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Abuelnadar EH, Ramadan LM, Shahin HE, Alakilli SYM, Wahsh E, El-Beltagy NS, Salem ET, Hatata AS, El-Said AM, Alhelf M. Association of IL-6 G-174C (rs1800795) variant with the susceptibility to hepatocellular carcinoma in patients with chronic hepatitis. J Egypt Natl Canc Inst 2024; 36:32. [PMID: 39428452 DOI: 10.1186/s43046-024-00238-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 09/17/2024] [Indexed: 10/22/2024] Open
Abstract
AIM An ineffective immune response resulting from dysregulation of cytokine production might encourage viral persistence and cause chronic viral hepatitis to worsen. This study examined the relationship between alterations in interleukin-6 (IL-6) levels and the IL-6 - 174 G > C (rs1800795) polymorphism, as well as how this polymorphism affects the development and progression of chronic hepatitis brought on by hepatitis B (HBV) and hepatitis C (HCV) into hepatocellular carcinoma (HCC). PATIENTS AND METHODS Whole blood samples from 126 Egyptian patients with HCC (111 with HCV and 15 with HBV), as well as 126 age- and sex-matched healthy individuals, were used to extract DNA. Using PCR-based allele-specific amplification (ASA), the existence of the IL-6 G-174C polymorphism was investigated. Additionally, each participant's serum IL-6 levels were determined using an enzyme-linked immunosorbent assay (ELISA). RESULTS The primary observations revealed that HCC patients had greater serum levels of IL-6 compared to the control groups (p < 0.001). Patients with the variant (CG and GG) genotype in the HCC group were found to have more disease severity indicated by higher levels of alpha-fetoprotein (AFP) and a higher ascites grade, as well as increased inflammatory activity as defined by higher levels of IL-6 and C-reactive protein (CRP) (p < 0.001 for both) in comparison to patients with the wild-type (CC) genotype (p < 0.001 and p = 0.002, respectively). CONCLUSION The rs1800795 SNP in the IL-6 gene was associated with increased inflammatory activity and high levels of IL-6, indicating that this SNP may play a role in the development of HCC in Egyptian patients with chronic viral hepatitis.
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MESH Headings
- Humans
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/virology
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/etiology
- Liver Neoplasms/genetics
- Liver Neoplasms/virology
- Liver Neoplasms/blood
- Liver Neoplasms/etiology
- Interleukin-6/blood
- Interleukin-6/genetics
- Male
- Female
- Middle Aged
- Polymorphism, Single Nucleotide
- Genetic Predisposition to Disease
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/blood
- Hepatitis C, Chronic/virology
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/virology
- Hepatitis B, Chronic/blood
- Adult
- Case-Control Studies
- Genotype
- Egypt/epidemiology
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Affiliation(s)
- Eman H Abuelnadar
- Department of Laboratories, Mansoura University, Children Hospital, Mansoura, Egypt
| | - Lamiaa M Ramadan
- Department of Biochemistry, Biotechnology Research Institute, National Research Centre, Cairo, Egypt
| | - Hanaa Elsayed Shahin
- Nursing Department, College of Applied Medical Sciences, Jouf University, ElQurayyat, Saudi Arabia
- Department of Maternity and Newborn Health Nursing, Health Nursing, Menoufia University, Menoufia, Egypt
| | - Saleha Y M Alakilli
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Eman Wahsh
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Sinai University, Arish Branch, Al-Arish, North Sinai, 45511, Egypt
| | | | - Eman T Salem
- Department of Basic Sciences, Faculty of Physical Therapy, Horus University-Egypt, New Damietta, 34518, Egypt
| | - Abdelrahman S Hatata
- Mansoura Manchester Program, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Afaf M El-Said
- Genetic Unit, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
| | - Maha Alhelf
- Biotechnology School, Nile University, Giza, Egypt
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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Liu CR, Li YP, Wang YK, Zhang W, Hao M, Wang WJ, Li T, Dang SS. Peripheral blood T cell and cytokine levels in HBV-related liver disease patients. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2024; 32:293-301. [DOI: 10.11569/wcjd.v32.i4.293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/28/2024]
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Paul C, Besch C, Artzner T, Michard B, Cusumano C, Addeo P, Bachellier P, Faitot F. Additional value of interleukin-6 level to predict histopathological features of hepatocellular carcinoma before liver transplantation. Cytokine 2023; 169:156286. [PMID: 37385083 DOI: 10.1016/j.cyto.2023.156286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/13/2023] [Accepted: 06/24/2023] [Indexed: 07/01/2023]
Abstract
BACKGROUND & AIMS Inflammatory biomarkers are increasingly used as outcome predictors in the field of oncology and liver transplantation for HCC, but no study has shown the prognostic value of IL6 after LT. The goal of this study was to evaluate the predictive value of IL-6 on histopathological features of HCC on explant, its predictive value on recurrence risk and its additional value to other scores and inflammatory markers at the time of transplantation. METHODS From 2009 to 2019, all adults transplanted with a first liver graft and diagnosed with HCC on the explant analysis were retrospectively included (n = 229). Only patients who had a pre-LT IL6 level determination were analysed in this study (n = 204). RESULTS High IL-6 level at transplantation was associated with a significantly higher risk of vascular invasion (15% vs 6%; p = 0.023), microsatellitosis (11% vs 3%; p = 0.013), lower rate of histological response both in terms of complete response (2% vs 14%, p = 0.004) and of necrosis (p = 0.010). Patients with pre-LT IL-6 level > 15 ng/ml had a lower overall and cancer-specific survival (p = 0.013). Recurrence-free survival was lower in patients with IL-6 > 15 ng/ml with a 3-year recurrence-free survival of 88% versus 78% (p = 0.034). IL6 levels were significantly higher in patients with early recurrence compared to patients without (p = 0.002) or with late recurrence (p = 0.044). CONCLUSIONS IL6 level at transplantation is an independent predictor of pejorative histological features of HCC and is associated to the risk of recurrence.
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Affiliation(s)
- Chloé Paul
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France; University of Strasbourg, 4 Rue Kirschleger, 67000 Strasbourg, France
| | - Camille Besch
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France
| | - Thierry Artzner
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France
| | - Baptiste Michard
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France
| | - Caterina Cusumano
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France
| | - Pietro Addeo
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France; ICube Laboratory, University of Strasbourg, 300 Bd Sébastien Brant, 67400 Illkirch-Graffenstaden, France
| | - Philippe Bachellier
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France; University of Strasbourg, 4 Rue Kirschleger, 67000 Strasbourg, France
| | - François Faitot
- Service de Chirurgie Hépatique et Pancréatique, Chirurgie Générale et Transplantation, Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 1 avenue Molière, 67200 Strasbourg, France; University of Strasbourg, 4 Rue Kirschleger, 67000 Strasbourg, France; ICube Laboratory, University of Strasbourg, 300 Bd Sébastien Brant, 67400 Illkirch-Graffenstaden, France.
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Balaji S, Antony AK, Tonchev H, Scichilone G, Morsy M, Deen H, Mirza I, Ali MM, Mahmoud AM. Racial Disparity in Anthracycline-induced Cardiotoxicity in Breast Cancer Patients. Biomedicines 2023; 11:2286. [PMID: 37626782 PMCID: PMC10452913 DOI: 10.3390/biomedicines11082286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/13/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
Breast cancer has become the most common cancer in the US and worldwide. While advances in early detection and treatment have resulted in a 40% reduction in breast cancer mortality, this reduction has not been achieved uniformly among racial groups. A large percentage of non-metastatic breast cancer mortality is related to the cardiovascular effects of breast cancer therapies. These effects appear to be more prevalent among patients from historically marginalized racial/ethnic backgrounds, such as African American and Hispanic individuals. Anthracyclines, particularly doxorubicin and daunorubicin, are the first-line treatments for breast cancer patients. However, their use is limited by their dose-dependent and cumulative cardiotoxicity, manifested by cardiomyopathy, ischemic heart disease, arrhythmias, hypertension, thromboembolic disorders, and heart failure. Cardiotoxicity risk factors, such as genetic predisposition and preexisting obesity, diabetes, hypertension, and heart diseases, are more prevalent in racial/ethnic minorities and undoubtedly contribute to the risk. Yet, beyond these risk factors, racial/ethnic minorities also face unique challenges that contribute to disparities in the emerging field of cardio-oncology, including socioeconomic factors, food insecurity, and the inability to access healthcare providers, among others. The current review will address genetic, clinical, and social determinants that potentially contribute to this disparity.
