自身免疫性疾病是再生障碍性贫血的危险因素：一项孟德尔随机化分析

doi:10.12122/j.issn.1673-4254.2025.04.23

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (4): 871-879.doi: 10.12122/j.issn.1673-4254.2025.04.23

• • 上一篇

自身免疫性疾病是再生障碍性贫血的危险因素：一项孟德尔随机化分析

李文婕¹(), 洪耀南¹, 黄蕊¹, 李煜宸¹, 张莹¹, 张蕴¹^,²^,³, 吴迪炯¹^,²^,³()

^1.浙江中医药大学附属第一医院//浙江省中医院，浙江杭州 310006
^2.浙江中医药大学附属第一临床医学院，浙江杭州 310053
^3.国家中医（血液病）临床研究基地，浙江杭州 310053

收稿日期:2024-11-13 出版日期:2025-04-20 发布日期:2025-04-28
通讯作者: 吴迪炯 E-mail:17280150095@163.com;wudijiong@zcmu.edu.cn
作者简介:李文婕，在读本科生，E-mail: 17280150095@163.com
基金资助:
国家自然科学基金(82174138);浙江省卫生健康科技计划(2022RC216);浙江省名老中医专家传承工作室建设项目(GZS2021022)

Causal relationship between autoimmune diseases and aplastic anemia: A Mendelian randomization study

Wenjie LI¹(), Yaonan HONG¹, Rui HUANG¹, Yuchen LI¹, Ying ZHANG¹, Yun ZHANG¹^,²^,³, Dijiong WU¹^,²^,³()

^1.First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310006, China
^2.First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310053, China
^3.National Traditional Chinese Medicine Clinical Research Base of Hematology, Hangzhou 310053, China

Received:2024-11-13 Online:2025-04-20 Published:2025-04-28
Contact: Dijiong WU E-mail:17280150095@163.com;wudijiong@zcmu.edu.cn
Supported by:
National Natural Science Foundation of China(82174138)

摘要/Abstract

摘要：

目的采用孟德尔随机化分析来探讨10种自身免疫性疾病（ADs）与再生障碍性贫血（AA）之间的因果关联。方法利用公开的全基因组关联研究数据获取ADs与AA的单核苷酸多态性（SNPs）并进行分析。以逆方差加权法（IVW）为主要分析方法，MR Egger法、Weighted Mode法、Weighted median法、Simple Mode法则作为补充分析。使用heterogeneity函数和pleiotropy函数等分别进行异质性检验和水平多效性分析，采用留一法评估孟德尔随机化分析结果的稳健性。结果两样本孟德尔随机化的IVW法分析显示，类风湿性关节炎（OR=1.094，95% CI：1.023-1.170，P=0.009，P. adjust=0.042）、系统性红斑狼疮（OR=1.111，95% CI：1.021-1.208，P=0.015，P. adjust=0.036）、桥本甲状腺炎（OR=1.206，95% CI：1.049-1.387，P=0.009，P. adjust=0.029）和干燥综合征（OR=1.173，95% CI：1.054-1.306，P=0.004，P. adjust=0.035）与再生障碍性贫血呈显著正向因果关联，Weighted median法等分析结果同样支持以上结果。敏感性分析显示不存在水平多效性和异质性，留一法显示因果关系稳健。未发现格雷夫斯病、溃疡性结肠炎、克罗恩病、自身免疫性肝炎、原发性胆汁性胆管炎和原发性硬化性胆管炎与AA发病直接相关的证据（P>0.05，P. adjust>0.05），与AA不存在因果关联。反向孟德尔随机化结果及多重校正显示，AA不是ADs（P. adjust>0.05）的影响因素。结论本研究在基因水平上支持类风湿性关节炎、系统性红斑狼疮、桥本甲状腺炎和干燥综合征是再生障碍性贫血的危险因素，证实了这4种ADs在增加AA风险方面存在因果关系。

关键词: 孟德尔随机化, 因果关联, 自身免疫性疾病, 再生障碍性贫血

Abstract:

