Association between inflammatory cytokines and premature ovarian insufficiency: a bidirectional Mendelian randomization study
GAO Zengjie1,2, KONG Xiangyan2, LI Lailai2, CHAI Yihui2
1. Guizhou Hospital of Beijing Jishuitan Hospital, Guiyang, Guizhou 550014, China; 2. Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550025, China
Abstract：Objective To examine the causal relationship between inflammatory cytokines and premature ovarian insufficiency (POI) using bidirectional Mendelian randomization (MR) approach, so as to provide the basis for the prevention and treatment of POI. Methods The data for 91 inflammatory cytokines were sourced from the IEU OpenGWAS database, comprising 14 824 participants. GWAS data for POI were sourced from the FinnGen database, including 118 484 individuals (among which 254 were POI cases). MR analysis was performed using the inverse variance weighted (IVW) method with inflammatory cytokines as exposure and POI as the outcome for forward MR analysis and POI as the exposure and inflammatory cytokines as outcome for reverse MR analysis. Sensitivity analysis were conducted using Cochran's Q test, MR-Egger regression, and the MR-PRESSO test. Results Forward MR analysis demonstrated statistically significant associations between POI and interleukin-10 (OR=0.410, 95%CI: 0.233-0.721), interleukin-33 (OR=2.826, 95%CI: 1.228-6.504), C-C motif chemokine ligand 19 (OR=0.583, 95%CI: 0.364-0.932), monocyte chemoattractant protein-3 (OR=0.559, 95%CI: 0.335-0.936), interleukin-18 receptor 1 (OR=1.370, 95%CI: 1.030-1.821), and interleukin-13 (OR=1.990, 95%CI: 1.034-3.832). Reverse MR analysis revealed significant negative associations between POI and 15 inflammatory cytokines, including C-C motif chemokine ligand 23 (OR=0.981, 95%CI: 0.968-0.994) and axin-1 (OR=0.978, 95%CI: 0.963-0.994). Sensitivity analysis showed no evidence of heterogeneity or horizontal pleiotropy (all P>0.05). Conclusion Elevated levels of interleukin-33, interleukin-18 receptor 1 and interleukin-13 were associated with an increased risk of POI, while POI may be associated with decreased levels of 15 inflammatory cytokines including C-C motif chemokine ligand 23 and axin-1.
[1] CHON S J,UMAIR Z,YOON M S.Premature ovarian insufficiency:past,present,and future[J/OL].Front Cell Dev Biol,2021[2025-03-12].https://doi.org/10.3389/fcell.2021.672890. [2] CHENG C H,CHEN L R,CHEN K H.Osteoporosis due to hormone imbalance:an overview of the effects of estrogen deficiency and glucocorticoid overuse on bone turnover[J].Int J Mol Sci,2022,23(3):1376-1392. [3] KIM H K,KIM T J.Current status and future prospects of stem cell therapy for infertile patients with premature ovarian insufficiency[J].Biomolecules,2024,14(2):242-272. [4] 高红娜,王文君.慢性炎症与卵巢功能不全发病机制及其治疗的研究进展[J].中华生殖与避孕杂志,2023,43(9):964-967. GAO H N,WANG W J.Research progress on the pathogenesis and treatment of chronic inflammation and ovarian insufficiency[J].Chin J Reprod Contracep,2023,43(9):964-967.