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Causal relationship between circulating immune cells and gastric cancer: a bidirectional Mendelian randomization analysis using UK Biobank and FinnGen datasets
循环免疫细胞与胃癌之间的因果关系：使用英国生物样本库和 FinnGen 数据集的双向孟德尔随机化分析

Weimin Yang 1 1 ^(1){ }^{1}, Yang O u 1 O u 1 Ou^(1)\mathbf{O u}^{1}, Hui Luo 2 2 ^(2){ }^{2}, Lijuan You 3 3 ^(3){ }^{3}, Heng Du 4 Du 4 Du^(4)\mathrm{Du}^{4}
杨 1 1 ^(1){ }^{1} 伟民 ， 杨 O u 1 O u 1 Ou^(1)\mathbf{O u}^{1} ， 罗慧 2 2 ^(2){ }^{2} ， 游 3 3 ^(3){ }^{3} 丽娟 ， 恒 Du 4 Du 4 Du^(4)\mathrm{Du}^{4} 1 1 ^(1){ }^{1} Department of Surgery, Beijing Jishuitan Hospital Guizhou Hospital, Guiyang, China; 2 2 ^(2){ }^{2} Department of Gastrointestinal Surgery, Guizhou Provincial People's Hospital, Guiyang, China; 3 3 ^(3){ }^{3} Department of Anesthesiology, Huanggang Central Hospital Affiliated to Yangtze University, Huanggang, China; 4 4 ^(4){ }^{4} Department of Gastrointestinal Surgery, Huanggang Central Hospital Affiliated to Yangtze University, Huanggang, China
1 1 ^(1){ }^{1} 北京积水潭医院 贵州医院外科，中国贵阳; 2 2 ^(2){ }^{2} 贵州省人民医院胃肠外科， 贵阳， 中国; 3 3 ^(3){ }^{3} 长江大学附属黄冈市中心医院麻醉科，中国黄冈; 4 4 ^(4){ }^{4} 长江大学附属黄冈市中心医院胃肠外科， 中国 黄冈Contributions: (I) Conception and design: W Yang, L You, H Du; (II) Administrative support: H Du; (III) Provision of study materials or patients: W Yang, Y Ou; (IV) Collection and assembly of data: Y Ou, H Luo; (V) Data analysis and interpretation: W Yang, L You, H Du; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
贡献： （I） 构思和设计：W Yang、L You、H Du;（II） 行政支持：H Du;（III） 提供学习材料或患者：W Yang、Y Ou;（IV） 资料收集与汇编：Y Ou， H Luo;（V） 数据分析和解释：W Yang， L You， H Du;（VI） 稿件写作：所有作者;（VII） 稿件最终批准：所有作者。Correspondence to: Lijuan You, MD. Department of Anesthesiology, Huanggang Central Hospital Affiliated to Yangtze University, Huangzhou District, No. 11, Kaopeng Street, Huanggang 438000, China. Email: youlijuan_hg@163.com; Heng Du, MD. Department of Gastrointestinal Surgery, Huanggang Central Hospital Affiliated to Yangtze University, Huangzhou District, No. 11, Kaopeng Street, Huanggang 438000, China. Email: 522594853@qq.com.
通信对象：Lijuan You，医学博士。长江大学附属黄冈市中心医院麻醉科，黄州区，黄冈区 11 号，黄冈 438000。电子邮件： youlijuan_hg@163.com;Heng Du，医学博士。长江大学附属黄冈中心医院胃肠外科，黄州区，黄冈区高朋街 11 号，中国 黄冈 438000。电子邮件：522594853@qq.com。

