Natural killer cells-related immune traits and amyotrophic lateral sclerosis: A Mendelian randomization study

Abstract

BackgroundObservational studies have suggested that peripheral immune disorders are associated with amyotrophic lateral sclerosis (ALS). Previous studies predominantly focused on changes in adaptive immunity. However, emerging evidence showed natural killer (NK) cells, an essential component of innate immunity, were involved in the degeneration of motor neurons. However, the causal relationship between dysregulated NK cells-related immune traits and ALS remains unclear.ObjectiveThis study aimed to explore the causal relationship between NK cells-related immune traits and the risk of ALS.Materials and methodsSingle nucleotide polymorphisms (SNPs) significantly associated with NK cells-related immune traits were selected as instrumental variables to estimate their causal effects on ALS. SNPs from a genome-wide association study (GWAS) on NK cells-related immune traits were used as exposure instruments, including an absolute NK-cells count, absolute HLA-DR+ NK-cells count, NK cells/lymphocytes, NK cells/CD3– lymphocytes, HLA DR+ NK cells/NK cells, HLA DR+ NK cells/CD3– lymphocytes, and the median fluorescence intensities of CD16–CD56+ on NK cells and HLA-DR+ NK cells. Summary-level GWAS statistics of ALS were used as the outcome data. Exposure and outcome data were analyzed using the two-sample Mendelian randomization (MR) method.ResultsEach one standard deviation increase in the expression levels of CD16–CD56+ on NK cells and HLA-DR+ NK cells were associated with a lower risk of ALS in both the MR-Egger and inverse variance weighted methods (P < 0.05). The results proved robust under all sensitivity analyses. Neither instrumental outliers nor heterogeneity were detected.ConclusionOur results suggest that higher expression levels of CD16–CD56+ on NK cells and HLA-DR+ NK cells are associated with a lower risk of ALS.

Circulating inflammatory proteins and risk of Parkinson’s disease and other neurodegenerative disorders: a two-sample Mendelian randomization study

“…All these ndings suggest that peripheral immune dysregulation is a remarkable pathological marker of NDDs. With MR analysis, previous studies have also shown several blood immune cell traits are causally correlated with 4 NDDs, including AD 20,21 , PD 21,22,59 , ALS 21,23 , and MS 24,25 . In this study, we provided new evidence that peripheral in ammatory proteins are also causally associated with NDDs, which further support the causal role of peripheral immune dysregulation in the pathogenesis of NDDs.…”

“…Considering the critical role of peripheral in ammation in the occurrence of NDDs, it is important to examine whether peripheral immune molecules or cells were causally associated with the risk of NDDs using MR analysis. Previous studies have used MR analysis to estimate the causal associations between immune cell traits and neurological diseases, such as AD 20,21 , PD 21,22 , ALS 21,23 , MS 24,25 , myasthenia gravis 26 , and subarachnoid hemorrhage 27 . However, how the circulating in ammatory proteins causally associate with NDDs remains to be identi ed.…”

Identifying the causal relationship between immune factors and osteonecrosis: a two-sample Mendelian randomization study

“…Implying an activated cell state, HLA DR + NK cells, a subclass of NK cells, were found to be prolific in cytokine production, such as IFN-γ and TNF-α, which play a role in bone remodeling and osteoclast activation 54 , 55 . Moreover, activation of these HLA DR + NK cells might potentially trigger or exacerbate an inflammatory cascade 56 , thereby disrupting bone homeostasis and vascular systems, leading to bone ischemia and necrosis. In summary, the relationship between these HLA DR + NK cells and osteonecrosis could be multi-faceted, involving both direct and indirect impacts on bone tissue integrity, blood supply, and immune regulation.…”

Investigating Potential Drug Targets in Intracranial Aneurysms through Mendelian Randomization and Transcriptome Analyses

“…To this end, we conducted a follow-up exploration of the correlation between NK cells and IAs. In clinical practice, there is a crucial problem in that deleting immune cell classification is often not feasible because it can severely disrupt the immune system [47,48]. To the best of our knowledge, recent studies have not investigated the specific classification of IAs.…”