白细胞介素与肺结核因果关联的孟德尔随机化研究

王兴斌; 赵昌明; 黄秋丽; 王玲; 张亚欣; 杨得杰; 王兆芬

doi:10.16462/j.cnki.zhjbkz.2024.07.013

白细胞介素与肺结核因果关联的孟德尔随机化研究

doi: 10.16462/j.cnki.zhjbkz.2024.07.013

王兴斌^{1, 2},
赵昌明¹,
黄秋丽¹,
王玲¹,
张亚欣¹,
杨得杰¹,
王兆芬^1, ,

1.
青海大学医学部公共卫生系，西宁 810001
2.
青海省西宁市城西区西关社区医院，西宁 810007

基金项目:

青海省自然科学基金 2020-ZJ-929

详细信息

通讯作者:
王兆芬, E-mail: kristy538@163.com

中图分类号: R181.3
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- 被引次数: 0
出版历程
- 收稿日期: 2023-10-07
- 修回日期: 2024-04-19
- 网络出版日期: 2024-08-19
- 刊出日期: 2024-07-10

Mendelian randomization study on the causal relationship between interleukins and pulmonary tuberculosis

1.
Department of Public Health, Medical School, Qinghai University, Xining 810001, China
2.
Xiguan Community Hospital, Chengxi District, Xining 810007, China

Funds:

Natural Science Foundation of Qinghai Province 2020-ZJ-929

More Information

Corresponding author: WANG Zhaofen, E-mail: kristy538@163.com

摘要

摘要: 目的采用两样本孟德尔随机化(Mendelian randomization, MR)方法研究多种白细胞介素(interleukin, IL)水平与患肺结核风险的因果关联。方法 IL和肺结核的数据分别来自3项公开发表的欧洲人群全基因组关联研究(genome-wide association studies, GWAS)汇总数据。根据预设的阈值和连锁不平衡等要求从汇总数据中提取了与多种IL密切相关的单核苷酸多态性(single nucleotide polymorphism, SNP)位点作为工具变量，研究主要采用逆方差加权(inverse variance weighted, IVW)、MR-Egger回归和加权中位数估计法(weighted median estimator, WME)评估9种IL水平与肺结核风险之间的因果效应。同时，对结果进行了水平多效性和异质性的检验以保证其稳定性，采用方向性检验检查是否存在反向因果效应。结果 IVW结果显示，尚未发现IL-1RA、IL-2RA、IL-6、IL-6RA、IL-8、IL-17、IL-I8与肺结核风险之间存在因果关联(均P＞0.05)。IL-16水平的增加与肺结核风险增加有关(OR=1.210, 95% CI: 1.032~1.419, P=0.019, P_校正=0.086)，而IL-27水平的增加与肺结核风险降低有关(OR=0.875, 95% CI: 0.788~0.970, P=0.011, P_校正=0.086)，结果在3种MR方法中稳定并且方向一致，同时不存在反向因果关系。结论尚未发现IL-1RA、IL-2RA、IL-6、IL-6RA、IL-8、IL-17、IL-I8与肺结核之间存在因果关联。IL-16水平的增加与肺结核风险增加有关，而IL-27水平的增加与肺结核风险降低有关。
- 孟德尔随机化 /
- 白细胞介素 /
- 肺结核 /
- 因果关联
Abstract: Objective This study aims to determine the causal association between multiple interleukin (IL) levels and the risk of tuberculosis by using a two-sample Mendelian randomization (MR) method. Methods The data on interleukins and tuberculosis were obtained from the the pooled data of three published genome-wide association studies(GWAS) accomplished in European populations. According to preset thresholds and requirements of linkage disequilibrium, the single nucleotide polymorphism(SNP) loci closely related to a variety of interleukins were extracted from the summarized data as instrumental variables, the causal effect of nine interleukin levels on the risk of tuberculosis was assessed by using inverse variance weighting (IVW), mr-egger regression, and weighted median estimation. At the same time, the horizontal pleiotropy and heterogeneity were tested to ensure the stability of the results, and the directional test was used to check reverse causality effect. Results According to the IVW results, there were no causal relationships among interleukins of IL-1RA, IL-2RA, IL-6, IL-6RA, IL-8, IL-17, IL-18 and pulmonary tuberculosis (P>0.05). Higher levels of IL-16 were correlated with an increased risk of tuberculosis (OR=1.210, 95% CI: 1.032-1.419, P=0.019, P_adjusted=0.086). In contrast, rised IL-27 levels suggested a lower risk of tuberculosis (OR=0.875, 95% CI: 0.788-0.97, P=0.011, P_adjusted=0.086). These findings remained robust and consistent across all three MR testing methods with no reverse causality. Conclusions No causal relationship has been found among interleukins of IL-1RA, IL-2RA, IL-6, IL-6RA, IL-8, IL-17, IL-18 and pulmonary tuberculosis. Higher IL-16 levels are linked to an increased risk of developing tuberculosis, while the increase in IL-27 levels is associated with a decreased risk of pulmonary tuberculosis.
- Mendelian randomization /
- Interleukins /
- Pulmonary tuberculosis /
- Causal association