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Affiliation(s)
- Swetha Balaji
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA; (S.B.); (A.K.A.); (H.T.); (G.S.); (M.M.); (H.D.); (I.M.); (M.M.A.)
| | - Antu K. Antony
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA; (S.B.); (A.K.A.); (H.T.); (G.S.); (M.M.); (H.D.); (I.M.); (M.M.A.)
| | - Harry Tonchev
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA; (S.B.); (A.K.A.); (H.T.); (G.S.); (M.M.); (H.D.); (I.M.); (M.M.A.)
| | - Giorgia Scichilone
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA; (S.B.); (A.K.A.); (H.T.); (G.S.); (M.M.); (H.D.); (I.M.); (M.M.A.)
| | - Mohammed Morsy
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA; (S.B.); (A.K.A.); (H.T.); (G.S.); (M.M.); (H.D.); (I.M.); (M.M.A.)
| | - Hania Deen
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA; (S.B.); (A.K.A.); (H.T.); (G.S.); (M.M.); (H.D.); (I.M.); (M.M.A.)
| | - Imaduddin Mirza
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA; (S.B.); (A.K.A.); (H.T.); (G.S.); (M.M.); (H.D.); (I.M.); (M.M.A.)
| | - Mohamed M. Ali
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA; (S.B.); (A.K.A.); (H.T.); (G.S.); (M.M.); (H.D.); (I.M.); (M.M.A.)
| | - Abeer M. Mahmoud
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA; (S.B.); (A.K.A.); (H.T.); (G.S.); (M.M.); (H.D.); (I.M.); (M.M.A.)
- Department of Kinesiology, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA
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Tabikhanova LE, Osipova LP, Churkina TV, Kovalev SS, Filipenko ML, Voronina EN. Increased Frequencies of the ‒174G and ‒572C IL6 Alleles in Populations of Indigenous Peoples of Siberia Compared to Russians. Mol Biol 2023; 57:329-337. [PMID: 37128211 PMCID: PMC10131552 DOI: 10.1134/s002689332302019x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/16/2022] [Accepted: 09/29/2022] [Indexed: 05/03/2023]
Abstract
Abstract-The study of immune response and inflammation gene polymorphisms in a genogeographic context is relevant in the study of human populations. Here, in the indigenous populations of Siberia the frequencies of polymorphic variants ‒174G/C (rs1800795) and ‒572C/G (rs1800796) of the IL6 gene encoding the proinflammatory cytokine IL-6 were determined. For the first time, it was shown that the frequencies of the ‒174G and ‒572C alleles, which determine increased inflammatory response and are also associated with several diseases were statistically significantly higher in ethnic groups of Buryats, Teleuts, Yakuts, Dolgans and Tuvinians than in Russians living in Siberia. These values were in the intermediate position between those in the European and East-Asian groups. We hypothesize an adaptive role of these IL6 genetic variants in human settlement from Africa to the Eurasian continent. However, due to the departure from the traditional way of life and the increasing anthropogenic environmental pollution, the risk of diseases whose pathogenesis is based on inflammation in indigenous Siberian populations is likely increased.
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Affiliation(s)
- L. E. Tabikhanova
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - L. P. Osipova
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - T. V. Churkina
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - S. S. Kovalev
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - M. L. Filipenko
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - E. N. Voronina
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
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Cytokine pathway variants modulate platelet production: IFNA16 is a thrombocytosis susceptibility locus in humans. Blood Adv 2022; 6:4884-4900. [PMID: 35381074 PMCID: PMC9631663 DOI: 10.1182/bloodadvances.2021005648] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 03/09/2022] [Indexed: 02/08/2023] Open
Abstract
Inflammatory stimuli have divergent effects on peripheral platelet counts, although the mechanisms of thrombocytopenic and thrombocytotic responses remain poorly understood. A candidate gene approach targeting 326 polymorphic genes enriched in thrombopoietic and cytokine signaling pathways was applied to identify single nucleotide variants (SNVs) implicated in enhanced platelet responses in cohorts with reactive thrombocytosis (RT) or essential (myeloproliferative neoplasm [MPN]) thrombocytosis (ET). Cytokine profiles incorporating a 15-member subset, pathway topology, and functional interactive networks were distinct between ET and RT, consistent with distinct regulatory pathways of exaggerated thrombopoiesis. Genetic studies using aggregate (ET + RT) or ET-restricted cohorts identified associations with 2 IFNA16 (interferon-α16) SNVs, and the ET associations were validated in a second independent cohort (P = .0002). Odds ratio of the combined ET cohort (n = 105) was 4.92, restricted to the JAK2V617F-negative subset (odds ratio, 5.01). ET substratification analysis by variant IFNA16 exhibited a statistically significant increase in IFN-α16 levels (P = .002) among 16 quantifiable cytokines. Recombinantly expressed variant IFN-α16 encompassing 3 linked non-synonymous SNVs (E65H95P133) retained comparable antiviral and pSTAT signaling profiles as native IFN-α16 (V65D95A133) or IFN-α2, although both native and variant IFN-α16 showed stage-restricted differences (compared with IFN-α2) of IFN-regulated genes in CD34+-stimulated megakaryocytes. These data implicate IFNA16 (IFN-α16 gene product) as a putative susceptibility locus (driver) within the broader disrupted cytokine network evident in MPNs, and they provide a framework for dissecting functional interactive networks regulating stress or MPN thrombopoiesis.
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Zheng M, Fang W, Yu M, Ding R, Zeng H, Huang Y, Mi Y, Duan C. IL-6 and IL-10 gene polymorphisms and cirrhosis of liver risk from a comprehensive analysis. BMC Endocr Disord 2021; 21:242. [PMID: 34886817 PMCID: PMC8656043 DOI: 10.1186/s12902-021-00906-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 11/23/2021] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Different inflammatory and immune cytokines play a key role in the development of cirrhosis of liver (CL). To investigate the association between interleukin-6,10 (IL-6,10) genes polymorphisms and CL risk through comparison of the allele and genotype distribution frequencies by meta-analysis. METHODS A literature search covered with the PubMed, Embase, Cochrane Library, Web of Science, Google Scholar, SinoMed (CNKI and Wanfang) through 20th April, 2021. Odds ratios (OR) and 95% confidence intervals (CI) were used to assess the strength of associations. RESULTS After a comprehensive search, three common polymorphisms (rs1800872, rs1800871, rs1800896) in IL-10 gene were selected, and three common polymorphisms (rs1800795, rs1800796, rs1800797) in IL-6 gene were also identified. The important finding was that IL-10 rs1800872 was a risk factor for CL development. For example, there has a significantly increased relationship between rs1800872 polymorphism and CL both in the whole group (OR: 1.30, 95%CI: 1.01-1.67 in heterozygote model), Asian population (OR: 1.40, 95%CI: 1.03-1.88 in heterozygote model) and hospital-based source of control (OR: 1.40, 95%CI: 1.01-1.96 in dominant model). In addition, significant association was found between rs1800896 and primary biliary cirrhosis subtype disease (OR: 1.30, 95%CI: 1.01-1.68 in allelic contrast model). No association was observed in all three polymorphisms in IL-6 gene. CONCLUSION Our present study suggests that the IL-10 rs1800872 and rs1800896 polymorphisms is potentially associated with the risk of CL susceptibility.
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Affiliation(s)
- Minghui Zheng
- Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
| | - Weizhen Fang
- Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
| | - Menglei Yu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
- Emergency Department, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Rui Ding
- Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
| | - Hua Zeng
- Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China
| | - Yan Huang
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
- Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou, Guangdong, 510080, People's Republic of China.
| | - Yuanyang Mi
- Department of Urology, Affiliated Hospital of Jiangnan University, 1000 Hefeng Rd, Wuxi, 214000, People's Republic of China.
| | - Chaohui Duan
- Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
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Impact of interleukin IL-6 rs-1474347 and IL-10 rs-1800896 genetic polymorphisms on the susceptibility of HCV-infected Egyptian patients to hepatocellular carcinoma. Immunol Res 2021; 68:118-125. [PMID: 32504406 DOI: 10.1007/s12026-020-09126-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) is considered leading cause of cirrhosis and hepatocellular carcinoma (HCC). We aimed to examine the association of IL-6 and IL-10 single-nucleotide polymorphisms with the progression of chronic HCV (CHC) infection to cirrhosis and HCC. For comparative purposes, four groups were enrolled; chronic HCV group (CHC, n = 22), HCV-related liver cirrhosis group (HCV-LC, n = 22), HCV-related HCC group (HCV-HCC, n = 54), and an apparently healthy control group (controls, n = 48). HCC diagnosis and staging were in concordance to Barcelona Clinic Liver Cancer (BCLC) staging system. IL-6 rs-1474347 and IL-10 rs-1800896 genotyping was performed by allelic (VIC- and FAM-labeled) discrimination method using assay-on-demand TaqMan real-time PCR assays. For IL-6 rs1474347, the AA genotype was more frequent in CHC, HCV-LC, and HCV-HCC compared to controls. Also, the IL-6 rs1474347 AC genotype was favorable for the progression of HCV chronic infection to cirrhosis and HCC. On the other hand, the IL-10 rs1800896 TT genotype was found to be prominent in the HCC group. Additionally, the IL-10 rs180096 TT genotype was favorable for the progression of chronic HCV infection to cirrhosis and HCC. Furthermore, higher levels of AFP were observed in HCC patients with IL-6 rs1474347 AA genotype and HCC patients with IL-10 rs1800896 CC and TT genotypes. Screening for IL-6 rs 1474347 AC genotype and IL-10 rs180096 TT genotype as well as the determination of AFP level showed to be good markers for examining the susceptibility of HCV Egyptian patients to develop cirrhosis and HCC.
