Genetically defined causal effects of natural killer cells related traits in risk of infection: a Mendelian randomization study

Abstract

BackgroundThe intricate interplay between genetics and immunology often dictates the host’s susceptibility to various diseases. This study explored the genetic causal relationship between natural killer (NK) cell-related traits and the risk of infection.MethodsSingle-nucleotide polymorphisms (SNPs) significantly associated with NK cell-related traits were selected as instrumental variables to estimate their genetic causal effects on infection. SNPs from a genome-wide association study (GWAS) on NK cell-related traits, including absolute cell counts, median fluorescence intensities reflecting surface antigen levels, and relative cell counts, were used as exposure instruments. Summary-level GWAS statistics of four phenotypes of infection were used as the outcome data. The exposure and outcome data were analyzed via the two-sample Mendelian randomization method.ResultsEach one standard deviation increase in the expression level of human leukocyte antigen (HLA)-DR on HLA-DR+ NK cells was associated with a lower risk of pneumonia (P < 0.05). An increased HLA-DR+ NK/CD3− lymphocyte ratio was related to a lower of risk of pneumonia (P < 0.05). Each one standard deviation increase in the absolute count of HLA-DR+ NK cells was associated with a lower risk of both bacterial pneumonia and pneumonia (P < 0.05). An increased HLA-DR+ NK/NK ratio was associated with a decreased risk of both pneumonia and bacterial pneumonia (P < 0.05). The results were robust under all sensitivity analyses. No evidence for heterogeneity, pleiotropy, or potential reverse causality was detected. Notably, our analysis did not reveal any significant associations between NK cell-related traits and other phenotypes of infection, including cellulitis, cystitis, and intestinal infection.ConclusionsHLA-DR+ NK cells could be a novel immune cell trait associated with a lower risk of bacterial pneumonia or pneumonia.