基于孟德尔随机化探讨不同亚型子宫内膜异位症与血清尿酸水平间的因果关系

doi:10.12280/gjfckx.20251363

摘要/Abstract

摘要：

目的：利用孟德尔随机化（Mendelian randomization，MR）方法探讨不同亚型子宫内膜异位症（endometriosis，EMs）与血清尿酸（serum uric acid，SUA）水平间的因果关系。方法：采用来自欧洲人群的公开发表的全基因组关联研究（genome-wide association study，GWAS）汇总数据进行分析，SUA数据来源于跨种族GWAS数据中的欧洲子集（样本288 649例）；EMs暴露数据来源于芬兰人群FinnGen队列（队列包含样本500 348例，其中女性282 064例），共包含7个亚型，分别为总体表型、美国生殖医学会（American Society for Reproductive Medicine，ASRM）Ⅲ~Ⅳ期重度型、深部浸润型、卵巢型、盆腔腹膜型、直肠阴道隔型及子宫型EMs。采用逆方差加权法（inverse variance weighted，IVW）作为主要分析方法，并进一步采用MR-Egger回归、加权中位数法以及简单众数法与加权众数法进行补充分析。采用Cochran's Q检验评估异质性，通过MR-Egger回归及其截距检验与MR-PRESSO方法检测水平多效性，并采用留一法评估结果的稳定性。结果：以EMs各亚型为暴露、SUA为结局的正向MR分析结果显示：ASRMⅢ~Ⅳ期重度型（β=0.025 9，SE=0.007 8，P=0.000 9）、卵巢型（β=0.023 2，SE=0.006 6，P=0.000 4）及盆腔腹膜型（β=0.025 2，SE=0.011 9，P=0.034 8）EMs与SUA升高存在显著正向因果关系，其余亚型未见显著因果效应。敏感性分析结果未观察到明显的异质性或水平多效性。以SUA为暴露、各EMs亚型为结局的反向分析中，所有IVW方法的比值比均呈正向，但差异无统计学意义（P>0.05）；在反向MR分析中，加权中位数法显示在ASRMⅢ~Ⅳ期重度型与卵巢型亚型中，SUA与EMs风险呈正向关联，差异有统计学意义（P<0.05）。结论：ASRMⅢ~Ⅳ期重度型EMs、卵巢型EMs以及盆腔腹膜型EMs可能通过遗传途径导致SUA水平升高，而SUA升高对EMs发病风险未见显著的因果效应。

关键词: 子宫内膜异位症, 尿酸, 孟德尔随机化分析, 全基因组关联研究

Abstract:

Objective: To explore the causal relationship between different subtypes of endometriosis (EMs) and serum uric acid (SUA) levels using Mendelian randomization (MR) analysis. Methods: The analysis utilized publicly available summary data from genome-wide association study (GWAS) of European ancestry. GWAS data for SUA were derived from the European subset of a trans-ancestry meta-analysis (sample size n=288 649). Exposure data for EMs and its subtypes were obtained from the Finnish population in the FinnGen cohort (total sample n=500 348, including 282 064 females). Seven EMs subtypes were analyzed: overall EMs, ASRM (American Society for Reproductive Medicine) stages Ⅲ-Ⅳ severe EMs, deep infiltrating EMs, ovarian EMs, pelvic peritoneal EMs, rectovaginal septum EMs, and uterine EMs. The inverse variance weighted (IVW) method served as the primary analysis. Complementary analyses were conducted using MR-Egger regression, weighted median, simple mode, and weighted mode methods. Heterogeneity was assessed using Cochran's Q test. Horizontal pleiotropy was evaluated via MR-Egger regression with its intercept test and the MR-PRESSO method. The robustness of results was tested using the leave-one-out sensitivity analysis. Results: In the forward MR analysis with EMs subtypes as exposures and SUA as the outcome, significant positive causal effects were observed for ASRM stage Ⅲ-Ⅳ severe EMs (β=0.025 9, SE=0.007 8, P=0.000 9), ovarian EMs (β=0.023 2, SE=0.006 6, P=0.000 4), and pelvic peritoneal EMs (β=0.025 2, SE=0.011 9, P=0.034 8), indicating these subtypes causally increased SUA levels. No significant causal effects were found for the other subtypes. Sensitivity analyses revealed no substantial heterogeneity or horizontal pleiotropy. In the reverse MR analysis with SUA as the exposure and EMs subtypes as outcomes, while all odds ratios from the IVW method were positive, none reached statistical significance (P>0.05). However, the weighted median method in the reverse analysis indicated statistically significant positive associations between SUA and the risk of ASRM stage Ⅲ-Ⅳ severe EMs and ovarian EMs (P<0.05). Conclusions: ASRM stage Ⅲ-Ⅳ severe EMs, ovarian EMs, and pelvic peritoneal EMs may causally increase SUA levels through genetic pathways. Conversely, evidence for a causal effect of elevated SUA on the risk of developing EMs was not significant.