Objective To investigate the causal associations between autoimmune diseases and aplastic anemia (AA) using Mendelian randomization analysis. Methods Publicly available genome-wide association study (GWAS) data were utilized to obtain single nucleotide polymorphisms (SNPs) associated with autoimmune diseases and AA for analysis. The inverse variance weighted (IVW) method was employed as the primary analytical approach, with MR Egger, Weighted Mode, Weighted Median, and Simple Mode methods serving as complementary analyses. Heterogeneity and pleiotropy analyses were conducted using designated functions, and the robustness of Mendelian randomization results was assessed using leave-one-out analysis. Results The two-sample Mendelian randomization analysis using the IVW method revealed significant positive causal associations of rheumatoid arthritis (OR=1.094, 95% CI: 1.023-1.170, P=0.009, adjusted P=0.042), systemic lupus erythematosus (OR=1.111, 95% CI: 1.021-1.208, P=0.015, adjusted P=0.036), Hashimoto thyroiditis (OR=1.206, 95% CI: 1.049-1.387, P=0.009, adjusted P=0.029), and Sicca syndrome (OR=1.173, 95% CI: 1.054-1.306, P=0.004, adjusted P=0.035) with AA, which was supported by the results from the Weighted Median method. Sensitivity analyses indicated no evidence of pleiotropy or heterogeneity, and leave-one-out analysis confirmed the robustness of the causal relationships. No direct evidence was found linking Graves' disease, ulcerative colitis, Crohn's disease, autoimmune hepatitis, primary biliary cholangitis, or primary sclerosing cholangitis with AA (P>0.05, adjusted P>0.05), indicating a lack of causal association. Reverse Mendelian randomization results and multiple corrections indicated that AA was not an influencing factor for autoimmune diseases (adjusted P>0.05). Conclusion Our findings support at the genetic level that rheumatoid arthritis, systemic lupus erythematosus, Hashimoto thyroiditis, and Sicca syndrome are risk factors for AA, and confirm a causal association of the these 4 autoimmune diseases with an increased risk of AA.

Key words: Mendelian randomization, causal association, autoimmune diseases, aplastic anemia

李文婕, 洪耀南, 黄蕊, 李煜宸, 张莹, 张蕴, 吴迪炯. 自身免疫性疾病是再生障碍性贫血的危险因素：一项孟德尔随机化分析[J]. 南方医科大学学报, 2025, 45(4): 871-879.

Wenjie LI, Yaonan HONG, Rui HUANG, Yuchen LI, Ying ZHANG, Yun ZHANG, Dijiong WU. Causal relationship between autoimmune diseases and aplastic anemia: A Mendelian randomization study[J]. Journal of Southern Medical University, 2025, 45(4): 871-879.