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Harun-Or-Roshid M, Ali MB, Mollah MNH. Statistical meta-analysis to investigate the association between the Interleukin-6 (IL-6) gene polymorphisms and cancer risk. PLoS One 2021; 16:e0247055. [PMID: 33684135 PMCID: PMC7939379 DOI: 10.1371/journal.pone.0247055] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 01/30/2021] [Indexed: 01/18/2023] Open
Abstract
A good number of genome-wide association studies (GWAS), including meta-analyses, reported that single nucleotide polymorphisms (SNPs) of the IL-6 gene are significantly associated with various types of cancer risks, though some other studies reported insignificant association with cancers, in the literature. These contradictory results may be due to variations in sample sizes and/or deficiency of statistical modeling. Therefore, an attempt is made to provide a more comprehensive understanding of the association between the IL-6 gene SNPs (rs1800795, rs1800796, rs1800797) and different cancer risks, giving the weight on a large sample size, including different cancer types and appropriate statistical modeling with the meta-dataset. In order to attain a more reliable consensus decision about the association between the IL-6 gene polymorphisms and different cancer risks, in this study, we performed a multi-case statistical meta-analysis based on the collected information of 118 GWAS studies comprising of 50053 cases and 65204 control samples. Results from this Meta-analysis indicated a significant association (p-value < 0.05) of the IL-6 gene rs1800796 polymorphism with an overall increased cancer risk. The subgroup analysis data based on cancer types exhibited significant association (p-value < 0.05) of the rs1800795 polymorphism with an overall increased risk of cervical, liver and prostate cancers; the rs1800796 polymorphism with lung, prostate and stomach cancers; and the rs1800797 polymorphism with cervical cancer. The subgroup analysis of ethnicity data showed a significant association (p-value < 0.05) of an overall cancer risk with the rs1800795 polymorphism for the African and Asian populations, the rs1800796 polymorphism for the Asian only and the rs1800797 polymorphism in the African population. Comparative discussion showed that our multi-case meta-analyses received more support than any previously reported individual meta-analysis about the association between the IL-6 gene polymorphisms and cancer risks. Results from this study, more confidently showed that the IL-6 gene SNPs (rs1800795, rs1800796 and rs1800797) in humans are associated with increased cancer risks. Therefore, these three polymorphisms of the IL-6 gene have the potential to be evaluated as a population based rapid, low-cost PCR prognostic biomarkers for different types of cancers diagnosis and research.
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Affiliation(s)
- Md. Harun-Or-Roshid
- Bioinformatics Laboratory, Department of Statistics, University of Rajshahi, Rajshahi, Bangladesh
| | - Md. Borqat Ali
- Bioinformatics Laboratory, Department of Statistics, University of Rajshahi, Rajshahi, Bangladesh
| | - Md. Nurul Haque Mollah
- Bioinformatics Laboratory, Department of Statistics, University of Rajshahi, Rajshahi, Bangladesh
- * E-mail: (MNHM); (J)
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Association between interleukin 6 polymorphisms (rs1800796, rs1800795, rs2069837, rs17147230, and rs1800797) and hepatocellular carcinoma susceptibility: a meta-analysis. Clin Exp Hepatol 2020; 6:359-366. [PMID: 33511285 PMCID: PMC7816640 DOI: 10.5114/ceh.2020.102171] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 09/26/2020] [Indexed: 12/22/2022] Open
Abstract
Aim of the study We reported the association between interleukin 6 polymorphisms (rs1800796, rs1800795, rs2069837, rs17147230, and rs1800797) and hepatocellular carcinoma (HCC) susceptibility in a meta-analysis. Material and methods The studies were retrieved by searching the search terms in Scopus, PubMed, Web of Science, and Cochrane Library databases until June 2020. The analyses were done by RevMan 5.3 software using odds ratios (ORs) and 95% confidence intervals (CIs) and the analysis of publication bias and sensitivity analyses were performed by CMA 2.0 software. Results Searching through the databases, 316 records were retrieved and finally 13 studies were analyzed in the present meta-analysis. For the rs1800797 polymorphism, there was an elevated risk of AA genotype (OR = 2.68, p = 0.03) in HCC patients compared to healthy controls. Also, there was an elevated risk of AA (OR = 3.06, p = 0.04) and GA (OR = 2.61, p = 0.005) genotypes in HCC patients compared to liver cirrhosis patients. For rs2069837 polymorphism, there was an elevated risk of GG genotype (OR = 2.25, p = 0.01) in HCC patients compared to healthy controls. For rs17147230, T allele (OR = 1.31, p = 0.03) and TT genotype (OR = 1.83, p = 0.02) had elevated risks in HCC patients compared to healthy controls. Conclusions The present meta-analysis confirmed that there was an elevated risk of the AA and GA genotypes of rs1800797 polymorphism and the GG genotype of rs2069837, and the T allele and TT genotype of rs17147230 in HCC.
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An PP, Feng LN, Zhang XX, Jin QL. Association of interleukin-6 gene polymorphisms with the risk of hepatocellular carcinoma: An up-to-date meta-analysis. Medicine (Baltimore) 2020; 99:e23659. [PMID: 33327352 PMCID: PMC7738155 DOI: 10.1097/md.0000000000023659] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND This study was aimed to evaluate the association between interleukin-6 (IL-6) gene polymorphisms and the risk of hepatocellular carcinoma (HCC) in a meta-analysis. METHODS A literature search was performed for case-control studies published during May, 1993 to May, 2020 focusing on IL-6 gene polymorphisms (-174G > C, -572G > C, and -597G > A) and HCC susceptibility by using PubMed, Cochrane Database, EMBASE, Web of science, and China National Knowledge Infrastructure. From 128 full-text articles, 11 were included in this meta-analysis. I index was used to assess heterogeneity and Newcastle-Ottawa Scale was utilized for quality assessment. RESULTS For IL-6 -174G > C polymorphism, in codominant (GG vs CC: odds ratios [OR] = 2.78, 95% confidence intervals [CI] = 1.25-6.19, P = .01, I = 16%) and recessive (GG+GC vs CC: OR = 2.76, 95% CI = 1.29-5.90, P = .009, I = 3%) models, IL-6 -174G>C polymorphism was significantly associated with the risk of HCC. In dominant (GG vs CC+GC: OR = 1.80, 95% CI = 0.92-3.54, P = .09, I = 86%) and allele (G vs C: OR = 1.49, 95% CI = 0.95-2.32, P = .08, I = 68%) models, IL-6 -174G>C polymorphism had no impact on the risk of HCC. However, in non-Italian Caucasian population, IL-6 -174G>C polymorphism was significantly related to the occurrence of HCC in both dominant (GG vs CC+GC: OR = 3.26, 95% CI = 2.29-4.65, P < .00001, I = 0%) and allele (G vs C: OR = 2.48, 95% CI = 1.48-4.15, P = .0006) models. Such correlations also could be observed when healthy individuals were selected as controls. For IL-6 -572G>C and -597G>A polymorphisms, no significant association was observed in all models, regardless of the source of control and population subgroups. No publication bias could be calculated when Begg and Egger tests were employed. CONCLUSION This meta-analysis indicated that IL-6 -174G>C polymorphism was significantly related with the risk for HCC, especially in non-Italian Caucasian population. No significant association was observed for the correlation between IL-6 -572G>C and -597G>A polymorphisms and HCC susceptibility.