Abstract 抽象

Background: The role of immune cells in cancer pathogenesis remains controversial due to conflicting reports, potentially arising from various confounding factors. Emerging evidence suggests that cancer can also influence immune cell populations and functions, making it challenging to investigate their causal relationship. Traditional observational studies often fail to eliminate all confounding factors and are prone to reverse causality. Therefore, we employ Mendelian randomization (MR) to determine the causal relationship between immune cells and cancer, as this method can identify causal relationships independent of confounding factors and avoid reverse causality. Methods: Genome-wide association study (GWAS) summary statistics on immune traits, encompassing 310 immune cell phenotypes, were obtained from 3,757 European individuals, with peripheral blood immune cells tested using flow cytometry. GWAS summary statistics for gastric cancer were derived from 476,116 European individuals across two large-scale biobanks: the UK Biobank and FinnGen. Gastric cancer was identified by the International Classification of Diseases, 9th Revision (ICD-9), and 10th Revision (ICD-10) codes. Significant single nucleotide polymorphisms (SNPs) for immune traits were extracted at a threshold of P < 1 × 10 − 5 P < 1 × 10 − 5 P < 1xx10^(-5)\mathrm{P}<1 \times 10^{-5}, while a threshold of P < 5 × 10 − 8 P < 5 × 10 − 8 P < 5xx10^(-8)\mathrm{P}<5 \times 10^{-8} was used for gastric cancer GWAS data. Linkage imbalance-based clumping was performed to obtain independent SNPs , and those with F < 10 F < 10 F < 10\mathrm{F}<10 were excluded to mitigate weak instrument bias. Phenoscanner V2 was used to exclude SNPs directly associated with potential confounders or outcomes. Two-sample MR was conducted using five MR methods, with inverse-variance-weighted (IVW) as the primary analysis method. A false discovery rate (FDR) correction was used to reduce the likelihood of type 1 errors. In addition, we conducted MR-Egger intercept tests and Cochran’s Q tests. Results: The numbers of CD 4 − CD 8 − T CD 4 − CD 8 − T CD4^(-)CD8^(-)T\mathrm{CD} 4^{-} \mathrm{CD} 8^{-} \mathrm{T} cells and IgD − CD 27 − B IgD − CD 27 − B IgD^(-)CD27^(-)B\mathrm{IgD}^{-} \mathrm{CD} 27^{-} \mathrm{B} cells were positively correlated with the development of gastric cancer, with odds ratios (ORs) of 1.15 [ 95 % 95 % 95%95 \% confidence interval (CI), 1.07-1.24; P < 0.001 ; P FDR = 0.041 P < 0.001 ; P FDR = 0.041 P < 0.001;P_(FDR)=0.041\mathrm{P}<0.001 ; \mathrm{P}_{\mathrm{FDR}}=0.041; IVW method] and 1.07 ( 95 % 95 % 95%95 \% CI, 1.03 − 1.11 ; P = 0.001 ; P FDR = 0.187 1.03 − 1.11 ; P = 0.001 ; P FDR = 0.187 1.03-1.11;P=0.001;P_(FDR)=0.1871.03-1.11 ; \mathrm{P}=0.001 ; \mathrm{P}_{\mathrm{FDR}}=0.187; IVW method), respectively. However, the percentage of IgD + CD 24 − B IgD + CD 24 − B IgD^(+)CD24^(-)B\mathrm{IgD}^{+} \mathrm{CD} 24^{-} \mathrm{B} cells in lymphocytes were negatively associated with the development of gastric cancer ( OR = 0.90 ; 95 % CI , 0.84 − 0.96 ; P = 0.002 ; P FDR = 0.187 OR = 0.90 ; 95 % CI , 0.84 − 0.96 ; P = 0.002 ; P FDR = 0.187 OR=0.90;95%CI,0.84-0.96;P=0.002;P_(FDR)=0.187\mathrm{OR}=0.90 ; 95 \% \mathrm{CI}, 0.84-0.96 ; \mathrm{P}=0.002 ; \mathrm{P}_{\mathrm{FDR}}=0.187; IVW method). MR analysis of the above three immune cell phenotypes showed no significant heterogeneity or horizontal pleiotropy. In the reverse MR analysis, gastric cancer was not causally associated with any of the immune cell phenotypes. Conclusions: Circulating CD 4 − CD − T CD 4 − CD − T CD4^(-)CD^(-)T\mathrm{CD} 4^{-} \mathrm{CD}^{-} \mathrm{T} cells and IgD − CD 27 − B IgD − CD 27 − B IgD^(-)CD27^(-)B\mathrm{IgD}^{-} \mathrm{CD} 27^{-} \mathrm{B} cells are positively correlated with the development of gastric cancer, while the percentage of IgD + CD 24 − IgD + CD 24 − IgD^(+)CD24^(-)\mathrm{IgD}^{+} \mathrm{CD} 24^{-}B cells in lymphocytes are negatively
背景：由于相互矛盾的报道，免疫细胞在癌症发病机制中的作用仍然存在争议，这可能是由各种混杂因素引起的。新出现的证据表明，癌症还会影响免疫细胞群和功能，这使得研究它们的因果关系具有挑战性。传统的观察性研究往往无法消除所有混杂因素，并且容易出现反向因果关系。因此，我们采用孟德尔随机化 （MR） 来确定免疫细胞与癌症之间的因果关系，因为这种方法可以识别独立于混杂因素的因果关系并避免反向因果关系。方法：从 3,757 名欧洲个体那里获得了关于免疫特征的全基因组关联研究 （GWAS） 汇总统计数据，包括 310 种免疫细胞表型，并使用流式细胞术测试了外周血免疫细胞。胃癌的 GWAS 汇总统计数据来自两个大型生物库（英国生物库和 FinnGen）的 476,116 名欧洲个体。胃癌由国际疾病分类第 9 版（ICD-9）和第10版（ICD-10）代码确定。免疫性状的显著单核苷酸多态性 （SNP） 在阈值 处 P < 1 × 10 − 5 P < 1 × 10 − 5 P < 1xx10^(-5)\mathrm{P}<1 \times 10^{-5} 提取，而阈值 of P < 5 × 10 − 8 P < 5 × 10 − 8 P < 5xx10^(-8)\mathrm{P}<5 \times 10^{-8} 用于胃癌 GWAS 数据。进行基于连锁不平衡的聚集以获得独立的 SNP，并排除那些具有 F < 10 F < 10 F < 10\mathrm{F}<10 SNP 的 SNP 以减轻弱仪器偏倚。Phenoscanner V2 用于排除与潜在混杂因素或结果直接相关的 SNP。使用 5 种 MR 方法进行双样本 MR，逆方差加权 （IVW） 作为主要分析方法。 使用错误发现率 （FDR） 校正来降低 1 型错误的可能性。此外，我们还进行了 MR-Egger 截距检验和 Cochran Q 检验。结果： 细胞数 CD 4 − CD 8 − T CD 4 − CD 8 − T CD4^(-)CD8^(-)T\mathrm{CD} 4^{-} \mathrm{CD} 8^{-} \mathrm{T} 和 IgD − CD 27 − B IgD − CD 27 − B IgD^(-)CD27^(-)B\mathrm{IgD}^{-} \mathrm{CD} 27^{-} \mathrm{B} 细胞数与胃癌的发生呈正相关，比值比 （ORs） 为 1.15 [ 95 % 95 % 95%95 \% 置信区间 （CI），1.07-1.24; P < 0.001 ; P FDR = 0.041 P < 0.001 ; P FDR = 0.041 P < 0.001;P_(FDR)=0.041\mathrm{P}<0.001 ; \mathrm{P}_{\mathrm{FDR}}=0.041 ;IVW 方法] 和 1.07 （ 95 % 95 % 95%95 \% CI， 1.03 − 1.11 ; P = 0.001 ; P FDR = 0.187 1.03 − 1.11 ; P = 0.001 ; P FDR = 0.187 1.03-1.11;P=0.001;P_(FDR)=0.1871.03-1.11 ; \mathrm{P}=0.001 ; \mathrm{P}_{\mathrm{FDR}}=0.187 ;IVW 方法）。然而，淋巴细胞中细胞的百分比 IgD + CD 24 − B IgD + CD 24 − B IgD^(+)CD24^(-)B\mathrm{IgD}^{+} \mathrm{CD} 24^{-} \mathrm{B} 与胃癌的发生呈负相关 （ OR = 0.90 ; 95 % CI , 0.84 − 0.96 ; P = 0.002 ; P FDR = 0.187 OR = 0.90 ; 95 % CI , 0.84 − 0.96 ; P = 0.002 ; P FDR = 0.187 OR=0.90;95%CI,0.84-0.96;P=0.002;P_(FDR)=0.187\mathrm{OR}=0.90 ; 95 \% \mathrm{CI}, 0.84-0.96 ; \mathrm{P}=0.002 ; \mathrm{P}_{\mathrm{FDR}}=0.187 ;IVW 方法）。上述 3 种免疫细胞表型的 MR 分析显示无显著异质性或水平多效性。在反向 MR 分析中，胃癌与任何免疫细胞表型均无因果关系。结论： 循环 CD 4 − CD − T CD 4 − CD − T CD4^(-)CD^(-)T\mathrm{CD} 4^{-} \mathrm{CD}^{-} \mathrm{T} 细胞和 IgD − CD 27 − B IgD − CD 27 − B IgD^(-)CD27^(-)B\mathrm{IgD}^{-} \mathrm{CD} 27^{-} \mathrm{B} 细胞与胃癌的发生呈正相关，而淋巴细胞中 IgD + CD 24 − IgD + CD 24 − IgD^(+)CD24^(-)\mathrm{IgD}^{+} \mathrm{CD} 24^{-} B 细胞的百分比呈负相关

