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. 2024 Apr 9:15:1345416.
doi: 10.3389/fimmu.2024.1345416. eCollection 2024.

Causal relationship between the immune cells and ankylosing spondylitis: univariable, bidirectional, and multivariable Mendelian randomization

Chaofan Qin #  1 , Qingshuai Yu #  1 , Zhongliang Deng  1 , You Zhang  1 , Mingxin Chen  1 , Xin Wang  1 , Tao Hu  1 , Bo Lei  1 , Zhengjian Yan  1 , Si Cheng  1
Affiliations

Causal relationship between the immune cells and ankylosing spondylitis: univariable, bidirectional, and multivariable Mendelian randomization

Chaofan Qin et al. Front Immunol. .

Abstract

Background: Ankylosing spondylitis (AS) is an autoimmune disease that affects millions of individuals. Immune cells have been recognized as having a crucial role in the pathogenesis of AS. However, their relationship has not been fully explored.

Methods: We chose to employ Mendelian randomization (MR) to investigate the potential correlation between immune cells and AS. We sourced the data on immune cells from the latest genome-wide association studies (GWASs). We obtained data on AS from the FinnGen consortium. Our comprehensive univariable MR analysis covered 731 immune cells to explore its potential causal relationship with AS. The primary analysis method was inverse-variance weighted (IVW). Additionally, we used Cochran's Q test and the MR-Egger intercept test to assess the presence of pleiotropy and heterogeneity. We examined whether our results could be influenced by individual single-nucleotide polymorphisms (SNPs) using the leave-one-out test. We conducted a bidirectional MR to investigate the reverse relationship. We also applied multivariable MR to decrease the potential influence between the immune cells.

Results: Overall, our univariable MR analysis revealed eight immune cells associated with AS. Among these, four immune cells contributed to an increased risk of AS, while four immune cells were identified as protective factors for AS. However, the Bonferroni test confirmed only one risk factor and one protective factor with a significance level of p < 6.84E-05. CD8 on effector memory CD8+ T cell could increase the risk of AS (p: 1.2302E-05, OR: 2.9871, 95%CI: 1.8289-4.8786). HLA DR on CD33dim HLA DR+ CD11b+ could decrease the risk of AS (p: 1.2301E-06, OR: 0.5446, 95%CI: 0.4260-0.6962). We also identified a bidirectional relationship between CD4 on CD39+ activated CD4 regulatory T cells and AS utilizing the bidirectional MR. To address potential confounding among immune cells, we employed multivariable MR analysis, which revealed that only one immune cell had an independent effect on AS. HLA DR on CD33dim HLA DR+ CD11b+ could decrease the risk of AS (p: 2.113E-06, OR: 0.0.5423, 95%CI: 0.4210-0.6983). Our findings were consistently stable and reliable.

Conclusions: Our findings indicated a potential link between immune cells and AS, which could provide a new idea for future research. Nevertheless, the specific underlying mechanisms require further exploration.

Keywords: ankylosing spondylitis; bidirectional Mendelian randomization; immune cells; multivariable Mendelian randomization; univariable Mendelian randomization.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic presentation of (A) univariable, (B) multivariable, and (C) bidirectional.
Figure 2
Figure 2
Scatter plots of effects of immune cells on the AS using univariable MR. (A) Terminally differentiated CD8+ T cell %CD8+ T cell. (B) HLA DR+ CD8+ T cell absolute count. (C) HLA DR+ CD8+ T cell %lymphocyte. (D) HLA DR on CD14− CD16+ monocyte. (E) CD8 on effector memory CD8+ T cell. (F) CD4 on CD39+ activated CD4 regulatory T cell. (G) HLA DR on CD33dim HLA DR+ CD11b+. (H) HLA DR on CD33dim HLA DR+ CD11b−. AS, ankylosing spondylitis; MR, Mendelian randomization.
Figure 3
Figure 3
Forest plots of effects of immune cells on the AS using univariable MR. AS, ankylosing spondylitis; IVW, inverse-variance weighted; OR, odds ratio; CI, confidence interval; MR, Mendelian randomization.
Figure 4
Figure 4
The result of bidirectional MR between CD4 on CD39+ activated CD4 regulatory T cell and AS. (A) The scatter plot of CD4 on CD39+ activated CD4 regulatory T cell on AS. (B) The scatter plot of AS on CD4 on CD39+ activated CD4 regulatory T cell. (C) The leave-one-out plot of CD4 on CD39+ activated CD4 regulatory T cell on AS. (D) The leave-one-out plot of AS on CD4 on CD39+ activated CD4 regulatory T cell. MR, Mendelian randomization; AS, ankylosing spondylitis.
Figure 5
Figure 5
Forest plots of the bidirectional MR and multivariable MR. AS, ankylosing spondylitis; IVW, inverse-variance weighted; OR, odds ratio; CI, confidence interval; MR, Mendelian randomization. (A) Forest plots of bidirectional MR. (B) Forest plots of the multivariable MR.
Figure 6
Figure 6
The leave-one-out plot of HLA DR on CD14− CD16+ monocyte on AS. (A) The leave-one-out plot of HLA DR on CD14− CD16+ monocyte on AS with the rs6917212. (B) The leave-one-out plot of HLA DR on CD14− CD16+ monocyte on AS without the rs6917212. AS, ankylosing spondylitis.
Figure 7
Figure 7
The leave-one-out plot of univariable MR. (A) Terminally differentiated CD8+ T cell %CD8+ T cell. (B) HLA DR+ CD8+ T cell absolute count. (C) HLA DR+ CD8+ T cell %lymphocyte. (D) HLA DR on CD14− CD16+ monocyte. (E) CD8 on effector memory CD8+ T cell. (F) CD4 on CD39+ activated CD4 regulatory T cell. (G) HLA DR on CD33dim HLA DR+ CD11b+. (H) HLA DR on CD33dim HLA DR+ CD11b−. MR, Mendelian randomization.
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The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by the Chongqing Medical Scientific Research Project (Grant No. 2024WSJK057).