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Affiliation(s)
| | - Li-Na Feng
- Department of Hepatology, the First Hospital of Jilin University, Changchun, Jilin province, China
| | - Xiao-Xue Zhang
- Department of Hepatology, the First Hospital of Jilin University, Changchun, Jilin province, China
| | - Qing-Long Jin
- Department of Hepatology, the First Hospital of Jilin University, Changchun, Jilin province, China
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12
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Gomes Dos Santos A, Watanabe EH, Ferreira DT, Oliveira J, Nakanishi ÉS, Oliveira CS, Bocchi E, Novaes CTG, Cruz F, Carvalho NB, Sato PK, Yamashiro-Kanashiro EH, Pontillo A, de Freitas VLT, Onuchic LF, Shikanai-Yasuda MA. A Specific IL6 Polymorphic Genotype Modulates the Risk of Trypanosoma cruzi Parasitemia While IL18, IL17A, and IL1B Variant Profiles and HIV Infection Protect Against Cardiomyopathy in Chagas Disease. Front Immunol 2020; 11:521409. [PMID: 33193300 PMCID: PMC7642879 DOI: 10.3389/fimmu.2020.521409] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 09/24/2020] [Indexed: 12/13/2022] Open
Abstract
Background Chagas disease caused by Trypanosoma cruzi (T. cruzi) affects approximately six million individuals worldwide. Clinical manifestations are expected to occur due to the parasite persistence and host immune response. Herein we investigated potential associations between IL1B, IL6, IL17A, or IL18 polymorphism profiles and cardiomyopathy or T. cruzi parasitemia, as well as the impact of HIV infection on cardiopathy. Methods Two hundred twenty-six patients and 90 control individuals were analyzed. IL1B rs1143627 T>C, IL6 rs1800795 C>G, IL17A rs2275913 G>A, IL18 rs187238 C>G, and IL18 rs1946518 C>A SNVs were analyzed by real-time PCR and T. cruzi parasitemia by PCR. Results Our data revealed association between a cytokine gene polymorphism and parasitemia never previously reported. The IL6 rs1800795 CG genotype lowered the risk of positive parasitemia (OR = 0.45, 95% CI 0.24–0.86, P = 0.015). Original findings included associations between IL17A rs2275913 AA and IL18 s1946518 AA genotypes with decreased risk of developing cardiomyopathy (OR = 0.27, 95% CI 0.07–0.97, P = 0.044; and OR = 0.35, 95% CI 0.14–0.87, P = 0.023, respectively). IL18 rs1946518 AA and IL1B rs1143627 TC were associated with reduced risk for cardiomyopathy severity, including NYHA (New York Heart Association) class ≥ 2 (OR = 0.21, 95% CI 0.06–0.68, P = 0.009; and OR = 0.48, 95% CI 0.24–0.95, P = 0.036, respectively) and LVEF (left ventricular ejection fraction) <45% for IL18 rs1946518 AA (OR = 0.22, 95% CI 0.05–0.89, P = 0.034). A novel, unexpected protective effect of HIV infection against development/progression of cardiomyopathy was identified, based on a lower risk of developing cardiopathy (OR = 0.48, 95% CI 0.23–0.96, P = 0.039), NYHA class ≥ 2 (OR = 0.15, 95% CI 0.06–0.39, P < 0.001), and LVEF < 45% (OR = 0.03, 95% CI 0.00–0.25, P = 0.001). Digestive involvement was negatively associated with NYHA ≥ 2 and LVEF < 45% (OR = 0.20, 95% CI 0.09–0.47, P < 0.001; and OR = 0.24, 95% CI 0.09–0.62, P = 0.004, respectively). Conclusions Our data support a protective role of IL17A AA, IL18 AA, and IL1B TC genotypes against development/progression of cardiomyopathy and a modulatory effect of the IL6 CG genotype on the risk of parasitemia in Chagas disease. Notably, HIV infection was shown to protect against development/progression of cardiopathy, potentially associated with a synergistic effect of HIV and highly active antiretroviral therapy (HAART), attenuating a Th1-mediated response in the myocardium. This proposed hypothesis requires confirmation, however, in larger and more comprehensive future studies.
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Affiliation(s)
- Alexandra Gomes Dos Santos
- Department of Infectious and Parasitic Diseases, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Elieser Hitoshi Watanabe
- Department of Medicine, Divisions of Molecular Medicine and Nephrology, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Daiane Tomomi Ferreira
- Laboratory of Immunology (LIM 48), Hospital das Clínicas, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Jamille Oliveira
- Department of Infectious and Parasitic Diseases, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Érika Shimoda Nakanishi
- Laboratory of Immunology (LIM 48), Hospital das Clínicas, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Claudia Silva Oliveira
- Department of Infectious and Parasitic Diseases, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Edimar Bocchi
- Heart Institute, Hospital das Clínicas, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | | | - Fatima Cruz
- Heart Institute, Hospital das Clínicas, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Noemia Barbosa Carvalho
- Division of Infectious Diseases, Hospital das Clinicas, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Paula Keiko Sato
- Laboratory of Immunology (LIM 48), Hospital das Clínicas, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Edite Hatsumi Yamashiro-Kanashiro
- Laboratory of Immunology (LIM 48), Hospital das Clínicas, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil.,Instituto de Medicina Tropical, University of São Paulo, São Paulo, Brazil
| | - Alessandra Pontillo
- Departament of Immunology, Instituto de Ciências Biomédicas (ICB), University of São Paulo, São Paulo, Brazil
| | - Vera Lucia Teixeira de Freitas
- Department of Infectious and Parasitic Diseases, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil.,Laboratory of Immunology (LIM 48), Hospital das Clínicas, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Luiz Fernando Onuchic
- Department of Medicine, Divisions of Molecular Medicine and Nephrology, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
| | - Maria Aparecida Shikanai-Yasuda
- Department of Infectious and Parasitic Diseases, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil.,Laboratory of Immunology (LIM 48), Hospital das Clínicas, Faculdade de Medicina, University of São Paulo, São Paulo, Brazil
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13
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Ali YBM, Moussa SG, Shahen SM, Dewir MA, El-Sayed IH. Association between interleukin-6 gene polymorphism and iron regulation in hemodialysis patients infected with HCV. ACTA ACUST UNITED AC 2020; 42:437-447. [PMID: 32720970 PMCID: PMC7860661 DOI: 10.1590/2175-8239-jbn-2019-0188] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 05/12/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUNDS Hepcidin is related to the pathogenesis of chronic renal failure anemia, which is considered a chronic inflammatory state as well as HCV infection. IL-6 stimulates the release of hepcidin from the liver, suppresses intestinal iron uptake, and releases iron from internal stores. METHOD To detect the association between IL-6 gene polymorphism and anemia markers, 80 hemodialysis (HD) patients [40 negative HCV HD patients and 40 positive HCV HD patients] were studied by routine chemistry and complete blood count, in addition to the assessment of serum hepcidin, iron parameters [serum iron and serum ferritin], and hepatitis C markers. IL-6 polymorphism -174G/C was determined by MS-PCR, while IL-6 polymorphisms -597G/A and -572 G/C were detected by PCR-SSP. RESULTS Hepcidin was non-significantly elevated in HCV-positive compared with HCV-negative hemodialysis patients. A statistically significant difference was detected between the negative and positive HCV HD patients in frequencies of IL-6 -174 G/C and -597 G/A (P≤ 0.01 and P≤ 0.001, respectively). On the other hand, a non-significant difference was reported between negative and positive HCV HD patients in the frequencies of IL-6 -572 G/C. CONCLUSIONS Our study indicated that IL-6 -174 G/C and -597 G/A polymorphisms may play a role in HCV susceptibility in HD patients. Additional prospective studies on a larger population are needed to confirm our findings.
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Affiliation(s)
- Yasser B M Ali
- University of Sadat City, Genetic Engineering and Biotechnology Research Institute (GEBR), Molecular Biology Department, Sadat City, Egypt
| | - Saad G Moussa
- University of Sadat City, Genetic Engineering and Biotechnology Research Institute (GEBR), Molecular Biology Department, Sadat City, Egypt
| | - Samar M Shahen
- University of Sadat City, Genetic Engineering and Biotechnology Research Institute (GEBR), Molecular Biology Department, Sadat City, Egypt
| | - Mohammed A Dewir
- Desouk General Hospital, Hemodialysis Unit, Kafr El-Sheikh, Egypt
| | - Ibrahim H El-Sayed
- Kafr El-Sheikh University, Faulty of Science, Biochemistry Department, Kafr El-Sheikh, Egypt
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14
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Abstract
BACKGROUND Several studies have explored the associations between interleukin-6 (IL-6) gene polymorphisms and the susceptibility to liver diseases, however, results remain ambiguous. The goal of this study was to conduct a meta-analysis to provide more credible evidence. METHODS Studies identified in the PubMed, Cochrane Library, and EMBASE databases were used to perform a meta-analysis via the STATA software. Pooled odds ratios (OR) were calculated under fixed- and random-effects models to estimate the potential genetic associations. RESULTS Twenty-five case-control studies involving 5813 cases and 5298 controls were included in this meta-analysis. Overall, the pooled results suggested that rs1800795 polymorphism was significantly associated with the risk of liver diseases in heterozygote (GC vs CC; OR = 1.57) and dominant (GG+GC vs CC: OR = 1.47) models; rs1800796 polymorphism was significantly associated with the susceptibility to liver diseases in heterozygote (GG vs GC; OR = 0.58) and recessive (GG vs GC+CC: OR = 0.68) models; rs1800797 polymorphism was significantly associated with genetic predisposition to liver diseases in homozygote (GG vs AA: OR = 1.63), heterozygote (GA vs AA; OR = 1.53) and dominant (GG + GA vs AA: OR = 1.61) models. A similar conclusion was found in the HBV, HCV, HCC, NASH and alcoholic liver disease of all ethnic populations for rs1800795; HBV and Asian subgroups for rs1800796; HCV and non-Asian subgroups for rs1800797. However, IL-6 rs2069837 and rs2066992 polymorphisms did not exhibit significant associations with the risk of liver diseases under any genetic models. CONCLUSION This meta-analysis suggests that patients carrying G (rs1800795), C (rs1800796) or G (rs1800797) allele or genotypes of IL-6 may be more likely to suffer from liver diseases, which was ethnic-dependent.