Key words: Endometriosis, Uric acid, Mendelian randomization analysis, Genome-wide association study

笪慧, 徐传花, 黄龙萍, 尹湘涵, 朱媛媛. 基于孟德尔随机化探讨不同亚型子宫内膜异位症与血清尿酸水平间的因果关系[J]. 国际妇产科学杂志, 2026, 53(4): 430-437.

DA Hui, XU Chuan-hua, HUANG Long-ping, YIN Xiang-han, ZHU Yuan-yuan. Mendelian Randomization Study on the Causal Relationship between Different Endometriosis Subtypes and Serum Uric Acid Levels[J]. Journal of International Obstetrics and Gynecology, 2026, 53(4): 430-437.

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参考文献 21

[1]	Zondervan KT, Becker CM, Koga K, et al. Endometriosis[J]. Nat Rev Dis Primers, 2018, 4(1):9. doi: 10.1038/s41572-018-0008-5. pmid: 30026507
[2]	Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis[J]. Fertil Steril, 2012, 98(3):511-519. doi: 10.1016/j.fertnstert.2012.06.029. pmid: 22819144
[3]	Chang LY, Hou XX, Li DJ, et al. Metabolite changes in patients with endometriosis: new potential diagnostic and therapeutic targets[J]. Reprod Dev Med, 2025, 9(2):108-118. doi: 10.1097/rd9.0000000000000122.
[4]	Collie B, Troisi J, Lombardi M, et al. The Current Applications of Metabolomics in Understanding Endometriosis: A Systematic Review[J]. Metabolites, 2025, 15(1):50. doi: 10.3390/metabo15010050.
[5]	Adamyan L, Pivazyan L, Zarova E, et al. Metabolomic biomarkers of endometriosis: A systematic review[J]. J Endometr Uterine Disord, 2024, 7:100077. doi: 10.1016/j.jeud.2024.100077.
[6]	Ortiz CN, Torres-Reverón A, Appleyard CB. Metabolomics in endometriosis: challenges and perspectives for future studies[J]. Reprod Fertil, 2021, 2(2):R35-R50. doi: 10.1530/RAF-20-0047.
[7]	Li J, Guan L, Zhang H, et al. Endometrium metabolomic profiling reveals potential biomarkers for diagnosis of endometriosis at minimal-mild stages[J]. Reprod Biol Endocrinol, 2018, 16(1):42. doi: 10.1186/s12958-018-0360-z.
[8]	Du L, Zong Y, Li H, et al. Hyperuricemia and its related diseases: mechanisms and advances in therapy[J]. Signal Transduct Target Ther, 2024, 9(1):212. doi: 10.1038/s41392-024-01916-y.
[9]	Garmendia JV, De Sanctis CV, Hajdúch M, et al. Endometriosis: An Immunologist's Perspective[J]. Int J Mol Sci, 2025, 26(11):5193. doi: 10.3390/ijms26115193.
[10]	Leone Roberti Maggiore U, Chiappa V, Ceccaroni M, et al. Epidemiology of infertility in women with endometriosis[J]. Best Pract Res Clin Obstet Gynaecol, 2024, 92:102454. doi: 10.1016/j.bpobgyn.2023.102454.
[11]	Tin A, Marten J, Halperin Kuhns VL, et al. Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels[J]. Nat Genet, 2019, 51(10):1459-1474. doi: 10.1038/s41588-019-0504-x. pmid: 31578528
[12]	Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population[J]. Nature, 2023, 613(7944):508-518. doi: 10.1038/s41586-022-05473-8.
[13]	Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies[J]. Hum Mol Genet, 2014, 23(R1):R89-98. doi: 10.1093/hmg/ddu328.
[14]	Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data[J]. Genet Epidemiol, 2013, 37(7):658-665. doi: 10.1002/gepi.21758.
[15]	Lu J, Ling X, Liu L, et al. Emerging hallmarks of endometriosis metabolism: A promising target for the treatment of endometriosis[J]. Biochim Biophys Acta Mol Cell Res, 2023, 1870(1): 119381. doi: 10.1016/j.bbamcr.2022.119381.
[16]	Marečková M, Garcia-Alonso L, Moullet M, et al. An integrated single-cell reference atlas of the human endometrium[J]. Nat Genet, 2024, 56(9):1925-1937. doi: 10.1038/s41588-024-01873-w.
[17]	Yin W, Zhou QL, OuYang SX, et al. Uric acid regulates NLRP3/IL-1β signaling pathway and further induces vascular endothelial cells injury in early CKD through ROS activation and K⁺ efflux[J]. BMC Nephrol, 2019, 20(1):319. doi: 10.1186/s12882-019-1506-8.
[18]	Hu J, Xu W, Yang H, et al. Uric acid participating in female reproductive disorders: a review[J]. Reprod Biol Endocrinol, 2021, 19(1):65. doi: 10.1186/s12958-021-00748-7.
[19]	McGrath IM, Montgomery GW, Mortlock S. Insights from Mendelian randomization and genetic correlation analyses into the relationship between endometriosis and its comorbidities[J]. Hum Reprod Update, 2023, 29(5):655-674. doi: 10.1093/humupd/dmad009. pmid: 37159502
[20]	Dolińska W, Draper H, Othman L, et al. Accuracy and utility of blood and urine biomarkers for the noninvasive diagnosis of endometriosis: a systematic literature review and meta-analysis[J]. F&S Rev, 2023, 4(2):116-130. doi: 10.1016/j.xfnr.2022.12.001.
[21]	Parasar P, Ozcan P, Terry KL. Endometriosis: Epidemiology, Diagnosis and Clinical Management[J]. Curr Obstet Gynecol Rep, 2017, 6(1):34-41. doi: 10.1007/s13669-017-0187-1.

