Gloria Y F Ho1, Tao Wang, Siqun L Zheng, Lesley Tinker, Jianfeng Xu, Thomas E Rohan, Sylvia Wassertheil-Smoller, Xiaonan Xue, Leonard H Augenlicht, Ulrike Peters, Amanda I Phipps, Howard D Strickler, Marc J Gunter, Mary Cushman. 1. Authors' Affiliations: Departments of Epidemiology and Population Health and Medicine, Albert Einstein College of Medicine, Bronx, New York; Center for Genomics and Personalized Medicine Research, Wake Forest University, Winston-Salem, North Carolina; Public Health Sciences Division, Fred Hutchinson Cancer Research Center; University of Washington, Seattle, Washington; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; and Departments of Medicine and Pathology, University of Vermont, Burlington, Vermont.
Abstract
BACKGROUND: Soluble cytokine receptors and receptor antagonist of proinflammatory cytokines can modify cytokine signaling and may affect cancer risk. METHODS: In a case-cohort study nested within the Women's Health Initiative cohort of postmenopausal women, we assessed the associations of plasma levels of interleukin (IL)-1 receptor antagonist (IL-1Ra) and the soluble receptors of IL-1 (sIL-1R2), IL-6 (sIL-6R and sgp130), and TNF (sTNFR1 and sTNFR2) with risk of colorectal cancer in 433 cases and 821 subcohort subjects. Baseline levels of estradiol, insulin, leptin, IL-6, and TNF-α measured previously were also available for data analysis. RESULTS: After adjusting for significant covariates, including age, race, smoking, colonoscopy history, waist circumference, and levels of estrogen, insulin, and leptin, relatively high levels of sIL-6R and sIL-1R2 were associated with reduced colorectal cancer risk [HRs comparing extreme quartiles (HRQ4-Q1) for sIL-6R, 0.56; 95% confidence interval (CI), 0.38-0.83; HRQ4-Q1 for sIL-1R2, 0.44; 95% CI, 0.29-0.67]. The associations with IL-1Ra, sgp130, sTNFR1, and sTNFR2 were null. The inverse association of sIL-1R2 with colorectal cancer risk persisted in cases diagnosed ≤5 and >5 years from baseline blood draw; the association with sIL-6R, however, was not evident in the latter group, possibly indicating that relatively low levels of sIL-6R in cases might be due to undiagnosed cancer at the time of blood draw. CONCLUSIONS: High circulating levels of sIL-1R2 may be protective against colorectal carcinogenesis and/or be a marker of reduced risk for the disease. IMPACT: sIL-1R2 has potential to be a chemopreventive and/or immunotherapeutic agent in inflammation-related diseases.
BACKGROUND: Soluble cytokine receptors and receptor antagonist of proinflammatory cytokines can modify cytokine signaling and may affect cancer risk. METHODS: In a case-cohort study nested within the Women's Health Initiative cohort of postmenopausal women, we assessed the associations of plasma levels of interleukin (IL)-1 receptor antagonist (IL-1Ra) and the soluble receptors of IL-1 (sIL-1R2), IL-6 (sIL-6R and sgp130), and TNF (sTNFR1 and sTNFR2) with risk of colorectal cancer in 433 cases and 821 subcohort subjects. Baseline levels of estradiol, insulin, leptin, IL-6, and TNF-α measured previously were also available for data analysis. RESULTS: After adjusting for significant covariates, including age, race, smoking, colonoscopy history, waist circumference, and levels of estrogen, insulin, and leptin, relatively high levels of sIL-6R and sIL-1R2 were associated with reduced colorectal cancer risk [HRs comparing extreme quartiles (HRQ4-Q1) for sIL-6R, 0.56; 95% confidence interval (CI), 0.38-0.83; HRQ4-Q1 for sIL-1R2, 0.44; 95% CI, 0.29-0.67]. The associations with IL-1Ra, sgp130, sTNFR1, and sTNFR2 were null. The inverse association of sIL-1R2 with colorectal cancer risk persisted in cases diagnosed ≤5 and >5 years from baseline blood draw; the association with sIL-6R, however, was not evident in the latter group, possibly indicating that relatively low levels of sIL-6R in cases might be due to undiagnosed cancer at the time of blood draw. CONCLUSIONS: High circulating levels of sIL-1R2 may be protective against colorectal carcinogenesis and/or be a marker of reduced risk for the disease. IMPACT: sIL-1R2 has potential to be a chemopreventive and/or immunotherapeutic agent in inflammation-related diseases.
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