correlated. These findings provide insight into the relationship between immune cells and gastric cancer pathogenesis and may serve as a basis for the development of immunotherapies for gastric cancer.
相关。这些发现为免疫细胞与胃癌发病机制之间的关系提供了见解，并可能作为开发胃癌免疫疗法的基础。
Keywords: Immune cells; gastric cancer; Mendelian randomization (MR); genetic; causal association
关键词：免疫细胞;胃癌;孟德尔随机化 （MR）;遗传;因果关联
Submitted Mar 24, 2024. Accepted for publication Aug 01, 2024. Published online Sep 05, 2024.
提交于 2024 年 3 月 24 日。已接受发布 2024 年 8 月 1 日.2024 年 9 月 5 日在线发布。
doi: 10.21037 / 10.21037 / 10.21037//10.21037 / tcr-24-480
doi： TCR-24-480 10.21037 / 10.21037 / 10.21037//10.21037 /
View this article at: https://dx.doi.org/10.21037/tcr-24-480
查看此文章： https://dx.doi.org/10.21037/tcr-24-480

Introduction 介绍

Globally, gastric cancer is the fifth most common type of cancer, with over a million cases diagnosed each year (1). There is a poor prognosis for gastric cancer, and it is the third leading cause of cancer-related deaths (1,2). Currently, surgery and chemotherapy are the most commonly used treatments for gastric cancer (3-6). Immunotherapy is an emerging therapy that has been shown to have a number of advantages, including durable responses, long-term survival benefits, and a lower level of toxicity (7-10). Understanding the relationship between the immune system and gastric cancer may assist in the development of new immunotherapy
在全球范围内，胃癌是第五大最常见的癌症类型，每年诊断出超过 100 万例 （1）。胃癌的预后很差，它是癌症相关死亡的第三大原因 （1,2）。目前，手术和化疗是胃癌最常用的治疗方法 （3-6）。免疫疗法是一种新兴疗法，已被证明具有许多优势，包括持久的反应、长期生存益处和较低的毒性水平 （7-10）。了解免疫系统与胃癌之间的关系可能有助于开发新的免疫疗法