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Affiliation(s)
- Xuehan Wang
- Department of Bio-medicine, Beijing City University, Beijing
| | - Zhenghui Yan
- Department of Bio-medicine, Beijing City University, Beijing
| | - Qingjian Ye
- Department of Gynecology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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15
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Zhou L, Zheng Y, Tian T, Liu K, Wang M, Lin S, Deng Y, Dai C, Xu P, Hao Q, Kang H, Dai Z. Associations of interleukin-6 gene polymorphisms with cancer risk: Evidence based on 49,408 cancer cases and 61,790 controls. Gene 2018; 670:136-147. [PMID: 29842912 DOI: 10.1016/j.gene.2018.05.104] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 05/03/2018] [Accepted: 05/25/2018] [Indexed: 12/11/2022]
Abstract
Many molecular epidemiologic studies have shown that interleukin-6 (IL-6) polymorphisms are significantly associated with susceptibility for various cancers. However, the conclusions of these studies are inconsistent. The purpose of the present study was to explore the association between three common IL-6 loci (rs1800795, rs1800796, and rs1800797) and the risk for various cancers. We systematically searched the PubMed, Web of Science, Wanfang and China national knowledge infrastructure (CNKI) databases for relevant publications and obtained 108 eligible studies, involving 49,408 cancer patients and 61,790 cancer-free controls. Odds ratio (OR), 95% confidence interval (CI), and false positive reporting probability (FPRP) were used to evaluate cancer risk. All statistical analyses were performed using the R software meta package. We observed a non-significant association between rs1800795 and overall cancer risk, while rs1800797 was found to have a false positive association with overall risk of cancer. Subgroup analyses of rs1800797 also suggested non-significant association and rs1800795 played a protective role in liver cancer. Rs1800796 was found to be associated with overall cancer risk, particularly in Asian patients and those with prostate cancer. These findings provide evidence that IL-6 polymorphisms may affect cancer risk.
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Affiliation(s)
- Linghui Zhou
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Yi Zheng
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Tian Tian
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Kang Liu
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Meng Wang
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Shuai Lin
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Yujiao Deng
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Cong Dai
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Peng Xu
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Qian Hao
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Huafeng Kang
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
| | - Zhijun Dai
- Department of Oncology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
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16
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Lu H, Han M, Yuan X, Tursun K, Zhang Y, Li Y, Li Z, Feng S, Zhou L, Pan Z, Wang Q, Han K, Liu S, Cheng J. Role of IL-6-mediated expression of NS5ATP9 in autophagy of liver cancer cells. J Cell Physiol 2018; 233:9312-9319. [PMID: 29227529 DOI: 10.1002/jcp.26343] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 11/21/2017] [Accepted: 11/29/2017] [Indexed: 12/21/2022]
Abstract
This study aimed to investigate the relationship between interleukin-6 (IL-6) and NS5ATP9 in autophagy of liver cancer cells. Autophagy is one of the important regulators of the replication of hepatitis C virus and the survival of tumors. IL-6 is a multifunctional cytokine that plays an important role in autophagy and development of many kinds of tumors. However, the role of IL-6 in autophagy has not been fully explored. A previous study had shown that a novel gene, NS5ATP9, could modulate autophagy. The present study demonstrated that human IL-6 recombinant protein induced autophagy of HepG2 cells. Conversely, autophagy decreased after IL-6 was silenced or neutralized with monoclonal antibody against human IL-6. In addition, NS5ATP9 was upregulated by IL-6 via nuclear factor-kappaB activation, as detected by Western blot. Further studies indicated that the induction of autophagy by IL-6 could be attenuated by silencing NS5ATP9. Interestingly, the expression of NS5ATP9, in turn, resulted in the upregulation of IL-6. In conclusion, IL-6 could induce autophagy by expressing NS5ATP9, while NS5ATP9 upregulated IL-6 levels in turn, which further induced autophagy.
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Affiliation(s)
- Hongping Lu
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Ming Han
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.,Peking University Ditan Teaching Hospital, Beijing, China
| | - Xiaoxue Yuan
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Kelbinur Tursun
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.,The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Yu Zhang
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Yaru Li
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Zhongshu Li
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Shenghu Feng
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.,Peking University Ditan Teaching Hospital, Beijing, China
| | - Li Zhou
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.,Peking University Ditan Teaching Hospital, Beijing, China
| | - Zhipeng Pan
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.,Dalian University, Dalian, China
| | - Qi Wang
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Kai Han
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Shunai Liu
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China
| | - Jun Cheng
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.,Peking University Ditan Teaching Hospital, Beijing, China
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17
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Influence of the IL6 − 147C/G polymorphism on clinical characteristics of chronic hepatitis C in Brazilian patients. GENE REPORTS 2017. [DOI: 10.1016/j.genrep.2017.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Motawi T, Shaker OG, Hussein RM, Houssen M. Polymorphisms of α1-antitrypsin and Interleukin-6 genes and the progression of hepatic cirrhosis in patients with a hepatitis C virus infection. Balkan J Med Genet 2017; 19:35-44. [PMID: 28289587 PMCID: PMC5343329 DOI: 10.1515/bjmg-2016-0034] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Hepatitis C virus (HCV) infection represents a serious health problem. The –174 G/C mutation in the pro inflammatory cytokine interleukin-6 (IL-6) is associated with developing liver diseases. Likewise, the S and Z mutations in the serine protease inhibitor α1-antitrypsin (A1AT) are associated with pulmonary emphysema and/or liver cirrhosis. We explored the distribution of the single nucleotide polymorphisms (SNPs) of IL-6 and A1AT genes in chronic HCV-infected patients and evaluated their impact on the progression of liver cirrhosis. One hundred and fifty Egyptian HCV-infected patients together with 100 healthy controls were enrolled in this study. The patient groups were subdivided into chronic hepatitis patients (n = 85) and cirrhotic patients (n = 65). The SNP of IL-6 (–174 G/C, rs1800795), A1AT Z mutation (342 Glu/Lys, rs28929474) and A1AT S mutation (264 Glu/Val, rs17580) were determined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Cirrhotic patients exhibited significantly increased frequency of the A1AT S allele compared with the controls (34.6 vs. 5.0%), while the chronic hepatitis patients showed a higher frequency of the A1AT Z allele compared with the controls (14.7 vs. 2.5%). Remarkably, IL-6 (CC genotype) was detected only in the chronic hepatitis patients. Multivariate regression analysis showed that aspartate transaminase (AST) and the S alleles of A1AT, represented as SS+MS genotypes, were significantly independent predictors for development of liver cirrhosis. We concluded that inheritance of deficient S and Z alleles of the A1AT gene but not IL-6 (–174 G/C), were associated with progressive liver diseases.
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Affiliation(s)
- T Motawi
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - O G Shaker
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - R M Hussein
- Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - M Houssen
- Department of Biochemistry, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt
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19
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Cardiac echoparameters (geometry and dimensions), interleukin 6, and anthropometric measurements in Egyptian adolescents with hepatitis C and hepatocellular carcinoma. EGYPTIAN LIVER JOURNAL 2017. [DOI: 10.1097/01.elx.0000526967.41371.51] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
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20
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Lorente L, Martín MM, Pérez-Cejas A, Barrios Y, Solé-Violán J, Ferreres J, Labarta L, Díaz C, Jiménez A. Association between Interleukin-6 Promoter Polymorphism (-174 G/C), Serum Interleukin-6 Levels and Mortality in Severe Septic Patients. Int J Mol Sci 2016; 17:ijms17111861. [PMID: 27834822 PMCID: PMC5133861 DOI: 10.3390/ijms17111861] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 11/01/2016] [Accepted: 11/04/2016] [Indexed: 12/29/2022] Open
Abstract
The association between interleukin (IL)-6 promoter polymorphism (-174 G/C), circulating IL-6 levels and mortality in septic patients has scarcely been addressed, and then only in studies of small sample size, and a direct association among them has not been previously reported. Therefore, the purpose of our study was to determine whether this association exists. An observational, prospective and multicenter study including severe septic patients was undertaken and serum IL-6 levels at severe sepsis diagnosis and IL-6 promoter polymorphism (-174 G/C) were determined. The end-point of the study was 30-day mortality. The study included 263 patients with the following genotypes of IL-6 promoter polymorphism (-174 G/C): 123 (46.8%) GG, 110 (41.8%) GC and 30 (11.4%) CC. CC homozygous patients showed lower sepsis-related organ failure assessment (SOFA) score, serum IL-6 levels and mortality at 30 days compared to those with other genotypes (GC or GG). On regression analysis, CC homozygous patients showed lower 30-day mortality than those with genotype GG (odds ratio = 0.21; 95% CI = 0.053−0.838; p = 0.03) or GC (hazard ratio = 0.28; 95% CI = 0.074−1.037; p = 0.06). The most important results of our study were that CC might be a favorable genotype in septic patients showing lower serum IL-6 levels and lower risk of death within 30 days.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, 38320 Santa Cruz de Tenerife, Spain.