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图 1 白细胞介素与肺结核之间关系的孟德尔随机化结果

IL-1RA，白细胞介素-1受体拮抗剂；IL-2RA，IL-2受体α亚基；IL-6RA，白细胞介素-6受体拮抗；SNP，单核苷酸多态性；PTB，肺结核。

Figure 1. Mendelian randomization results of the relationship between interleukin and tuberculosis

IL-1RA, interleukin 1 receptor antagonist; IL-2RA, IL-2 receptor α subunit; IL-6RA, interleukin 6 receptor antagonist; SNP, single nucleotide polymorphism; PTB, pulmonary tuberculosis.

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图 2 IL-16、IL-27孟德尔随机化散点图

SNP，单核苷酸多态性；PTB，肺结核。

Figure 2. Mendelian randomization scatter plot of IL-16 and IL-27

SNP, single nucleotide polymorphism; PTB, pulmonary tuberculosis.

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图 3 留一法敏感性分析图

MR: 孟德尔随机化；PTB: 肺结核；A表示IL-16对肺结核的MR留一法敏感性分析；B表示IL-27对肺结核的MR留一法敏感性分析。

Figure 3. Leave-one-out sensitivity analysis chart

MR: Mendelian randomization; PTB: pulmonary tuberculosis; A shows MR leave-one-out sensitivity analysis for IL-16 PTB; B shows MR leave-one-out sensitivity analysis for IL-27 PTB.

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表 1 白细胞介素与肺结核GWAS汇总数据概要

Table 1. Summary of GWAS summary data on interleukins and tuberculosis

变量 Variable	SNP数量 Number of SNP	来源 Source	样本量 (病例/对照) Sample size (case/control)	人种 Race	发表年份 Publication year	PMID
IL-1RA	13 081 270	Folkersen et al GWAS	21 758	欧洲人	2020	33067605
IL-6	11 782 139	Folkersen et al GWAS	21 758	欧洲人	2020	33067605
IL-6RA	13 137 746	Folkersen et al GWAS	21 758	欧洲人	2020	33067605
IL-8	12 717 989	Folkersen et al GWAS	21 758	欧洲人	2020	33067605
IL-16	13 102 566	Folkersen et al GWAS	21 758	欧洲人	2020	33067605
IL-I8	13 102 515	Folkersen et al GWAS	21 758	欧洲人	2020	33067605
IL-27	13 102 608	Folkersen et al GWAS	21 758	欧洲人	2020	33067605
IL-2RA	9 583 519	Ahola-Olli et al GWAS	3 677	欧洲人	2016	27989323
IL-17	9 786 653	Ahola-Olli et al GWAS	7 760	欧洲人	2016	27989323
肺结核Tuberculosis	20 170 225	https://r9.finngen.fi/	36 715(1 793/374 922)	欧洲人	2022
注：GWAS, 全基因组关联研究；PMID, Pubmed唯一标识码; SNP，单核苷酸多态性; IL, 白细胞介素。 Note: GWAS, genome-wide association study; PMID, Pubmed unique identifier; SNP, single nucleotide polymorphism; IL, interleukin.

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表 2 多效性和敏感性分析结果

Table 2. Pleiotropy and sensitivity analysis results

暴露变量 Exposure variable	MR-egger检验 MR-egger test		Cochran′s Q检验 Cochran′s Q test		MR-PRESSO检验 MR-PRESSO test
暴露变量 Exposure variable	截距 Intercept	P值 value	Q值 value	P值 value	Global test P值 Global test P value	偏误检验P值 Distortion test P value
IL-16	-0.019 542	0.577 977	1.976 758	0.577 244 7	0.540	-
IL-27	0.031 320 6	0.111 479	9.313 354	0.316 555 3	0.471	-
注：“-”表示无法获取。 Note: "-" indicates that it can′t be obtained.

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表 3 反向因果效应检验结果

Table 3. Reverse causality effect test results

暴露变量 Exposure variable	暴露r² Exposure r²	结局r² Outcome r²	Steiger P值 Steiger P value
IL-16	0.065 686 13	1.99×10^-5	< 0.000 1
IL-27	0.094 499 87	4.45×10^-5	< 0.000 1

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