Association Between NK Cell Genetic Variants and the Development of Long COVID Associated- and Prepandemic Small Fiber Neuropathy

Long coronavirus disease 2019 (COVID) (LC) symptoms including pain and autonomic dysfunction are in some patients associated with small-fiber neuropathy (SFN). The pathomechanisms underlying SFN are mostly unclear. Natural killer (NK) cells play a crucial role in immune regulation, viral clearance and nerve metabolism. The aim of this study was to identify associations between development of small-fiber dysfunction dependent and independent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and human genetic markers associated with specific NK cell functions. The genetic markers assessed in all cohorts included: FCGR3A, IGHG1, HLA-E, NKG2C, and rs9916629. Genotyping was performed using TaqMan assays, Sanger sequencing and touchdown polymerase chain reaction. We assessed human cytomegalovirus (HCMV) IgG serostatus in all participants, and screened for anti-neuronal, anti-glial and anti-ganglioside autoantibodies in both patient cohorts. We included 50 LC patients with newly-emerged symptoms of small-fiber dysfunction after SARS-CoV-2 infection, 27 prepandemic SFN patients and 320 control persons. Markers associated with low NKG2C response, that is, deletion of the NKG2C gene and lack of prior HCMV infection (IgG seronegativity), occurred significantly more frequently in prepandemic SFN patients compared to LC patients and controls (p = 0.0109 and 0.0005, respectively). In conclusion, markers of impaired NKG2C pathways are associated with prepandemic SFN, but not with Long COVID-associated small-fiber dysfunction.