Highlight box 高亮框

Key findings 主要发现

  • The absolute numbers of CD 4 − CD 8 − T CD 4 − CD 8 − T CD4^(-)CD8^(-)T\mathrm{CD} 4^{-} \mathrm{CD} 8^{-} \mathrm{T} cells and IgD − CD 27 − B IgD − CD 27 − B IgD^(-)CD27^(-)B\mathrm{IgD}^{-} \mathrm{CD} 27^{-} \mathrm{B} cells were positively correlated with the development of gastric cancer.
    细胞和 IgD − CD 27 − B IgD − CD 27 − B IgD^(-)CD27^(-)B\mathrm{IgD}^{-} \mathrm{CD} 27^{-} \mathrm{B} 细胞的 CD 4 − CD 8 − T CD 4 − CD 8 − T CD4^(-)CD8^(-)T\mathrm{CD} 4^{-} \mathrm{CD} 8^{-} \mathrm{T} 绝对数量与胃癌的发生呈正相关。
  • The percentage of IgD + CD 24 − B IgD + CD 24 − B IgD^(+)CD24^(-)B\mathrm{IgD}^{+} \mathrm{CD} 24^{-} \mathrm{B} cells in lymphocytes was negatively associated with the development of gastric cancer.
    淋巴细胞中细胞的百分比 IgD + CD 24 − B IgD + CD 24 − B IgD^(+)CD24^(-)B\mathrm{IgD}^{+} \mathrm{CD} 24^{-} \mathrm{B} 与胃癌的发生呈负相关。
  • Gastric cancer was not causally associated with any of the immune cell phenotypes in the reverse Mendelian randomization (MR) analysis.
    在反向孟德尔随机化 （MR） 分析中，胃癌与任何免疫细胞表型均无因果关系。

What is known and what is new?
什么是已知的，什么是新的？

  • The immune system plays a crucial role in cancer immune surveillance, but the relationship between circulating immune cells and gastric cancer remains largely unknown.
    免疫系统在癌症免疫监测中起着至关重要的作用，但循环免疫细胞与胃癌之间的关系在很大程度上仍然未知。
  • This study used bidirectional two-sample MR to demonstrate that certain immune cell traits, including CD 4 − CD 8 − T CD 4 − CD 8 − T CD4^(-)CD8^(-)T\mathrm{CD} 4^{-} \mathrm{CD} 8^{-} \mathrm{T} cells, IgD − IgD − IgD^(-)\mathrm{IgD}^{-} CD 27 − B CD 27 − B CD27^(-)B\mathrm{CD} 27^{-} \mathrm{B} cells, and IgD + CD 24 − B IgD + CD 24 − B IgD^(+)CD24^(-)B\mathrm{IgD}{ }^{+} \mathrm{CD} 24^{-} \mathrm{B} cells, are causally related to gastric cancer risk.
    本研究使用双向双样本 MR 来证明某些免疫细胞特征，包括 CD 4 − CD 8 − T CD 4 − CD 8 − T CD4^(-)CD8^(-)T\mathrm{CD} 4^{-} \mathrm{CD} 8^{-} \mathrm{T} 细胞、 IgD − IgD − IgD^(-)\mathrm{IgD}^{-} CD 27 − B CD 27 − B CD27^(-)B\mathrm{CD} 27^{-} \mathrm{B} 细胞和 IgD + CD 24 − B IgD + CD 24 − B IgD^(+)CD24^(-)B\mathrm{IgD}{ }^{+} \mathrm{CD} 24^{-} \mathrm{B} 细胞，与胃癌风险有因果关系。