图/表 8

参考文献 38

1	Wang L, Liu H. Pathogenesis of aplastic Anemia[J]. Hematology, 2019, 24(1): 559-66.
2	王金鑫, 李昌年, 王腾, 等. 再生障碍性贫血患者外周血全外显子组高通量基因测序分析[J]. 中国病理生理杂志, 2024, 40(4): 729-34. DOI: 10.3969/j.issn.1000-4718.2024.04.019
3	Pisetsky DS. Pathogenesis of autoimmune disease[J]. Nat Rev Nephrol, 2023, 19(8): 509-24.
4	中华医学会血液学分会红细胞疾病（贫血）学组. 再生障碍性贫血诊断与治疗中国指南(2022年版)[J]. 中华血液学杂志, 2022, 43(11): 881-8.
5	Kelkka T, Tyster M, Lundgren S, et al. Anti-COX-2 autoantibody is a novel biomarker of immune aplastic Anemia [J]. Leukemia, 2022, 36(9): 2317-27.
6	Baumelou E, Guiguet M, Mary JY. Epidemiology of aplastic Anemia in France: a case-control study. I. medical history and medication use. the French cooperative group for epidemiological study of aplastic Anemia [J]. Blood, 1993, 81(6): 1471-8.
7	Stalder MP, Rovó A, Halter J, et al. Aplastic Anemia and conco-mitant autoimmune diseases[J]. Ann Hematol, 2009, 88(7): 659-65.
8	Best WR. Drug-associated blood dyscrasias[J]. Jama, 1963, 185(4): 286.
9	周广宇, 刘冬娜, 施丽. 类风湿关节炎合并再生障碍性贫血临床特点分析[J]. 中国实用医药, 2007, 2(32): 97. DOI: 10.3969/j.issn.1673-7555.2007.32.070
10	Chalayer É, Ffrench M, Cathébras P. Aplastic Anemia as a feature of systemic lupus erythematosus: a case report and literature review[J]. Rheumatol Int, 2015, 35(6): 1073-82.
11	Yang J, Lin W, Ma Y, et al. Investigation of the causal association between Parkinson's disease and autoimmune disorders: a bidirectional Mendelian randomization study[J]. Front Immunol, 2024, 15: 1370831.
12	Kaushansky K, A.Lichtman M, T.Prchal J, et al. Williams Hematology,10^th ed[M]. New York: McGraw-Hill Education, 2021: 563-8.
13	Zhang Y, Xiong Y, Shen S, et al. Causal association between tea consumption and kidney function: a mendelian randomization study[J]. Front Nutr, 2022, 9: 801591.
14	Zhou Y, Yin X, Wang C, et al. Gene association analysis to determine the causal relationship between immune-mediated inflammatory diseases and frozen shoulder[J]. Medicine: Baltimore, 2024, 103(19): e38055.
15	Yin M, Xu W, Pang J, et al. Causal relationship between osteoarthritis with atrial fibrillation and coronary atherosclerosis: a bidirectional Mendelian randomization study of European ancestry[J]. Front Cardiovasc Med, 2023, 10: 1213672.
16	Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases[J]. Nat Genet, 2018, 50(5): 693-8.
17	Wang J, Erlacher M, Fernandez-Orth J. The role of inflammation in hematopoiesis and bone marrow failure: What can we learn from mouse models[J]? Front Immunol, 2022, 13: 951937.
18	Bugatti S, Manzo A, Caporali R, et al. Inflammatory lesions in the bone marrow of rheumatoid arthritis patients: a morphological perspective[J]. Arthritis Res Ther, 2012, 14(6): 229.
19	Papadaki HA, Boumpas DT, Gibson FM, et al. Increased apoptosis of bone marrow CD34⁺ cells and impaired function of bone marrow stromal cells in patients with systemic lupus erythematosus[J]. Br J Haematol, 2001, 115(1): 167-74.
20	章赛芜, 武洵. 原发性干燥综合征并发贫血28例临床研究[J]. 临床血液学杂志, 2013, 26(1): 40-1.
21	Henry DA. Side-effects of non-steroidal anti-inflammatory drugs[J]. Baillière's Clin Rheumatol, 1988, 2(2): 425-54.
22	Wu JL, Huang H, Yu XJ. How does Hashimoto's thyroiditis affect bone metabolism[J]? Rev Endocr Metab Disord, 2023, 24(2): 191-205.
23	Chivasso C, Sarrand J, Perret J, et al. The involvement of innate and adaptive immunity in the initiation and perpetuation of sjögren's syndrome[J]. Int J Mol Sci, 2021, 22(2): E658.
24	Qin SS, Jiang YX, Ou Y, et al. Mendelian randomization of circulating proteome identifies IFN‑γ as a druggable target in aplastic Anemia [J]. Ann Hematol, 2024, 103(7): 2245-56.
25	Yamada H. Adaptive immunity in the joint of rheumatoid arthritis[J]. Immunol Med, 2022, 45(1): 1-11.
26	Liu W, Zhang S, Wang J. IFN-γ, should not be ignored in SLE[J]. Front Immunol, 2022, 13: 954706.
27	Zhang Y, Hussain M, Yang X, et al. Identification of moesin as a novel autoantigen in patients with sjögren's syndrome[J]. Protein Pept Lett, 2018, 25(4): 350-5.
28	Takamatsu H, Feng XM, Chuhjo T, et al. Specific antibodies to moesin, a membrane-cytoskeleton linker protein, are frequently detected in patients with acquired aplastic Anemia [J]. Blood, 2007, 109(6): 2514-20.
29	Wagatsuma M, Kimura M, Suzuki R, et al. Ezrin, radixin and moesin are possible autoimmune antigens in rheumatoid arthritis[J]. Mol Immunol, 1996, 33(15): 1171-6.
30	Kulasekararaj AG. Regulatory cells in immune-mediated aplastic anaemia-not T_regs but B_regs [J]. Br J Haematol, 2020, 190(4): 486-7.
31	Luo J, Su QY, Zhang Y, et al. pos0750 the status of bregs and breg-related cytokines in patients with systemic lupus erythematosus[J]. Ann Rheum Dis, 2022, 81: 660-1.
32	Luo J, Su QY, Li Q, et al. pos0455 the status of breg cells and breg-related cytokines in patients with rheumatoid arthritis[J]. Ann Rheum Dis, 2023, 82: 484-5.
33	Wang L, Cheng M, Wang Y, et al. Fasting-activated ventrolateral medulla neurons regulate T cell homing and suppress autoimmune disease in mice[J]. Nat Neurosci, 2024, 27(3): 462-70.
34	Kurosawa M, Arakaki R, Yamada A, et al. NF-κB2 controls the migratory activity of memory T cells by regulating expression of CXCR4 in a mouse model of sjögren's syndrome[J]. Arthritis Rheumatol, 2017, 69(11): 2193-202.
35	Arieta Kuksin C, Gonzalez-Perez G, Minter LM. CXCR4 expression on pathogenic T cells facilitates their bone marrow infiltration in a mouse model of aplastic Anemia [J]. Blood, 2015, 125(13): 2087-94.
36	Peng L, Zhu N, Mao J, et al. Expression levels of CXCR4 and CXCL12 in patients with rheumatoid arthritis and its correlation with disease activity[J]. Exp Ther Med, 2020, 20(3): 1925-34.
37	Wang A, Guilpain P, Chong BF, et al. Dysregulated expression of CXCR4/CXCL12 in subsets of patients with systemic lupus erythematosus[J]. Arthritis Rheum, 2010, 62(11): 3436-46.
38	Zheng W, Tang Y, Cheng M, et al. Dysregulated CXCL12 expression in osteoblasts promotes B-lymphocytes preferentially homing to the bone marrow in MRL/lpr mice[J]. Autoimmunity, 2024, 57(1): 2319207.

