Circulating inflammatory and immune response proteins and endometrial cancer risk: a nested case-control study and Mendelian randomization analyses.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2024-10-01 Epub Date: 2024-09-14 DOI:10.1016/j.ebiom.2024.105341

Sabrina E Wang, Vivian Viallon, Matthew Lee, Niki Dimou, Fergus Hamilton, Carine Biessy, Tracy O'Mara, Maria Kyrgiou, Emma J Crosbie, Therese Truong, Gianluca Severi, Rudolf Kaaks, Renée Turzanski Fortner, Matthias B Schulze, Benedetta Bendinelli, Sieri Sabina, Rosario Tumino, Carlotta Sacerdote, Salvatore Panico, Marta Crous-Bou, Maria-Jose Sánchez, Amaia Aizpurua, Daniel Rodriguez Palacios, Marcela Guevara, Ruth C Travis, Konstantinos K Tsilidis, Alicia Heath, James Yarmolinsky, Sabina Rinaldi, Marc J Gunter, Laure Dossus

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引用次数: 0

Abstract

Background: Inflammation and immune dysregulation are hypothesized contributors to endometrial carcinogenesis; however, the precise underlying mechanisms remain unclear.

Methods: We measured pre-diagnostically 152 plasma protein biomarkers in 624 endometrial cancer case-control pairs nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Odds ratios (ORs) were estimated using conditional logistic regression, accounting for confounding and multiple comparisons. Proteins considered as associated with endometrial cancer risk were further tested in a two-sample Mendelian randomization (MR) analysis using summary data from the UK Biobank (n = 52,363) and the Endometrial Cancer Association Consortium (12,270 cases and 46,126 controls).

Findings: In the EPIC nested case-control study, IL-6 [OR per NPX (doubling of concentration) = 1.28 (95% confidence interval (CI) 1.03-1.57)], HGF [1.48 (1.06-2.07)], PIK3AP1 [1.22 (1.00-1.50)] and CLEC4G [1.52 (1.00-2.32)] were positively associated; HSD11B1 [0.67 (0.49-0.91)], SCF [0.68 (0.49-0.94)], and CCL25 [0.80 (0.65-0.99)] were inversely associated with endometrial cancer risk; all estimates had multiple comparisons adjusted P-value > 0.05. In complementary MR analysis, IL-6 [OR per inverse-rank normalized NPX = 1.19 (95% CI 1.04-1.36)] and HSD11B1 [0.91 (0.84-0.99)] were associated with endometrial cancer risk.

Interpretation: Altered IL-6 signalling and reduced glucocorticoid activity via HSD11B1 might play important roles in endometrial carcinogenesis.

Funding: Funding for IIG_FULL_2021_008 was obtained from Wereld Kanker Onderzoek Fonds (WKOF), as part of the World Cancer Research Fund International grant programme; Funding for INCA_15849 was obtained from Institut National du Cancer (INCa).

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循环炎症和免疫反应蛋白与子宫内膜癌风险：巢式病例对照研究和孟德尔随机分析。

背景：炎症和免疫失调被认为是子宫内膜癌发生的诱因，但其确切的内在机制仍不清楚：方法：我们对欧洲癌症与营养前瞻性调查（EPIC）队列中嵌套的 624 对子宫内膜癌病例对照进行了诊断前测量，共测量了 152 种血浆蛋白生物标志物。在考虑混杂因素和多重比较的情况下，使用条件逻辑回归估算了比值比 (OR)。利用英国生物库（52,363 人）和子宫内膜癌协会联合会（12,270 例病例和 46,126 例对照）的汇总数据，在双样本孟德尔随机化（MR）分析中进一步检测了被认为与子宫内膜癌风险相关的蛋白质：在 EPIC 嵌套病例对照研究中，IL-6 [每 NPX（浓度加倍）OR = 1.28（95% 置信区间 (CI) 1.03-1.57）]、HGF [1.48 (1.06-2.07)] 、PIK3AP1 [1.22 (1.00-1.50)] 和 CLEC4G [1.52 (1.00-2.32)] 与子宫内膜癌呈正相关；IL-6、HGF、PIK3AP1 和 CLEC4G 与子宫内膜癌呈负相关。32）]呈正相关；HSD11B1 [0.67 (0.49-0.91)]、SCF [0.68 (0.49-0.94)] 和 CCL25 [0.80 (0.65-0.99)]与子宫内膜癌风险呈反相关；所有估计值的多重比较调整 P 值均大于 0.05。在补充性 MR 分析中，IL-6 [OR per inverse-rank normalized NPX = 1.19 (95% CI 1.04-1.36)]和 HSD11B1 [0.91 (0.84-0.99)]与子宫内膜癌风险相关：解读：通过HSD11B1改变IL-6信号和降低糖皮质激素活性可能在子宫内膜癌发生中发挥重要作用：IIG_FULL_2021_008的研究经费来自Wereld Kanker Onderzoek Fonds (WKOF)，是世界癌症研究基金国际资助项目的一部分；INCA_15849的研究经费来自Institut National du Cancer (INCa)。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.