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<p>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 (<i>n</i> = 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 <i>MUC5AC</i>, <i>IFNA10</i>, <i>ZNF778</i>, and <i>PTOV1</i> 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) (<i>p</i> = 0.027, OR = 2.59). Additionally, patients with variants in highly LoF-intolerant genes had a fourfold higher risk of death (<i>p</i> = 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.</p>

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Rare genetic variants and severe COVID-19 in previously healthy admixed Latin American adults

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月2日

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  • Gabriela Dias Rocha,
  • Pablo Rafael Silveira Oliveira,
  • Marcus Villander Barros de Oliveira Sá,
  • Túlio de Lima Campos,
  • Steffany Larissa Galdino Galisa,
  • Andreia Soares Silva,
  • Patricia Moura,
  • Raquel Bispo de São Pedro,
  • Natália Machado Tavares,
  • Viviane Sampaio Boaventura,
  • Sara Nunes,
  • Icaro Bonyek-Silva,
  • Juliana Ribeiro Caldas,
  • Eric Henrique Roma,
  • Jorge Reis Almeida,
  • Andrea Alice Silva,
  • Tatiana Baccin,
  • Andrea Cauduro de Castro,
  • Antônio Carlos Rosario Vallinoto,
  • Rosilene da Silva,
  • Eduardo José Melo dos Santos,
  • Cristiana Couto Garcia,
  • Renata Dezengrini Slhessarenko,
  • Anderson da Costa Armstrong,
  • Rodrigo Feliciano do Carmo,
  • Luydson Richardson Silva Vasconcelos

摘要

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.