The Effect of Peripheral Immune Cell Counts on the Risk of Multiple Sclerosis: A Mendelian Randomization Study

Abstract

ObjectivesMultiple sclerosis (MS) is a complex central nervous system (CNS) demyelinating disease, the etiology of which involves the interplay between genetic and environmental factors. We aimed to determine whether genetically predicted peripheral immune cell counts may have a causal effect on MS.MethodsWe used genetic variants strongly associated with cell counts of circulating leukocyte, lymphocyte, monocyte, neutrophil, eosinophil, and basophil, in addition to some subpopulations of T and B lymphocyte, as instrumental variables (IVs) to perform Mendelian randomization (MR) analyses. The effect of immune cell counts on MS risk was measured using the summary statistics from the International Multiple Sclerosis Genetics Consortium (IMSGC) genome-wide association studies (GWAS).ResultsOur findings indicated that higher leucocyte count [odds ratio (OR), 1.24; 95% confidence interval (CI), 1.07 - 1.43; p = 0.0039] and lymphocyte count (OR, 1.17; 95% CI, 1.01 – 1.35; p = 0.0317) were causally associated with MS susceptibility. In addition, we also found that increase of genetically predicted natural killer T (NKT) cell count is also associated with an increase MS risk (OR, 1.24; 95% CI, 1.06 - 1.45; p = 0.0082).ConclusionsThese findings show that the genetic predisposition to higher peripheral immune cell counts can exert a causal effect on MS risk, which confirms the crucial role played by peripheral immunity in MS. Particularly, the causal association between NKT cell count and MS underscores the relevance of exploring the functional roles of NKT cells in disease pathogenesis in future.

A systematic review of Mendelian randomization studies on multiple sclerosis

“…He et al (2022) have investigated the causal effect of immune and lymphocyte cell count counts, driven by the observation that some susceptibility loci lie in genes implicated in immunological pathways or that may have immune modulatory effects. They found a statistically significant causal effect between (i) leucocyte count and MS with an IVW OR = 1.24 (95% CI: 1.07–1.43), p = .004; (ii) lymphocyte count and MS with an IVW OR = 1.17 (95% CI: 1.01–1.35), p = .03; and (iii) natural killer T (NKT) cells absolute count (AC) and MS with an IVW OR = 1.24 (95% CI: 1.06–1.45), p = .008.…”

“…Notably, another study by Vandebergh, Becelaere, et al (2022) investigated the causal effect of IL-6 and IL-6 signalling, using both UK Biobank and CHARGE data as sources for the exposures, and showed a statistically significant causal estimate for IL-6 signalling only: OR (UK Biobank) = 1.14 (95% CI: 1.02-1.27), p = .02, and OR (CHARGE) = 1.51 (95% CI: 1.11-2.04), p = .01. He et al (2022) have investigated the causal effect of immune and lymphocyte cell count counts, driven by the observation that some susceptibility loci lie in genes implicated in immunological pathways or that may have immune modulatory effects. They found a statistically significant causal effect between (i) leucocyte count and MS with an IVW OR = 1.24 (95% CI: 1.07-1.43), p = .004; (ii) lymphocyte count and MS with an IVW OR = 1.17 (95% CI: 1.01-1.35), p = .03; and (iii) natural killer T (NKT) cells absolute count (AC) and MS with an IVW OR = 1.24 (95% CI: 1.06-1.45), p = .008.…”

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

“…All these findings 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 inflammatory proteins are also causally associated with NDDs, which further support the causal role of peripheral immune dysregulation in the pathogenesis of NDDs.…”

Causal association between immune cells and esophageal cancer: a bidirectional two-sample Mendelian randomization study

“…This finding provides further evidence for the significant involvement of peripheral immunity in the development of MS. The significance of investigating the functional roles of NKT cells in disease pathogenesis in the future is shown by the causative relationship observed between the NKT cell count and multiple sclerosis (MS) [15]. Moreover, An increased level of monocytes and T lymphocytes in the blood is linked to an increased risk of type 2 diabetes (T2D), according to studies on the role of the immune system in diabetes.…”