were identified in 79 genes. Ultra-rare variants in MUC5AC, IFNA10, ZNF778, and PTOV1 were the most frequently observed. We report 17 novel variants, including those likely pathogenic or indicating strong loss-of-function (LoF) intolerance. Patients carrying prioritized rare variants had a significantly higher incidence of acute respiratory distress syndrome (ARDS) (p = 0.027, OR = 2.59). Additionally, patients with variants in highly LoF-intolerant genes had a fourfold higher risk of death (p = 0.0084, OR = 4.04). To date, this is the first genomic analysis of previously healthy young and middle-aged Latin American patients with severe COVID-19. Our findings highlight the importance of identifying population-specific genetic risk factors.