Inmaculada Ruiz-Lorente, Lourdes Gimeno, Alicia López-Abad, Pedro López Cubillana, Tomás Fernández Aparicio, Lucas Jesús Asensio Egea, Juan Moreno Avilés, Gloria Doñate Iñiguez, Pablo Luis Guzmán Martínez-Valls, Gerardo Server, Belén Ferri, José Antonio Campillo, Francisco Galindo, Francisco Boix, María Victoria Martínez-Sánchez, María Dolores Martínez-Hernández, Alfredo Minguela
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The objective of this work was to investigate the potential association of killer-cell immunoglobulin-like receptor 2DL5 (KIR2DL5) with BC risk, its interaction with tobacco smoking, and the underlying immune mechanisms.</p><p><strong>Methods: </strong>This case-control study analyzed KIR genotype in patients with BC (n = 325), as well as in healthy controls (HC, n = 925) and patients with other cancers (n = 862) as control groups. Immune assays assessed proliferation, cytotoxicity, cytokine, and intracellular nitric oxide (icNO) production by NK and T cells after anti-CD3/CD28 or <i>Bacillus</i> Calmette-Guérin (BCG) stimulation in 24 donors stratified by KIR2DL5 genotype. Multivariate logistic regression was used to evaluate BC predisposition.</p><p><strong>Results: </strong>The frequency of KIR2DL5 was higher in BC patients than in HC (64.6% vs. 53.6%, p = 0.004). Linear regression analysis revealed that, independent of other aKIRs within the B haplotype, KIR2DL5 was associated with BC susceptibility (HR = -1.167, p = 0.050), alongside other significant factors such as sex (HR = -1.465, p < 0.001), age (HR = -0.181, p < 0.001), and tobacco smoking (HR = -2.454, p < 0.001). The frequency of KIR2DL5 was higher among non-smokers compared to smokers in both healthy controls (61.4% vs. 44.6%, p < 0.05) and BC patients (72.9% vs. 60.8%, p < 0.05). Among non-smoking BC patients, KIR2DL5 was more frequently observed in small-sized (<3 cm), solid-pattern, non-muscle-invasive BC cases. Immune profiling revealed that KIR2DL5 was associated with increased icNO production by NK and T cells but showed no association with proliferation, cytokine secretion, or cytotoxicity.</p><p><strong>Discussion: </strong>KIR2DL5 is independently associated with BC, regardless of age, sex, or tobacco smoking status. 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引用次数: 0
摘要
吸烟是膀胱癌（BC）最重要的危险因素，其次是其他环境和饮食暴露。然而，主要的遗传决定因素仍未确定。这项工作的目的是研究杀伤细胞免疫球蛋白样受体2DL5 （KIR2DL5）与BC风险的潜在关联，其与吸烟的相互作用，以及潜在的免疫机制。方法：本病例对照研究分析了BC患者（n = 325）、健康对照组（n = 925）和其他癌症患者（n = 862）的KIR基因型。免疫试验评估了24例KIR2DL5基因型供体在抗cd3 /CD28或卡介苗刺激后NK细胞和T细胞的增殖、细胞毒性、细胞因子和细胞内一氧化氮（icNO）的产生。采用多变量logistic回归评估BC易感性。结果：KIR2DL5在BC患者中的表达频率高于HC患者（64.6% vs. 53.6%, p = 0.004）。线性回归分析显示，KIR2DL5与BC易感性（HR = -1.167, p = 0.050）、性别（HR = -1.465, p < 0.001）、年龄（HR = -0.181, p < 0.001）和吸烟（HR = -2.454, p < 0.001）相关，与B单倍型中其他akir无关。非吸烟者KIR2DL5的表达频率高于健康对照组（61.4%比44.6%,p < 0.05）和BC患者（72.9%比60.8%,p < 0.05）。在非吸烟BC患者中，KIR2DL5更常见于小尺寸(讨论：KIR2DL5与BC独立相关，与年龄、性别或吸烟状况无关。虽然免疫机制尚不清楚，但免疫效应细胞增强的一氧化氮产生可能在这种关联中起作用。
Interplay of KIR2DL5, nitric oxide, and tobacco smoking in predisposition to bladder cancer.
Introduction: Tobacco smoking is the most significant risk factor for bladder cancer (BC), followed by other environmental and dietary exposures. However, major genetic determinants remain unidentified. The objective of this work was to investigate the potential association of killer-cell immunoglobulin-like receptor 2DL5 (KIR2DL5) with BC risk, its interaction with tobacco smoking, and the underlying immune mechanisms.
Methods: This case-control study analyzed KIR genotype in patients with BC (n = 325), as well as in healthy controls (HC, n = 925) and patients with other cancers (n = 862) as control groups. Immune assays assessed proliferation, cytotoxicity, cytokine, and intracellular nitric oxide (icNO) production by NK and T cells after anti-CD3/CD28 or Bacillus Calmette-Guérin (BCG) stimulation in 24 donors stratified by KIR2DL5 genotype. Multivariate logistic regression was used to evaluate BC predisposition.
Results: The frequency of KIR2DL5 was higher in BC patients than in HC (64.6% vs. 53.6%, p = 0.004). Linear regression analysis revealed that, independent of other aKIRs within the B haplotype, KIR2DL5 was associated with BC susceptibility (HR = -1.167, p = 0.050), alongside other significant factors such as sex (HR = -1.465, p < 0.001), age (HR = -0.181, p < 0.001), and tobacco smoking (HR = -2.454, p < 0.001). The frequency of KIR2DL5 was higher among non-smokers compared to smokers in both healthy controls (61.4% vs. 44.6%, p < 0.05) and BC patients (72.9% vs. 60.8%, p < 0.05). Among non-smoking BC patients, KIR2DL5 was more frequently observed in small-sized (<3 cm), solid-pattern, non-muscle-invasive BC cases. Immune profiling revealed that KIR2DL5 was associated with increased icNO production by NK and T cells but showed no association with proliferation, cytokine secretion, or cytotoxicity.
Discussion: KIR2DL5 is independently associated with BC, regardless of age, sex, or tobacco smoking status. While the immunological mechanisms remain unclear, enhanced nitric oxide production by immune effector cells may play a role in this association.
期刊介绍：
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