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Crta Rosario s/n, 38010 Santa Cruz de Tenerife, Spain.
| | - Antonia Pérez-Cejas
- Laboratory Deparment, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, 38320 Santa Cruz de Tenerife, Spain.
| | - Ysamar Barrios
- Research Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna, 38320 Santa Cruz de Tenerife, Spain.
| | - Jordi Solé-Violán
- Intensive Care Unit, Hospital Universitario Dr. Negrín, Barranco de la Ballena s/n, 35010 Las Palmas de Gran Canaria, Spain.
| | - José Ferreres
- Intensive Care Unit, Hospital Clínico Universitario de Valencia, Avda, Blasco Ibáñez nº17, 46004 Valencia, Spain.
| | - Lorenzo Labarta
- Intensive Care Unit, Hospital San Jorge de Huesca, Avenida Martínez de Velasco nº36, 22004 Huesca, Spain.
| | - César Díaz
- Intensive Care Unit, Hospital Insular, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria, Spain.
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna-38320, 38320 Santa Cruz de Tenerife, Spain.
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Nasr MY, Ali Deeb AS, Badra G, El Sayed IH. Lack of Any Relationship Between Circulating Autoantibodies and Interleukin–6 Levels in Egyptian Patients Infected with the Hepatitis C Virus. Asian Pac J Cancer Prev 2016; 17:4977-4979. [PMID: 28032726 PMCID: PMC5454706 DOI: 10.22034/apjcp.2016.17.11.4977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Introduction: Elevated serum interleukin (IL) 6 has been reported in patients infected with the hepatitis C virus (HCV), but it remains debatable whether this influences the production of autoantibodies and the biochemical profile of HCV disease. Therefore, this current study was conducted to evaluate the relationship between IL-6 and circulating autoantibody levels in HCV positive patients. Methods: Levels of IL-6 in serum samples from 102 patients with HCV and 103 normal controls were determined by enzyme linked immunosorbent assay (ELISA). Autoantibodies were detected by immunofluorescence. Results: Levels of IL-6 were significantly higher (p=0.028) in patients infected with (HCV) compared with normal group. Autoantibodies were noted in in 43.1% of the patients; of these, 23.5% featured anti-nuclear antibodies (ANA+), 16.7% anti-smooth muscle antibodies (ASMA+), 7.8% anti-mitochondrial antibodies (AMA+), 17.6% anti-parietal cell antibodies (APCA+), 7.8% anti canalicular antibodies, and 2.9% anti reticulin antibodies (ARA+). No patients were found to be positive for anti-brush border antibodies (ABBA) or anti-ribosomal antibodies. (ARiA). No links with IL-6 levels were apparent. Conclusions: IL-6 levels are increased in patients infected with HCV disease and could influence the production of autoantibodies. However, this study did not provide evidence of a specific relationship between IL6 and circulating autoantibodies in such cases.
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Affiliation(s)
- Mohamed Y Nasr
- Molecular Biology department, Genetic Engineering and Biotechnology Research Institute, Sadat City University,Egypt.
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22
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Sghaier I, Mouelhi L, Rabia NA, Alsaleh BR, Ghazoueni E, Almawi WY, Loueslati BY. Genetic variants in IL-6 and IL-10 genes and susceptibility to hepatocellular carcinoma in HCV infected patients. Cytokine 2016; 89:62-67. [PMID: 28340949 DOI: 10.1016/j.cyto.2016.10.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 10/06/2016] [Accepted: 10/11/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC), a common primary liver malignancy, and the third leading cause of cancer-related death. The HCC risk increases with the severity of liver inflammation, and the clinical course of HCV infection depends on a balance between pro- and anti-inflammatory cytokines. The former includes interleukin (IL)-6, while the latter includes IL-10. However, the exact pathogenic mechanisms underlying IL-6 and IL-10 effects remain unclear. METHODS The present study evaluated 174 chronic HCV Tunisian patients. Polymorphisms of IL-6 (rs1880242, rs1474847, rs2069840, rs1800797, rs1800796, rs2069845, rs2069827, rs1474348, rs1800795), and IL-10 (rs1800896, rs1800871, rs1800872, rs1554286, rs1878672, rs1518111) were determined by real-time PCR. RESULTS Notable differences between chronic HCV-infected patients and HCC patients were observed for the three IL-10 SNPs; rs1800871 (-819T/C), rs1800872 (-592A/C), and rs1878672. Carriage of IL-6 rs1800796 G/G genotype, IL-6 rs1474358 C-allele, and IL-6 rs1800797 A-allele was more frequent in chronic HCV-infected patients than in HCC patients. On the other hand, IL-6 rs1474358 GG genotype had a favourable factor for HCC establishment. CONCLUSION IL-10 and IL-6 SNPs markedly influence the clinical outcomes of HCV infection. These SNPs could be used as biomarkers for early detection and molecular therapy for preventing HCC, and prognostic factors for predicting the clinical outcomes of HCC.
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Affiliation(s)
- Ikram Sghaier
- University of Tunis El Manar, Faculty of Sciences of Tunis, Laboratory of Mycology, Pathologies and Biomarkers: LR16ES05, 2092, Tunisia.
| | - Leila Mouelhi
- Charles Nicolle Hospital, Hepato-Gastro-Enterology Department, Tunis, Tunisia
| | - Noor A Rabia
- Department of Medical Biochemistry, Arabian Gulf University, Manama, Bahrain
| | - Bano R Alsaleh
- Department of Medical Biochemistry, Arabian Gulf University, Manama, Bahrain
| | | | - Wassim Y Almawi
- Department of Medical Biochemistry, Arabian Gulf University, Manama, Bahrain
| | - Besma Yacoubi Loueslati
- University of Tunis El Manar, Faculty of Sciences of Tunis, Laboratory of Mycology, Pathologies and Biomarkers: LR16ES05, 2092, Tunisia
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Dondeti MF, El-Maadawy EA, Talaat RM. Hepatitis-related hepatocellular carcinoma: Insights into cytokine gene polymorphisms. World J Gastroenterol 2016; 22:6800-6816. [PMID: 27570418 PMCID: PMC4974580 DOI: 10.3748/wjg.v22.i30.6800] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 06/11/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer, which is one of the most prevalent cancers among humans. Many factors are involved in the liver carcinogenesis as lifestyle and environmental factors. Hepatitis virus infections are now recognized as the chief etiology of HCC; however, the precise mechanism is still enigmatic till now. The inflammation triggered by the cytokine-mediated immune response, was reported to be the closest factor of HCC development. Cytokines are immunoregulatory proteins produced by immune cells, functioning as orchestrators of the immune response. Genes of cytokines and their receptors are known to be polymorphic, which give rise to variations in their genes. These variations have a great impact on the expression levels of the secreted cytokines. Therefore, cytokine gene polymorphisms are involved in the molecular mechanisms of several diseases. This piece of work aims to shed much light on the role of cytokine gene polymorphisms as genetic host factor in hepatitis related HCC.
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Mathew S, Abdel-Hafiz H, Raza A, Fatima K, Qadri I. Host nucleotide polymorphism in hepatitis B virus-associated hepatocellular carcinoma. World J Hepatol 2016; 8:485-498. [PMID: 27057306 PMCID: PMC4820640 DOI: 10.4254/wjh.v8.i10.485] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Revised: 12/04/2015] [Accepted: 03/07/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is etiologically linked with hepatitis B virus (HBV) and is the leading cause of death amongst 80% of HBV patients. Among HBV affected patients, genetic factors are also involved in modifying the risk factors of HCC. However, the genetic factors that regulate progression to HCC still remain to be determined. In this review, we discuss several single nucleotide polymorphisms (SNPs) which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection such as cyclooxygenase (COX)-2 expression specifically at COX-2 -1195G/A in Chinese, Turkish and Egyptian populations, tumor necrosis factor α and the three most commonly studied SNPs: PAT-/+, Lys939Gln (A33512C, rs2228001) and Ala499Val (C21151T, rs2228000). In genome-wide association studies, strong associations have also been found at loci 1p36.22, 11q22.3, 6p21 (rs1419881, rs3997872, rs7453920 and rs7768538), 8p12 (rs2275959 and rs37821974) and 22q11.21. The genes implicated in these studies include HLA-DQB2, HLA-DQA1, TCF19, HLA-C, UBE2L3, LTL, FDX1, MICA, UBE4B and PG. The SNPs found to be associated with the above-mentioned genes still require validation in association studies in order to be considered good prognostic candidates for HCC. Screening of these polymorphisms is very beneficial in clinical experiments to stratify the higher or lower risk for HCC and may help in designing effective and efficient HCC surveillance programs for chronic HBV-infected patients if further genetic vulnerabilities are detected.
