Xin Long1, Michelle Daya2, Jianping Zhao3, Nicholas Rafaels4, Huifang Liang3, Joseph Potee4, Monica Campbell4, Bixiang Zhang3, Maria Ilma Araujo5, Ricardo R Oliveira6, Rasika A Mathias4, Li Gao4, Ingo Ruczinski7, Steve N Georas8, Donata Vercelli9, Terri H Beaty7, Kathleen C Barnes10, Xiaoping Chen11, Qian Chen12. 1. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Clinical Study Center of Liver Surgery in Hubei Province, Wuhan, China; Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, Md. 2. Biomedical Informatics and Personalized Medicine, University of Colorado School of Medicine, Aurora, Colo. 3. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Clinical Study Center of Liver Surgery in Hubei Province, Wuhan, China. 4. Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, Md. 5. Servico de Imunologia, Hospital Universitario Professor Edgard Santos, Salvador, Brazil. 6. Instituto Goncalo Moniz, Fundacao Oswaldo Cruz - Bahia, Salvador, Brazil. 7. Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Md. 8. Department of Medicine, University of Rochester Medical Center, Rochester, NY. 9. Arizona Respiratory Center, University of Arizona, Tucson, Ariz. 10. Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, Md. Electronic address: Kathleen.Barnes@UCDenver.edu. 11. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Clinical Study Center of Liver Surgery in Hubei Province, Wuhan, China. Electronic address: chenxp@medmail.com.cn. 12. Division of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: chenqian201579@yahoo.com.
Abstract
BACKGROUND: Chronic schistosomiasis and its severe complication, periportal fibrosis, are characterized by a predominant Th2 response. To date, specific single nucleotide polymorphisms in ST2 have been some of the most consistently associated genetic variants for asthma. OBJECTIVE: We investigated the role of ST2 (a receptor for the Th2 cytokine IL-33) in chronic and late-stage schistosomiasis caused by Schistosoma japonicum and the potential effect of ST2 genetic variants on stage of disease and ST2 expression. METHODS: We recruited 947 adult participants (339 with end-stage schistosomiasis and liver cirrhosis, 307 with chronic infections without liver fibrosis, and 301 health controls) from a S japonicum-endemic area (Hubei, China). Six ST2 single nucleotide polymorphisms were genotyped. Serum soluble ST2 (sST2) was measured by ELISA, and ST2 expression in normal liver tissues, Hepatitis B virus-induced fibrotic liver tissues, and S japonicum-induced fibrotic liver tissues was measured by immunohistochemistry. RESULTS: We found sST2 levels were significantly higher in the end-stage group (36.04 [95% CI, 33.85-38.37]) compared with chronic cases and controls (22.7 [95% CI, 22.0-23.4], P < 1E-10). In addition, S japonicum-induced fibrotic liver tissues showed increased ST2 staining compared with normal liver tissues (P = .0001). Markers rs12712135, rs1420101, and rs6543119 were strongly associated with sST2 levels (P = 2E-10, 5E-05, and 6E-05, respectively), and these results were replicated in an independent cohort from Brazil living in a S mansoni endemic region. CONCLUSIONS: We demonstrate for the first time that end-stage schistosomiasis is associated with elevated sST2 levels and show that ST2 genetic variants are associated with sST2 levels in patients with schistosomiasis.
BACKGROUND:Chronic schistosomiasis and its severe complication, periportal fibrosis, are characterized by a predominant Th2 response. To date, specific single nucleotide polymorphisms in ST2 have been some of the most consistently associated genetic variants for asthma. OBJECTIVE: We investigated the role of ST2 (a receptor for the Th2 cytokine IL-33) in chronic and late-stage schistosomiasis caused by Schistosoma japonicum and the potential effect of ST2 genetic variants on stage of disease and ST2 expression. METHODS: We recruited 947 adult participants (339 with end-stage schistosomiasis and liver cirrhosis, 307 with chronic infections without liver fibrosis, and 301 health controls) from a S japonicum-endemic area (Hubei, China). Six ST2 single nucleotide polymorphisms were genotyped. Serum soluble ST2 (sST2) was measured by ELISA, and ST2 expression in normal liver tissues, Hepatitis B virus-induced fibrotic liver tissues, and S japonicum-induced fibrotic liver tissues was measured by immunohistochemistry. RESULTS: We found sST2 levels were significantly higher in the end-stage group (36.04 [95% CI, 33.85-38.37]) compared with chronic cases and controls (22.7 [95% CI, 22.0-23.4], P < 1E-10). In addition, S japonicum-induced fibrotic liver tissues showed increased ST2 staining compared with normal liver tissues (P = .0001). Markers rs12712135, rs1420101, and rs6543119 were strongly associated with sST2 levels (P = 2E-10, 5E-05, and 6E-05, respectively), and these results were replicated in an independent cohort from Brazil living in a S mansoni endemic region. CONCLUSIONS: We demonstrate for the first time that end-stage schistosomiasis is associated with elevated sST2 levels and show that ST2 genetic variants are associated with sST2 levels in patients with schistosomiasis.
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