Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19

J Clin Invest. 2021 Jul 15;131(14):e147834. doi: 10.1172/JCI147834.

Abstract

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.

Keywords: Genetic variation; Genetics; Infectious disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • COVID-19 / genetics*
  • COVID-19 / immunology*
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Cohort Studies
  • Exome Sequencing
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Infant
  • Infant, Newborn
  • Interferon Regulatory Factor-7 / genetics
  • Interferon Type I / genetics*
  • Interferon Type I / immunology*
  • Loss of Function Mutation*
  • Male
  • Middle Aged
  • SARS-CoV-2*
  • Severity of Illness Index
  • Toll-Like Receptor 3 / genetics
  • Whole Genome Sequencing
  • Young Adult

Substances

  • IRF7 protein, human
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • TLR3 protein, human
  • Toll-Like Receptor 3