What is the implication, and what should change now?
这意味着什么，现在应该改变什么？

  • The findings provide insight into the relationship between immune cells and gastric cancer pathogenesis, which may aid in the development of new immunotherapy targets for gastric cancer.
    这些发现为免疫细胞与胃癌发病机制之间的关系提供了见解，这可能有助于开发新的胃癌免疫治疗靶点。
  • Further research is required to confirm these causal relationships and investigate the underlying mechanisms between the identified immune cell traits and gastric cancer.
    需要进一步的研究来证实这些因果关系，并调查已鉴定的免疫细胞特征与胃癌之间的潜在机制。
    targets. 目标。
    The immune system of the host plays an important role in the immune surveillance of cancer and is capable of killing cancer cells through both innate and adapted immune responses (11). Despite this, there are contradictory reports regarding the role of immune cells in cancer pathogenesis (12-15). In gastric cancer, tumorinfiltrating dendritic cells and natural killer cells are generally associated with improved prognosis and enhanced anti-tumor immunity (16). In contrast, effector regulatory T cells and regulatory B cells can promote immune escape, leading to poorer outcomes (7). The prognostic implications of cytotoxic T cells ( CD + ) CD + (CD^(+))\left(\mathrm{CD}^{+}\right)are particularly complex (17-19); while some studies link high CD + T CD + T CD^(+)T\mathrm{CD}^{+} \mathrm{T} cell infiltration to better survival rates, others associate it with worse prognoses. These discrepancies likely arise from the intricate interplay between different immune cell subpopulations, the tumor microenvironment, and the stage of cancer progression. Thus, elucidating the causal relationships between immune cells and gastric cancer is crucial. However, traditional observational studies are often confounded by factors such as reverse causality, making it challenging to establish definitive causal links.
    宿主的免疫系统在癌症的免疫监视中起着重要作用，并且能够通过先天免疫应答和适应免疫应答杀死癌细胞 （11）。尽管如此，关于免疫细胞在癌症发病机制中的作用，仍存在相互矛盾的报道 （12-15）。在胃癌中，肿瘤浸润树突状细胞和自然杀伤细胞通常与改善预后和增强抗肿瘤免疫有关 （16）。相比之下，效应调节性 T 细胞和调节性 B 细胞可促进免疫逃逸，从而导致较差的结果 （7）。细胞毒性 T 细胞 ( CD + ) CD + (CD^(+))\left(\mathrm{CD}^{+}\right) 的预后意义特别复杂 （17-19）;虽然一些研究将高 CD + T CD + T CD^(+)T\mathrm{CD}^{+} \mathrm{T} 细胞浸润与更好的存活率联系起来，但其他研究将其与更差的预后联系起来。这些差异可能是由于不同免疫细胞亚群、肿瘤微环境和癌症进展阶段之间错综复杂的相互作用引起的。因此，阐明免疫细胞与胃癌之间的因果关系至关重要。然而，传统的观察性研究经常被反向因果关系等因素所混淆，这使得建立明确的因果关系具有挑战性。
Mendelian randomization (MR) is an emerging genetic epidemiological method based on Mendel’s genetic inheritance laws (20). MR uses genetic variations as instrumental variants (IVs), which are randomly assigned at conception prior to disease onset (21). Therefore, MR can be used to identify causal relationships independent of confounding factors and avoid reverse causality (22-24). In recent years, MR analysis has increasingly been utilized to identify possible risk factors for gastric cancer (25-27). Several MR studies have also examined the causal relationship between inflammatory biomarkers and gastric cancer, including interleukin-6 (28), interleukin-10 (29), and C-reactive protein (30).
孟德尔随机化 （MR） 是一种基于孟德尔基因遗传定律的新兴遗传流行病学方法 （20）。MR 使用遗传变异作为工具变异 （IV），在疾病发作前受孕时随机分配 （21）。因此，MR 可用于识别独立于混杂因素的因果关系并避免反向因果关系 （22-24）。近年来，MR 分析越来越多地用于确定胃癌的可能危险因素 （25-27）。几项 MR 研究还检查了炎症生物标志物与胃癌之间的因果关系，包括白细胞介素-6 （28）、白细胞介素-10 （29） 和 C 反应蛋白 （30）。
While previous studies have primarily focused on the impact of immune cells on cancer development, emerging evidence suggests that cancer itself can influence immune cell populations and function. This bidirectional relationship
虽然以前的研究主要集中在免疫细胞对癌症发展的影响上，但新出现的证据表明，癌症本身可以影响免疫细胞群和功能。这种双向关系
Figure 1 Three key assumptions of the mendelian analysis study and the design of our study design. MR, Mendelian randomization; IV, instrumental variable.
图 1 孟德尔分析研究的三个关键假设和我们研究设计的设计。MR，孟德尔随机化;IV，工具变量。
between cancer and the immune system is known as cancer immunoediting (31). During this process, the tumor can shape the immune response, potentially leading to changes in circulating immune cell populations ( 31 , 32 ) ( 31 , 32 ) (31,32)(31,32). Therefore, investigating the bidirectional relationship between the immune cells and gastric cancer is crucial for understanding the complex interplay between them.
癌症与免疫系统之间的相互作用称为癌症免疫编辑 （31）。在此过程中，肿瘤可以塑造免疫反应，可能导致循环免疫细胞群发生变化 ( 31 , 32 ) ( 31 , 32 ) (31,32)(31,32) 。因此，研究免疫细胞和胃癌之间的双向关系对于理解它们之间复杂的相互作用至关重要。
However, to our knowledge, no MR study has examined the possible causal link between circulating immune cells and gastric cancer risk. Therefore, in this study, we conducted a bidirectional two-sample MR analysis using large-scale genome-wide association study (GWAS) data to determine the causal relationship between immune cell traits and gastric cancer. We present this article in accordance with the STROBE-MR reporting checklist (available at https://tcr. amegroups.com/article/view/10.21037/tcr-24-480/rc).
然而，据我们所知，没有 MR 研究检查循环免疫细胞与胃癌风险之间可能的因果关系。因此，在这项研究中，我们使用大规模全基因组关联研究 （GWAS） 数据进行了双向双样本 MR 分析，以确定免疫细胞特征与胃癌之间的因果关系。我们根据 STROBE-MR 报告清单（可在 https://tcr 上获得）来介绍本文。amegroups.com/article/view/10.21037/tcr-24-480/rc）。

