Complex causal association between genetically predicted 731 immunocyte phenotype and leukaemia: A bidirectional Two-sample mendelian randomization analysis

Chenyang Fan ^1,2* Pengying Yuan ³ Weifeng Zhang ^1,2 Haijing Chen ^1,2 Xinli Zhou ^1,2 Yucheng Zhang ^1,2 Gengda Zhu ^1,2 Chengyulong Zheng ^1,2 Lixiang Yan ^1,2* Zhexin Shi ^1,2*

• ¹ First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Nankai District, China
• ² National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, tianjing, China
• ³ University Hospital of International Business and Economics, Beijing, China

Immunity and leukemia are closely related. However, the immune system encompasses a large and complex taxonomy, and observational studies have not fully elucidated the causal relationship between the two.This study intends to elucidate the causal relationship between 731 immunocyte phenotypes and leukemia by bidirectional Mendelian randomization (MR).Applying large-scale genome-wide association study (GWAS) pooled data, we selected 731 immunocyte phenotypes with three leukemia typologies for bidirectional Two-sample MR analysis. We applied inverse variance weighted (IVW) as the primary research method. Besides that, we applied four methods, MR Egger, Weighted median, Simple mode, and Weighted mode, to strengthen the persuasiveness of our findings. Finally, we confirmed the stability and credibility of the resulting data through sensitivity analysis.The results showed that nine immunocyte phenotypes were bidirectionally causally associated with acute myeloid leukemia (AML) (P<0.05). Among them, eight immunocyte phenotypes were positively correlated in both directions with the AML risk relationship (P<0.05, OR>1). In addition, when natural killer absolute count (NKAC) was used as an exposure factor, the positive MR results were negatively correlated (P<0.05, OR<1). When AML was used as an exposure factor, the inverse MR results were positively correlated (P<0.05, OR>1). There was a bidirectional causal association between 1 immunocyte phenotype (CD4+ CD8dim %lymphocyte) and chronic myeloid leukemia (CML) (P<0.05). When CD4+ CD8dim %lymphocyte was used as an exposure factor, positive MR results were positively correlated (P<0.05, OR>1). When CML was used as an exposure factor, the inverse MR results were negatively correlated (P<0.05, OR<1). No bidirectional causal association between immunocyte phenotypes and acute lymphoblastic leukemia was found in this study. None of the sensitivity analyses indicated multiplicity and heterogeneity of the included IVs (P>0.05).This study demonstrated a close and complex association between the immune system and leukemia progression through genetics. The setting of immune cell therapy against leukemia deserves further investigation.