亚型	表型编码	病例数（例）	对照数（例）	SNP（个）
EMs（总体表型）	N14_ENDOMETRIOSIS	20 190	130 160	20 445 427
ASRMⅢ~Ⅳ期EMs	N14_ENDOMETRIOSIS_ASRM_STAGE3_4	10 127	271 937	20 459 052
深部浸润型EMs	N14_ENDOMETRIOSIS_DEEP	3 806	271 937	20 458 731
卵巢型EMs	N14_ENDOMETRIOSIS_OVARY	7 878	130 160	20 441 679
盆腔腹膜型EMs	N14_ENDOMETRIOSIS_PELVICPERITONEUM	7 617	130 160	20 441 630
直肠阴道隔型EMs	N14_ENDOMETRIOSIS_RECTPVAGSEPT_VAGINA	3 226	130 160	20 440 157
子宫型EMs（子宫腺肌病）	N14_ENDOMETRIOSIS_UTERUS	5 673	130 160	20 441 278

亚型	表型编码	病例数（例）	对照数（例）	SNP（个）
EMs（总体表型）	N14_ENDOMETRIOSIS	20 190	130 160	20 445 427
ASRMⅢ~Ⅳ期EMs	N14_ENDOMETRIOSIS_ASRM_STAGE3_4	10 127	271 937	20 459 052
深部浸润型EMs	N14_ENDOMETRIOSIS_DEEP	3 806	271 937	20 458 731
卵巢型EMs	N14_ENDOMETRIOSIS_OVARY	7 878	130 160	20 441 679
盆腔腹膜型EMs	N14_ENDOMETRIOSIS_PELVICPERITONEUM	7 617	130 160	20 441 630
直肠阴道隔型EMs	N14_ENDOMETRIOSIS_RECTPVAGSEPT_VAGINA	3 226	130 160	20 440 157
子宫型EMs（子宫腺肌病）	N14_ENDOMETRIOSIS_UTERUS	5 673	130 160	20 441 278