Association of KIR gene polymorphisms with COVID-19 disease

Hajeer, Ali H.; Jawdat, Dunia; Massadeh, Salam; Aljawini, Nora; Abedalthagafi, Malak; Arabi, Yaseen M.; Alaamery, Manal

doi:10.1016/j.clim.2021.108911

Cited by 21 publications

(22 citation statements)

References 30 publications

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“…Moreover, this study also found a significant association between AA KIR-haplotypes and patients with severe COVID-19 disease compared to symptomatic-paucisymptomatic patients. In contrast to the Sardinian study, Bx genotypes were associated with COVID-19 patients in Soudhi Arabian population ( Hajeer et al, 2022 ). A study in Turkey revealed an association between COVID-19 and specific centromeric and telomeric halves of KIR haplotypes with HLA class I ligands ( Beksac et al, 2021 ).…”

Section: Discussioncontrasting

confidence: 88%

“…Only five studies have investigated the impact of KIR receptors on SARS-CoV-2 infection ( Beksac et al, 2021 ; Bernal et al, 2021 ; Lesan et al, 2021 ; Littera et al, 2021 ; Hajeer et al, 2022 ). In contrast to our findings, a study with a small number of 16 patients from the German Caucasian cohort revealed that patients with activating KIR2DS5 were recovered from COVID-19 in a shorter time than the individuals negative for the KIR2DS5 gene ( Lesan et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

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Individualized Constellation of Killer Cell Immunoglobulin-Like Receptors and Cognate HLA Class I Ligands that Controls Natural Killer Cell Antiviral Immunity Predisposes COVID-19

et al. 2022

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Background: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causes coronavirus disease-2019 (COVID-19) in some individuals, while the majority remain asymptomatic. Natural killer (NK) cells play an essential role in antiviral defense. NK cell maturation and function are regulated mainly by highly polymorphic killer cell immunoglobulin-like receptors (KIR) and cognate HLA class I ligands. Herein, we tested our hypothesis that the individualized KIR and HLA class I ligand combinations that control NK cell function determine the outcome of SARS-CoV-2 infection.Methods: We characterized KIR and HLA genes in 200 patients hospitalized for COVID-19 and 195 healthy general population controls.Results: The KIR3DL1+HLA-Bw4+ [Odds ratio (OR) = 0.65, p = 0.03] and KIR3DL2+HLA-A3/11+ (OR = 0.6, p = 0.02) combinations were encountered at significantly lower frequency in COVID-19 patients than in the controls. Notably, 40% of the patients lacked both of these KIR+HLA+ combinations compared to 24.6% of the controls (OR = 2.04, p = 0.001). Additionally, activating receptors KIR2DS1+KIR2DS5+ are more frequent in patients with severe COVID-19 than patients with mild disease (OR = 1.8, p = 0.05). Individuals carrying KIR2DS1+KIR2DS5+ genes but missing either KIR3DL1+HLA-Bw4+ combination (OR = 1.73, p = 0.04) or KIR3DL2+HLA-A3/11+ combination (OR = 1.75, p = 0.02) or both KIR3DL1+HLA-Bw4+ and KIR2DL2+HLA-A3/11+ combinations (OR = 1.63, p = 0.03) were more frequent in the COVID-19 cohort compared to controls.Conclusions: The absence of KIR3DL1+HLA-Bw4+ and KIR3DL2+HLA-A3/11+ combinations presumably yields inadequate NK cell maturation and reduces anti-SARS-CoV-2 defense, causing COVID-19. An increased frequency of KIR2DS1+KIR2DS5+ in severe COVID-19 patients suggests vigorous NK cell response triggered via these activating receptors and subsequent production of exuberant inflammatory cytokines responsible for severe COVID-19. Our results demonstrate that specific KIR-HLA combinations that control NK cell maturation and function are underlying immunogenetic variables that determine the dual role of NK cells in mediating beneficial antiviral and detrimental pathologic action. These findings offer a framework for developing potential host genetic biomarkers to distinguish individuals prone to COVID-19.