Exposure/outcome	Year	Population	Sample size	Number of SNPs	PMID
RA	2021	153 457	16 380 169	NA	finn-b-M13_RHEUMA
SLE	NA	307 587	21 303 557	NA	FinnGen ID: SLE_FG
HT	2021	395 640	24 146 037	34594039	ebi-a-GCST90018855
GD	NA	412 181	21 306 349	NA	FinnGen ID: E4_GRAVES_STRICT
UC	2021	214 620	16 380 459	NA	finn-b-K11_ULCER
CD	NA	411 973	21 306 343	NA	FinnGen ID: K11_CD_STRICT2
SS	2021	214 435	16 380 454	NA	finn-b-M13_SJOGREN
AIH	2021	485 234	24 198 482	34594039	ebi-a-GCST90018785
PBC	NA	307 113	21 303 548	NA	FinnGen ID: CHIRBIL_PRIM
PSC	NA	363 484	21 305 253	NA	FinnGen ID: K11_CHOLANGI
AA	2021	473 500	24 192 378	34594039	ebi-a-GCST90018794

Exposure/outcome	Year	Population	Sample size	Number of SNPs	PMID
RA	2021	153 457	16 380 169	NA	finn-b-M13_RHEUMA
SLE	NA	307 587	21 303 557	NA	FinnGen ID: SLE_FG
HT	2021	395 640	24 146 037	34594039	ebi-a-GCST90018855
GD	NA	412 181	21 306 349	NA	FinnGen ID: E4_GRAVES_STRICT
UC	2021	214 620	16 380 459	NA	finn-b-K11_ULCER
CD	NA	411 973	21 306 343	NA	FinnGen ID: K11_CD_STRICT2
SS	2021	214 435	16 380 454	NA	finn-b-M13_SJOGREN
AIH	2021	485 234	24 198 482	34594039	ebi-a-GCST90018785
PBC	NA	307 113	21 303 548	NA	FinnGen ID: CHIRBIL_PRIM
PSC	NA	363 484	21 305 253	NA	FinnGen ID: K11_CHOLANGI
AA	2021	473 500	24 192 378	34594039	ebi-a-GCST90018794