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Affiliation(s)
- Shilu Mathew
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Hany Abdel-Hafiz
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Abbas Raza
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Kaneez Fatima
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
| | - Ishtiaq Qadri
- Shilu Mathew, Center of Excellence in Genomic Medicine Research, King Abdul Aziz University, Jeddah 21589, Saudi Arabia
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25
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Significance of Interleukin-6 in Papillary Thyroid Carcinoma. J Thyroid Res 2016; 2016:6178921. [PMID: 27034885 PMCID: PMC4808558 DOI: 10.1155/2016/6178921] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 02/17/2016] [Indexed: 12/18/2022] Open
Abstract
This study sought to reveal the significance of IL-6 in papillary thyroid carcinoma by determining its circulating levels, tumoral protein, and mRNA expressions. As compared to the healthy individuals, serum IL-6 was significantly higher in patients with benign thyroid diseases and PTC. Further, its level was significantly higher in PTC patients as compared to patients with benign thyroid diseases. ROC curves also confirmed a good discriminatory efficacy of serum IL-6 between healthy individuals and patients with benign thyroid diseases and PTC. The circulating IL-6 was significantly associated with poor overall survival in PTC patients. IL-6 immunoreactivity was significantly high in PTC patients as compared to the benign thyroid disease patients. Significantly higher IL-6 mRNA expression was also observed in the primary tumour tissues of PTC patients than the adjacent normal tissues. The protein expression of IL-6 at both the circulating and tissue level correlated with disease aggressiveness in PTC patients. Moreover, a significant positive correlation was observed between the IL-6 protein and mRNA expression in the primary tumours of PTC patients. Finally in conclusion, IL-6 has an important role in thyroid cancer progression. Thus targeting IL-6 signalling can help in clinical management of thyroid carcinoma patients.
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Circulating interleukin-6 and cancer: A meta-analysis using Mendelian randomization. Sci Rep 2015; 5:11394. [PMID: 26096712 PMCID: PMC4476043 DOI: 10.1038/srep11394] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 05/19/2015] [Indexed: 12/14/2022] Open
Abstract
Interleukin-6 (IL-6) plays a contributory role in the progression and severity of many forms of cancer; it however remains unclear whether the relevance between circulating IL-6 and cancer is causal. We therefore meta-analyzed published articles in this regard using IL-6 gene -174G/C variant as an instrument. Seventy-eight and six articles were eligible for the association of -174G/C variant with cancer and circulating IL-6, respectively. Overall analyses failed to identify any significance between -174G/C and cancer risk. In Asians, carriers of the -174CC genotype had an 1.95-fold increased cancer risk compared with the -174GG genotype carriers (P = 0.009). By cancer type, significance was only attained for liver cancer with the -174C allele conferring a reduced risk under allelic (odds ratio or OR = 0.74; P = 0.001), homozygous genotypic (OR = 0.59; P = 0.029) and dominant (OR = 0.67; P = 0.004) models. Carriers of the -174CC genotype (weighted mean difference or WMD = −4.23 pg/mL; P < 0.001) and -174C allele (WMD = −3.43 pg/mL; P < 0.001) had circulating IL-6 reduced significantly compared with the non-carriers. In further Mendelian randomization analysis, a reduction of 1 pg/mL in circulating IL-6 was significantly associated with an 12% reduced risk of liver cancer. Long-term genetically-reduced circulating IL-6 might be causally associated with a lower risk of liver cancer.
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27
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Bei CH, Bai H, Yu HP, Yang Y, Liang QQ, Deng YY, Tan SK, Qiu XQ. Combined effects of six cytokine gene polymorphisms and SNP-SNP interactions on hepatocellular carcinoma risk in Southern Guangxi, China. Asian Pac J Cancer Prev 2015; 15:6961-7. [PMID: 25169554 DOI: 10.7314/apjcp.2014.15.16.6961] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Cytokine gene single nucleotide polymorphisms (SNPs) are involved in the genesis and progression of hepatocellular carcinoma (HCC). We hypothesized that combined effects of cytokine gene SNPs and SNP-SNP interactions are associated with HCC risk. Six SNPs in cytokine genes (IL-2, IFN-γ, IL-1β, IL-6, and IL-10) were genotyped in a study of 720 Chinese HCC cases and 784 cancer-free controls. Although none of these SNPs individually had a significant effect on the risk of HCC, we found that the combined effects of these six SNPs may contribute to HCC risk (OR=1.821, 95% CI=1.078-3.075). This risk was pronounced among smokers, drinkers, and hepatitis B virus carriers. A SNP-SNP interaction between IL-2-330 and IFN-γ-1615 was associated with an increased HCC risk (OR=1.078, 95% CI=1.022-1.136). In conclusion, combined effects of SNPs and SNP-SNP interactions in cytokine genes may contribute to HCC risk.
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Affiliation(s)
- Chun-Hua Bei
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China E-mail :
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Cho HJ, Kim SS, Ahn SJ, Park SY, Park JH, Kim JK, Wang HJ, Cheong JY, Cho SW. Low serum interleukin-6 levels as a predictive marker of recurrence in patients with hepatitis B virus related hepatocellular carcinoma who underwent curative treatment. Cytokine 2015; 73:245-52. [PMID: 25797190 DOI: 10.1016/j.cyto.2015.02.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 02/25/2015] [Accepted: 02/27/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND We aimed to investigate the use of novel serum biomarkers for predicting the recurrence and survival of patients with hepatitis B virus (HBV)-related early hepatocellular carcinoma (HCC) after hepatic resection or radiofrequency ablation (RFA). METHODS One hundred and five patients with HBV-related HCC, who fulfilled the Milan criteria without vascular invasion and underwent hepatic resection or RFA, were followed-up for a median duration of 52months. Pretreatment serum concentrations of 16 cytokines including interleukin-6 (IL-6) were measured by using a Luminex 200 system. The measured serum cytokines and several clinical factors were analyzed retrospectively. RESULTS Univariate analysis showed that patients with lower pretreatment serum levels of IL-10, IL-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α had significantly shorter disease-free survival (DFS) than those with higher levels. Multivariate analysis revealed that a low serum IL-6 level (⩽33.00pg/mL; hazard ratio [HR]=5.39; 95% confidence interval [CI]=1.27-22.93; P=0.022), low platelet count (<100×10(9)/L; HR=2.23; 95% CI=1.28-3.89; P=0.005), and low serum albumin level (⩽3.5g/L; HR=2.26; 95% CI=1.28-3.97; P=0.005) had a negative prognostic impact on DFS. In the analysis for overall survival, a low serum platelet level (<100×10(9)/L; HR=2.80; 95% CI=1.31-5.99; P=0.008) and multiple tumor (⩾2; HR=4.05; 95% CI=1.56-10.48; P=0.004) showed a negative prognostic impact on the overall survival. CONCLUSION A low serum IL-6 level is, in addition to low platelet count and low serum albumin level, an independent prognostic factor for DFS in patients with HBV-related early HCC who underwent hepatic resection or RFA with curative intention.
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Affiliation(s)
- Hyo Jung Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Soon Sun Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Seun Joo Ahn
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Sun Young Park
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Joo Han Park
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Jae Keun Kim
- Department of Radiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hee Jung Wang
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Jae Youn Cheong
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Sung Won Cho
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea.