Methods 方法

Study design 研究设计

This is a bidirectional two-sample MR study. In the
这是一项双向双样本 MR 研究。在
forward MR analyses, immune cell traits were considered as exposures and gastric cancer was considered as outcome, whereas in the reverse MR analyses, gastric cancer was considered as exposure and immune cell traits as outcome. MR uses single nucleotide polymorphisms (SNPs) as IVs, and the valid IVs should fulfil the following three assumptions (33): first, IVs should be robustly associated with exposure (the relevance assumption); second, IVs should be independent of any confounding factors (the independence assumption); third, IVs affect outcome only through the risk factor, but not via other pathways (the exclusion limitation assumption). Figure 1 illustrates our study design.
正向 MR 分析，免疫细胞性状被视为暴露，胃癌被视为结果，而在反向 MR 分析中，胃癌被视为暴露，免疫细胞性状被视为结果。MR 使用单核苷酸多态性 （SNP） 作为 IV，有效的 IV 应满足以下三个假设 （33）：首先，IV 应与暴露稳健相关（相关性假设）;其次，IV 应该独立于任何混杂因素（独立性假设）;第三，IV 仅通过危险因素影响结局，而不通过其他途径（排除限制假设）。图 1 说明了我们的研究设计。

Data sources 数据源

GWAS-summary statistics for each immune trait are available through the GWAS Catalog (accession numbers GCST90001391 to GCST90001700) (34). A total of 310 immune cell phenotypes were analyzed, including absolute cell counts ( n = 118 ) ( n = 118 ) (n=118)(\mathrm{n}=118) and relative cell counts ( n = 192 n = 192 n=192\mathrm{n}=192 ). The GWAS on immune traits was performed using data from
每个免疫性状的 GWAS 摘要统计数据可通过 GWAS 目录（GCST90001391 至 GCST90001700 的登录号）获得 （34）。共分析了 310 种免疫细胞表型，包括绝对细胞计数 ( n = 118 ) ( n = 118 ) (n=118)(\mathrm{n}=118) 和相对细胞计数 （ n = 192 n = 192 n=192\mathrm{n}=192 ）。免疫特征的 GWAS 使用来自