Exposures	Outcomes	P	P.adjust
Rheumatoid arthritis	Aplastic anemia	0.008<0.05	0.042<0.05
Systemic lupus erythematosus		0.014<0.05	0.036<0.05
Hashimoto thyroiditis		0.008<0.05	0.028<0.05
Graves' disease		0.048<0.05	0.096
Ulcerative colitis		0.465	1.000
Crohn's disease		0.277	0.347
Sicca syndrome		0.003<0.05	0.035<0.05
Autoimmune hepatitis		0.149	0.213
Primary sclerosing cholangitis		0.343	0.381
Primary biliary cholangitis		0.133	0.222
Aplastic anemia	Rheumatoid arthritis	0.090	0.454
	Systemic lupus erythematosus	0.496	0.992
	Hashimoto thyroiditis	0.840	1.000
	Graves' disease	0.532	0.887
	Ulcerative colitis	0.950	1.000
	Crohn's disease	0.889	0.988
	Sicca syndrome	0.049<0.05	0.490
	Autoimmune hepatitis	0.220	0.735
	Primary sclerosing cholangitis	0.686	0.981
	Primary biliary cholangitis	0.369	0.922

Exposures	Outcomes	P	P.adjust
Rheumatoid arthritis	Aplastic anemia	0.008<0.05	0.042<0.05
Systemic lupus erythematosus		0.014<0.05	0.036<0.05
Hashimoto thyroiditis		0.008<0.05	0.028<0.05
Graves' disease		0.048<0.05	0.096
Ulcerative colitis		0.465	1.000
Crohn's disease		0.277	0.347
Sicca syndrome		0.003<0.05	0.035<0.05
Autoimmune hepatitis		0.149	0.213
Primary sclerosing cholangitis		0.343	0.381
Primary biliary cholangitis		0.133	0.222
Aplastic anemia	Rheumatoid arthritis	0.090	0.454
	Systemic lupus erythematosus	0.496	0.992
	Hashimoto thyroiditis	0.840	1.000
	Graves' disease	0.532	0.887
	Ulcerative colitis	0.950	1.000
	Crohn's disease	0.889	0.988
	Sicca syndrome	0.049<0.05	0.490
	Autoimmune hepatitis	0.220	0.735
	Primary sclerosing cholangitis	0.686	0.981
	Primary biliary cholangitis	0.369	0.922

Exposures	MR method	P (Heterogeneity)	Pleiotropy
Exposures	MR method	P (Heterogeneity)	P (MR Egger)	P (MR PRESSO)
Rheumatoid arthritis	MR Egger	0.148	0.805	0.356
Rheumatoid arthritis	IVW	0.213	0.805	0.356
Systemic lupus erythematosus	MR Egger	0.113	0.766	0.237
Systemic lupus erythematosus	IVW	0.186	0.766	0.237
Hashimoto thyroiditis	MR Egger	0.207	0.870	0.363
Hashimoto thyroiditis	IVW	0.299	0.870	0.363
Graves' disease	MR Egger	0.059	0.867	0.097
Graves' disease	IVW	0.087	0.867	0.097
Ulcerative colitis	MR Egger	0.902	0.541	0.937
Ulcerative colitis	IVW	0.902	0.541	0.937
Crohn's disease	MR Egger	0.118	0.558	0.159
Crohn's disease	IVW	0.146	0.558	0.159
Sicca syndrome	MR Egger	0.043	0.957	0.254
Sicca syndrome	IVW	0.098	0.957	0.254
Autoimmune hepatitis	MR Egger	0.728	0.520	0.763
Autoimmune hepatitis	IVW	0.755	0.520	0.763
Primary sclerosing cholangitis	MR Egger	0.348	0.525	0.385
Primary sclerosing cholangitis	IVW	0.387	0.525	0.385
Primary biliary cholangitis	MR Egger	0.764	0.849	NA
Primary biliary cholangitis	IVW	0.928	0.849	NA

自身免疫性疾病是再生障碍性贫血的危险因素：一项孟德尔随机化分析

Causal relationship between autoimmune diseases and aplastic anemia: A Mendelian randomization study

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[13]	杨楠，马肖容，张卉，曹星梅，陈银霞，何爱丽，刘捷，赵万红，张王刚. 猪抗人淋巴细胞球蛋白与兔抗人胸腺细胞球蛋白治疗重型再生障碍性贫血的疗效比较[J]. 南方医科大学学报, 2016, 36(03): 303-.
[14]	吕蒙，沈洁，李章芳，赵德福，陈志，万亨，郝宝珺. Treg/Th17细胞及相关细胞因子在Graves眼病中的作用及机制[J]. 南方医科大学学报, 2014, 34(12): 1809-.
[15]	邓伟，席亚明，曹长青. 肝炎相关再生障碍性贫血8例临床分析[J]. 南方医科大学学报, 2011, 31(08): 1443-.