Genetic Causal Relationship Between Systemic Lupus Erythematosus and Malignant Tumors of the Female Reproductive System: A GWAS Analysis in European Populations

IF 3.3 2区医学 Q2 GENETICS & HEREDITY

Human Mutation Pub Date : 2025-05-16 DOI:10.1155/humu/7447886

Jianbin Li, Zhuo Tang, Lei Zhang, Ning Tan, Wei Liu

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引用次数: 0

Abstract

Background: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that primarily affects women of reproductive age. Existing studies have demonstrated complex associations between SLE and various diseases, but its genetic relationship with malignant tumors of the female reproductive system has not been fully elucidated. This study is aimed at exploring the potential genetic associations and shared molecular basis between SLE and female reproductive system malignancies using genome-wide association studies (GWASs) and cross-trait analysis.

Methods: We selected genetic variants significantly associated with SLE (p < 5 × 10⁻⁸) from large-scale GWAS databases as genetic instruments and applied various statistical methods to analyze the associations between SLE and cervical cancer, endometrial cancer, ovarian cancer, vulvar cancer, vaginal cancer, and uterine cancer. The primary analysis was conducted using inverse variance weighting (IVW), supplemented by Egger regression, weighted median, and weighted mode methods. To control for potential confounders, we performed multivariable analysis while including BMI, estradiol, and CRP as covariates. Additionally, cross-trait analysis using the association analysis based on subset (ASSET) method was employed to identify shared genetic variants and their effect directions between SLE and uterine cancer.

Results: Genetic association analysis showed a significant negative association between SLE and endometrial cancer (OR = 0.972, 95% CI [0.946–0.998], p = 0.038), suggesting that SLE may be associated with a reduced risk of endometrial cancer. For uterine cancer, the weighted median method also indicated a marginally significant negative association (OR = 0.955, 95% CI [0.912–1.000], p = 0.049). Multivariable analysis further confirmed that the protective association between SLE and endometrial cancer remained significant after controlling for BMI, estradiol, and CRP (OR = 0.96, 95% CI [0.93–0.99], p = 0.014). However, no significant association was observed between SLE and cervical cancer, ovarian cancer, vulvar cancer, or vaginal cancer. Cross-trait analysis identified 193 shared genetic variants between SLE and endometrial cancer and 71 shared variants between SLE and uterine cancer, with rs2442719 and rs3131004 showing consistent effect directions in both comparisons.

Conclusion: This study provides genetic epidemiological evidence suggesting that SLE may have a protective effect against endometrial and uterine cancers and identifies potential shared genetic bases. These findings offer new insights into the relationship between SLE and gynecological tumors and may provide references for the prevention and treatment of related diseases.

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系统性红斑狼疮与女性生殖系统恶性肿瘤的遗传因果关系：欧洲人群的GWAS分析

背景：系统性红斑狼疮（SLE）是一种多系统自身免疫性疾病，主要影响育龄妇女。现有研究表明SLE与多种疾病之间存在复杂的关联，但其与女性生殖系统恶性肿瘤的遗传关系尚未完全阐明。本研究旨在通过全基因组关联研究（GWASs）和交叉性状分析，探索SLE与女性生殖系统恶性肿瘤之间潜在的遗传关联和共同的分子基础。方法：我们选择与SLE显著相关的遗传变异(p <；5 × 10−8)作为遗传工具，应用各种统计方法分析SLE与宫颈癌、子宫内膜癌、卵巢癌、外阴癌、阴道癌和子宫癌的相关性。初步分析采用方差反加权法（IVW），辅以Egger回归、加权中位数法和加权众数法。为了控制潜在的混杂因素，我们进行了多变量分析，同时将BMI、雌二醇和CRP作为协变量。此外，采用基于子集的关联分析（ASSET）方法进行交叉性状分析，确定SLE与子宫癌之间共有的遗传变异及其作用方向。结果：遗传关联分析显示SLE与子宫内膜癌呈显著负相关（OR = 0.972, 95% CI [0.946-0.998], p = 0.038），提示SLE可能与降低子宫内膜癌风险相关。对于子宫癌，加权中位数法也显示了极显著的负相关（OR = 0.955, 95% CI [0.912-1.000], p = 0.049）。多变量分析进一步证实，在控制BMI、雌二醇和CRP后，SLE与子宫内膜癌之间的保护性关联仍然显著（OR = 0.96, 95% CI [0.93-0.99], p = 0.014）。然而，SLE与宫颈癌、卵巢癌、外阴癌或阴道癌之间没有明显的关联。交叉性状分析发现，SLE与子宫内膜癌共有遗传变异193个，SLE与子宫癌共有遗传变异71个，其中rs2442719和rs3131004在两种比较中作用方向一致。结论：本研究提供了遗传流行病学证据，表明SLE可能对子宫内膜癌和子宫癌具有保护作用，并确定了潜在的共同遗传基础。这些发现为SLE与妇科肿瘤的关系提供了新的认识，并可为相关疾病的预防和治疗提供参考。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Human Mutation 医学-遗传学

CiteScore

8.40

自引率

5.10%

发文量

190

审稿时长

2 months

期刊介绍： Human Mutation is a peer-reviewed journal that offers publication of original Research Articles, Methods, Mutation Updates, Reviews, Database Articles, Rapid Communications, and Letters on broad aspects of mutation research in humans. Reports of novel DNA variations and their phenotypic consequences, reports of SNPs demonstrated as valuable for genomic analysis, descriptions of new molecular detection methods, and novel approaches to clinical diagnosis are welcomed. Novel reports of gene organization at the genomic level, reported in the context of mutation investigation, may be considered. The journal provides a unique forum for the exchange of ideas, methods, and applications of interest to molecular, human, and medical geneticists in academic, industrial, and clinical research settings worldwide.