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

doi:10.12122/j.issn.1673-4254.2025.04.23

Abstract

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

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.

Figures/Tables 8

References 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