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Section: Discussioncontrasting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Individualized Constellation of Killer Cell Immunoglobulin-Like Receptors and Cognate HLA Class I Ligands that Controls Natural Killer Cell Antiviral Immunity Predisposes COVID-19

et al. 2022

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“…In the context of SARS-CoV-2, the KIR AA genotype was associated to a severe COVID-19 disease, in particular, the KIR2DS4 was the most significantly associated with severity, followed by KIR3DL1. Interestingly, the AA genotype encodes for various inhibitory KIRs and only one activating KIR (178).…”

Section: Host Genetic Factorsmentioning

confidence: 99%

Hallmarks of Severe COVID-19 Pathogenesis: A Pas de Deux Between Viral and Host Factors

et al. 2022

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Two years into Coronavirus Disease 2019 (COVID-19) pandemic, a comprehensive characterization of the pathogenesis of severe and critical forms of COVID-19 is still missing. While a deep dysregulation of both the magnitude and functionality of innate and adaptive immune responses have been described in severe COVID-19, the mechanisms underlying such dysregulations are still a matter of scientific debate, in turn hampering the identification of new therapies and of subgroups of patients that would most benefit from individual clinical interventions. Here we review the current understanding of viral and host factors that contribute to immune dysregulation associated with COVID-19 severity in the attempt to unfold and broaden the comprehension of COVID-19 pathogenesis and to define correlates of protection to further inform strategies of targeted therapeutic interventions.

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“…Further protection could derive from interactions between killer-cell immunoglobulin-like receptors (KIRs), expressed on the surface of natural killer (NK) cells and their cognate human leukocyte antigen (HLA) Class I ligands ( 20 , 21 ). A recent study performed on the population of central southern Sardinia showed that KIR2DS2 in combination with HLA-C alleles of the C1 group exerts a potent protective effect against the adverse outcomes of COVID-19 ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

A Protective HLA Extended Haplotype Outweighs the Major COVID-19 Risk Factor Inherited From Neanderthals in the Sardinian Population

et al. 2022

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Sardinia has one of the lowest incidences of hospitalization and related mortality in Europe and yet a very high frequency of the Neanderthal risk locus variant on chromosome 3 (rs35044562), considered to be a major risk factor for a severe SARS-CoV-2 disease course. We evaluated 358 SARS-CoV-2 patients and 314 healthy Sardinian controls. One hundred and twenty patients were asymptomatic, 90 were pauci-symptomatic, 108 presented a moderate disease course and 40 were severely ill. All patients were analyzed for the Neanderthal-derived genetic variants reported as being protective (rs1156361) or causative (rs35044562) for severe illness. The β°39 C>T Thalassemia variant (rs11549407), HLA haplotypes, KIR genes, KIRs and their HLA class I ligand combinations were also investigated. Our findings revealed an increased risk for severe disease in Sardinian patients carrying the rs35044562 high risk variant [OR 5.32 (95% CI 2.53 - 12.01), p = 0.000]. Conversely, the protective effect of the HLA-A*02:01, B*18:01, DRB*03:01 three-loci extended haplotype in the Sardinian population was shown to efficiently contrast the high risk of a severe and devastating outcome of the infection predicted for carriers of the Neanderthal locus [OR 15.47 (95% CI 5.8 – 41.0), p < 0.0001]. This result suggests that the balance between risk and protective immunogenetic factors plays an important role in the evolution of COVID-19. A better understanding of these mechanisms may well turn out to be the biggest advantage in the race for the development of more efficient drugs and vaccines.

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Association of KIR gene polymorphisms with COVID-19 disease

Cited by 21 publications

References 30 publications

Individualized Constellation of Killer Cell Immunoglobulin-Like Receptors and Cognate HLA Class I Ligands that Controls Natural Killer Cell Antiviral Immunity Predisposes COVID-19

Individualized Constellation of Killer Cell Immunoglobulin-Like Receptors and Cognate HLA Class I Ligands that Controls Natural Killer Cell Antiviral Immunity Predisposes COVID-19

Hallmarks of Severe COVID-19 Pathogenesis: A Pas de Deux Between Viral and Host Factors

A Protective HLA Extended Haplotype Outweighs the Major COVID-19 Risk Factor Inherited From Neanderthals in the Sardinian Population

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