Deletion of the NKG2C receptor encoding KLRC2 gene and HLA-E variants are risk factors for severe COVID-19

Genet Med. 2021 May;23(5):963-967. doi: 10.1038/s41436-020-01077-7. Epub 2021 Jan 26.


Purpose: Host genetic variants may contribute to severity of COVID-19. NKG2C+ NK cells are potent antiviral effector cells, potentially limiting the extent of SARS-CoV-2 infections. NKG2C is an activating NK cell receptor encoded by the KLRC2 gene, which binds to HLA-E on infected cells leading to NK cell activation. Heterozygous or homozygous KLRC2 deletion (KLRC2del) may naturally occur and is associated with a significantly lower or absent NKG2C expression level. In addition, HLA-E*0101/0103 genetic variants occur, caused by a single-nucleotide polymorphism. We therefore investigated whether the severity of COVID-19 is associated with these genetic variants.

Methods: We investigated the distribution of KLRC2 deletion and HLA-E*0101/0103 allelic variants in a study cohort of 361 patients with either mild (N = 92) or severe (N = 269) COVID-19.

Results: Especially the KLRC2del, and at a lower degree the HLA-E*0101, allele were significantly overrepresented in hospitalized patients (p = 0.0006 and p = 0.01), particularly in patients requiring intensive care (p < 0.0001 and p = 0.01), compared with patients with mild symptoms. Both genetic variants were independent risk factors for severe COVID-19.

Conclusion: Our data show that these genetic variants in the NKG2C/HLA-E axis have a significant impact on the development of severe SARS-CoV-2 infections, and may help to identify patients at high-risk for severe COVID-19.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19*
  • Histocompatibility Antigens Class II
  • Humans
  • NK Cell Lectin-Like Receptor Subfamily C* / genetics
  • Risk Factors
  • SARS-CoV-2


  • Histocompatibility Antigens Class II
  • KLRC2 protein, human
  • NK Cell Lectin-Like Receptor Subfamily C