(in Chinese) [5] HUANG Y Q,HU C,YE H F,et al.Inflamm-aging:a new mechanism affecting premature ovarian insufficiency[J/OL].J Immunol Res,2019[2025-03-12].https://doi.org/10.1155/2019/8069898. [6] WANG J H,ZHAO X,LUO R,et al.The causal association between systemic inflammatory regulators and primary ovarian insufficiency:a bidirectional mendelian randomization study[J].J Ovarian Res,2023,16(1):191-199. [7] ZHANG Z Y,HAN S,SUN X W,et al.Causal relationships between 4 exposure factors and rotator cuff syndrome using mendelian randomization analysist[J/OL].Orthop J Sports Med,2025[2025-03-12].https://doi.org/10.1177/23259671241285860. [8] EMDIN C A,KHERA A V,KATHIRESAN S.Mendelian randomization[J].JAMA,2017,318(19):1925-1926. [9] FENG Z A,CHEN N,LI H,et al.Serum metabolites and risk of aortic dissection:a two-sample Mendelian randomization study[J].Indian J Thorac Cardiovasc Surg,2025,41(2):139-147. [10] 陈海苗,马岩,刘明奇,等.膳食成分与肠道微生物的孟德尔随机化研究[J].预防医学,2025,37(1):73-76,81. CHEN H M,MA Y,LIU M Q,et al.Mendelian randomization study on dietary components and gut microbiota[J].China Prev Med J,2025,37(1):73-76,81.(in Chinese) [11] WU Z S,ZHAO Y,ZHANG B,et al.Causal association between serum 25-hydroxyvitamin D levels and epilepsy:a two-sample bidirectional Mendelian randomization study[J/OL].Epilepsy Behav,2025,164[2025-03-12].https://doi.org/10.1016/j.yebeh.2024.110253 [12] ABUBAKAR M,RASOOL H F,JAVED I,et al.Comparative roles of IL-1,IL-6,IL-10,IL-17,IL-18,1L-22,IL-33,and IL-37 in various cardiovascular diseases with potential insights for targeted immunotherapy[J/OL].Cureus,2023,15(7)[2025-03-12].https://doi.org/10.7759/cureus.42494. [13] 黄仟润,王风笛,陈月璐,等.免疫因素与POI发病的相关研究进展[J].重庆医科大学学报,2025,50(1):19-22. HUANG Q R,WANG F D,CHEN Y L,et al.Research progress on the correlation between immune factors and the onset of premature ovarian insufficiency[J].J Chongqing Med Univ,2025,50(1):19-22.(in Chinese) [14] SHAKERIAN L,KOLAHDOOZ H,GAROUSI M,et al.IL-33/ST2 axis in autoimmune disease[J/OL].Cytokine,2022,158[2025-03-12].https://doi.org/10.1016/j.cyto.2022.156015. [15] TANG M X,SUN X D,LI P,et al.IL-33 and soluble ST2 in follicular fluid are associated with premature ovarian insufficiency[J/OL].Front Endocrinol(Lausanne),2024,15[2025-03-12].https://doi.org/10.3389/fendo.2024.1463371. [16] TRIVEDI S,LABUZ D,DEERING-RICE C E,et.al.IL-33 induces NF-κB activation in ILC2 that can be suppressed by in vivo and ex vivo 17β-estradiol[J/OL].Frontiers in Allergy,2022,3[2025-03-12].https://doi.org/10.3389/falgy.2022.1062412. [17] MOK M Y,LUO C Y,HUANG F P,et al.IL-33 orchestrated the interaction and immunoregulatory functions of alternatively activated macrophages and regulatory T cells in vitro[J].J Immunol,2023,211(7):1134-1143. [18] RUAN J Y,TIAN Q,LI S T,et al.The IL-33-ST2 axis plays a vital role in endometriosis via promoting epithelial:mesenchymal transition by phosphorylating β-catenin[J].Cell Commun Signal,2024,22(1):318-337. [19] PAWLIK K,CIAPAŁA K,CIECHANOWSKA A,et al.Pharmacological evidence of the important roles of CCR1 and CCR3 and their endogenous ligands CCL2/7/8 in hypersensitivity based on a murine model of neuropathic pain[J].Cells,2022,12(1):98-125. [20] CHEN B X,FAN P,SONG X,et al.The role and possible mechanism of the ferroptosis-related SLC7A11/GSH/GPX4 pathway in myocardial ischemia-reperfusion injury[J].BMC Cardiovasc Disord,2024,24(1):531-542.
