The natural killer cell-associated rs9916629-C allele is a novel genetic risk factor for fatal COVID-19

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Hannes Vietzen¹, Philippe L Furlano¹, Marianna Traugott²

¹Center for Virology, Medical University of Vienna, Vienna, Austria.

Journal of Medical Virology

|December 14, 2022

Insights

The rs9916629-C allele is a significant risk factor for severe and fatal COVID-19, independent of age or comorbidities. This genetic variant may serve as a prognostic marker for hospitalized patients.

Area of Science:

Immunogenetics
Virology
Human Genetics

Background:

COVID-19 severity is linked to host genetic factors influencing natural killer (NK) cell responses.
Polymorphisms in HLA-E, FcγRIIIa, and NKG2C receptors are associated with severe COVID-19.
The rs9916629-C/T polymorphism influences NK cell repertoire towards pro-inflammatory CD56bright NK cells.

Purpose of the Study:

To investigate the association of rs9916629-C/T variants with fatal COVID-19.
To compare the rs9916629-C/T variants with other known genetic risk factors.
To evaluate the prognostic potential of rs9916629-C/T for COVID-19 outcomes.

Main Methods:

Genotyping of rs9916629-C/T variants using TaqMan assays in 1042 surviving and 159 non-surviving COVID-19 patients, plus 1000 controls.
Comparison of allele frequencies between patient groups and controls.
Analysis of age, comorbidities, and other genetic variants (HLA-E, FcγRIIIa, KLRC2) in relation to COVID-19 severity.

Main Results:

The rs9916629-C allele was a significant risk factor for severe and fatal COVID-19 (p < 0.0001), independent of age and comorbidities.
Fatal COVID-19 occurred more frequently in younger patients with FcγRIIIa-158-V/V and older patients with KLRC2del variants.
Patients with the rs9916629-C allele showed a markedly increased risk for fatal COVID-19.

Conclusions:

The rs9916629-C allele is a strong independent risk factor for fatal COVID-19.
Genetic variants like rs9916629-C/T can serve as valuable prognostic markers for hospitalized COVID-19 patients.
Understanding genetic predispositions can aid in predicting disease outcomes and managing patient care.

Read full analysis

Abstract:

The severity of COVID-19 is associated with individual genetic host factors. Among these, genetic polymorphisms affecting natural killer (NK) cell responses, as variations in the HLA-E- (HLA-E*0101/0103), FcγRIIIa- (FcγRIIIa-158-F/V), and NKG2C- (KLRC2^wt/del ) receptor, were associated with severe COVID-19. Recently, the rs9916629-C/T genetic polymorphism was identified that indirectly shape the human NK cell repertoire towards highly pro-inflammatory CD56^bright NK cells. We investigated whether the rs9916629-C/T variants alone and in comparison to the other risk factors are associated with a fatal course of COVID-19. We included 1042 hospitalized surviving and 159 nonsurviving COVID-19 patients as well as 1000 healthy controls. rs9916629-C/T variants were genotyped by TaqMan assays and were compared between the groups. The patients' age, comorbidities, HLA-E*0101/0103, FcγRIIIa-158-F/V, and KLRC2^wt/del variants were also determined. The presence of the rs9916629-C allele was a risk factor for severe and fatal COVID-19 (p < 0.0001), independent of the patients' age or comorbidities. Fatal COVID-19 was more frequent in younger patients (<69.85 years) carrying the FcγRIIIa-158-V/V (p < 0.006) and in older patients expressing the KLRC2^del variant (p < 0.003). Thus, patients with the rs9916629-C allele have a significantly increased risk for fatal COVID-19 and identification of the genetic variants may be used as prognostic marker for hospitalized COVID-19 patients.

Keywords:

COVID-19 FcγRIIIa HLA-E NK cells NKG2C genetic polymorphism rs9916629

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