KIR2DL2/C1: A potential predictive immunogenetic marker to COVID-19 severity in Spanish patients

ABSTRACT

COVID-19 has aspects on its pathogenesis that still need elucidating and an analysis of clinical and immunogenetic factors in each cohort of patients is paramount to understanding how genetic variability can explain the multiple clinical spectra seen in patients infected with SARS-CoV-2. The aim of this study was to correlate the KIR polymorphism/HLA class I ligand interactions from patients and healthy subjects with either the susceptibility or severity to COVID-19. Genotyping of HLA-A, -B, -C and KIR genes were carried out from 459 symptomatic as well as 667 non-infected Spanish Caucasian individuals using Lifecodes HLA-SSO and KIR-SSO kits (ImmucorTM, USA) and analyzed in the Luminex in this uni-centre case-control study performed at the University Hospital of Salamanca, Spain. Comparative KIR gene analysis showed that KIR2DS4 was significantly more representative in healthy versus infected individuals. When comparing subgroups of infected patients, KIR2DS3 had a higher frequency in those who progressed to a more severity disease and yet with higher mortality rate. Three functional combinations were significant on univariate analysis: KIR2DL2/C1, KIR2DS2/C1, and KIR2DS3/C1. However, in the multivariate analysis, only the KIR2DL2/C1 interaction remained significant (OR = 15.2 (95% CI 1.5-147), p = 0.0189). Compared with the solo-clinical characteristics predictive model, that included well-known comorbidity variables such as hypertension, age, sex, diabetes, C-reactive protein, dyslipidemia, smoking, ferritin, and fibrinogen, the clinical-and-KIR-based model showed a better ability to discriminate between severe and nonsevere patients with higher sensitivity and specificity. Our results support a fundamental role of KIR/ligand interaction in the clinical course of COVID-19. Since the KIR2DL2 gene has a high frequency in Spain (60%), the analysis of the KIR2DL2/C1 in symptomatic patients who require hospitalization could be helpful to better determine their prognosis.