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Hamzawy M, Elsaid L, Shams A, Rashid L, Mahfouz S, Sharawy N. Study of the effects of cyclooxygenase-2 inhibitor on the promotion of hepatic tumorigenesis in rats fed a high fat diet. J Clin Exp Hepatol 2015; 5:14-21. [PMID: 25941430 PMCID: PMC4415194 DOI: 10.1016/j.jceh.2014.12.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 12/31/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/OBJECTIVE Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The highest prevalence of hepatitis is an important risk factor contributing to development of HCCs. However, an increasing number of cases are associated metabolic disease and steatohepatitis. Inflammation associated with many liver disease, seems to be a necessary pre-requisite for successful tumor initiation. Mechanisms that link high fat diet and inflammation initial stage of HCC are not completely understood. The present work was designed to investigate the effect of fat, through modulation of the insulin-like growth factors I and II (IGF-I and IGF-II), on the promotion of hepatocellular carcinoma, and the role of cyclooxygenase 2 (COX-2). METHODS two main groups of rats were used: control and HCC groups. The HCC group was further sub-divide in to two subgroups, HCC fed with standard diet and HCC fed with high fat diet. The effects of celecoxib were also investigated in HCC fed with high fat diet. RESULTS We found that high fat diet was associated with significant increases in COX2 and interleukin 6 (IL6) with significant promotion of HCC progression. The significant increase in IGF could contribute partially to the observed effects of high fat diet. In addition, celecoxib was found to significantly reduce HCC progression. CONCLUSIONS We conclude that COX2 could play central role in high prevalence of HCC observed with high fat diet. Several triggering factors such as IGF and IL6, together with the direct modulation of fat metabolism could open several novel preventive strategies of celecoxib treatment, and could be useful biomarkers for assessment of its pharmacological effects.
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Key Words
- AFP, alpha-fetoprotein
- CCl4, carbon-tetrachloride
- COX-2, cyclooxygenase 2
- FAS, fatty acid synthase
- FFA, free fatty acid
- GH, growth hormone
- H&E, Hematoxylin and Eosin stain
- HCC, hepatocellular carcinoma
- IGF
- IGF-I and IGF-II, insulin-like growth factors I and II
- IGFBP-3, insulin-like growth factor-binding protein 3
- IGFR, IGF receptor
- IL6, interleukin 6
- IκB, inhibitory protein
- JNK1, c-Jun N-terminal kinase-1
- MAPK, mitogen-activated protein kinase
- NFκB, nuclear factor-κB
- PAS, periodic acid Schiff stain
- PI3k, phosphatidylinositide 3-kinases
- TAG, triaceyl glycerol
- celecoxib
- fat diet
- hepatocellular carcinoma
- real time-PCR, real time-polymerase chain reaction
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Affiliation(s)
- Magda Hamzawy
- Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
- Address for correspondence: Nivin Sharawy, Kasr El-Aini, Cairo University, Al-Saray Street, 11562 Cairo, Egypt. Tel.: +202 01122433182; fax: +202 23628246.
| | - Laila Elsaid
- Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Asmaa Shams
- Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Laila Rashid
- Department of Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Soheir Mahfouz
- Department of Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Nivin Sharawy
- Department of Physiology, Faculty of Medicine, Cairo University, Cairo, Egypt
- Address for correspondence: Nivin Sharawy, Kasr El-Aini, Cairo University, Al-Saray Street, 11562 Cairo, Egypt. Tel.: +202 01122433182; fax: +202 23628246.
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Ding ZY, Wei YQ. Immunopathology of Hepatobiliary Tumors and Immunotherapy of Liver Cancers. CANCER IMMUNOLOGY 2015:199-215. [DOI: 10.1007/978-3-662-46410-6_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Su CH, Lin Y, Cai L. Genetic factors, viral infection, other factors and liver cancer: an update on current progress. Asian Pac J Cancer Prev 2014; 14:4953-60. [PMID: 24175758 DOI: 10.7314/apjcp.2013.14.9.4953] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Primary liver cancer is one of the most common cancers at the global level, accounting for half of all cancers in some undeveloped countries. This disease tends to occur in livers damaged through alcohol abuse, or chronic infection with hepatitis B and C, on a background of cirrhosis. Various cancer-causing substances are associated with primary liver cancer, including certain pesticides and such chemicals as vinyl chloride and arsenic. The strong association between HBV infection and liver cancer is well documented in epidemiological studies. It is generally acknowledged that the virus is involved through long term chronic infection, frequently associated with cirrhosis, suggesting a nonspecific mechanism triggered by the immune response. Chronic inflammation of liver, continuous cell death, abnormal cell growth, would increase the occurrence rate of genetic alterations and risk of disease. However, the statistics indicated that only about one fifth of HBV carries would develop HCC in lifetime, suggesting that individual variation in genome would also influence the susceptibility of HCC. The goal of this review is to highlight present level of knowledge on the role of viral infection and genetic variation in the development of liver cancer.
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Affiliation(s)
- Cheng-Hao Su
- Department of Emergency Countermeasure and Information Management, Xiamen Center for Disease Control and Prevention, Xiamen, China E-mail :
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Association between polymorphisms in tumor suppressor genes and oncogenes and risk of hepatocellular carcinoma: a case-control study in an HCC epidemic area within the Han Chinese population. Med Oncol 2014; 31:356. [PMID: 25412941 DOI: 10.1007/s12032-014-0356-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 11/12/2014] [Indexed: 02/08/2023]
Abstract
Data concerning the risk of hepatocellular carcinoma (HCC) and specific single nucleotide polymorphisms (SNPs) in an HBV-free population are currently limited. Therefore, we performed a case-control study to investigate the association between SNPs and the risk of HCC in individuals without chronic HBV infection. A total of 160 Han Chinese patients with HCC and an identical number of healthy controls were enrolled in this study. rs1042522, rs10814325, rs17401966, and rs2279744 genotypes were determined using matrix-associated laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS). CG and GG genotypes in rs1042522 and heterozygote and homozygote in rs2279744 were significantly associated with an elevated risk of HCC. Homozygous mutation of rs1081432 conferred a 2.68-fold risk of HCC (95% CI 1.35-5.34); however heterozygosity was not statistically significant. rs17401966 heterozygosity or homozygosity was not significantly associated with a increased risk of HCC. Several polymorphisms associated with a significantly increased risk of HCC were identified. These may serve as biomarkers in evaluating HCC risk in the general population.
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Saxena R, Chawla YK, Verma I, Kaur J. IL-6(-572/-597) polymorphism and expression in HBV disease chronicity in an Indian population. Am J Hum Biol 2014; 26:549-555. [PMID: 24841049 DOI: 10.1002/ajhb.22562] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Revised: 02/18/2014] [Accepted: 04/27/2014] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES This study evaluated the association among IL-6(-572) and IL-6(-597) genotypes, haplotypes, mRNA, and protein levels with hepatitis B virus (HBV)-Hepatocellular carcinoma (HCC) risk in India. METHODS For this, 403 participants (153 controls, 61 inactive HBV-carriers, 65 chronic-active HBV patients, 63 HBV-cirrhotics, and 61 HBV-HCC participants) were enrolled in the study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), ELISA, and RT-PCR methods were used for assessing polymorphism, protein, and the mRNA levels, respectively, of IL-6. RESULTS The study revealed that the IL-6(-572) GC genotype shared a positive association with hepatitis among controls, and a negative association with cirrhosis and consequent HCC development among carriers. However, the CC genotype shared a significant negative association with cirrhosis among controls and carriers. The IL-6(-597G>A), GA genotype acted as a potential protective factor for hepatitis, cirrhosis, and subsequent HCC development among carriers. The GA and CG haplotypes acted as a vital risk factor for HCC among controls and carriers. On the contrary, the CA haplotype was found to be a potential protective factor for HCC among carriers. Besides, the IL-6 levels significantly increased with cirrhosis development, as compared to carriers and hepatitis subjects. CONCLUSIONS These preliminary findings indicate a potential role of IL-6(-572/-597) genotypes in HBV disease pathogenesis in an Indian population.
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Affiliation(s)
- Roli Saxena
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
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Kalmady SV, Venkatasubramanian G, Shivakumar V, Gautham S, Subramaniam A, Jose DA, Maitra A, Ravi V, Gangadhar BN. Relationship between Interleukin-6 gene polymorphism and hippocampal volume in antipsychotic-naïve schizophrenia: evidence for differential susceptibility? PLoS One 2014; 9:e96021. [PMID: 24787542 PMCID: PMC4008499 DOI: 10.1371/journal.pone.0096021] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2013] [Accepted: 04/02/2014] [Indexed: 12/29/2022] Open
Abstract
Background Various lines of evidence including epidemiological, genetic and foetal pathogenetic models suggest a compelling role for Interleukin-6 (IL-6) in the pathogenesis of schizophrenia. IL-6 mediated inflammatory response triggered by maternal infection or stress induces disruption of prenatal hippocampal development which might contribute towards psychopathology during adulthood. There is a substantial lack of knowledge on how genetic predisposition to elevated IL-6 expression effects hippocampal structure in schizophrenia patients. In this first-time study, we evaluated the relationship between functional polymorphism rs1800795 of IL-6 and hippocampal gray matter volume in antipsychotic-naïve schizophrenia patients in comparison with healthy controls. Methodology We examined antipsychotic-naïve schizophrenia patients [N = 28] in comparison with healthy controls [N = 37] group matched on age, sex and handedness. Using 3 Tesla – MRI, bilateral hippocampi were manually segmented by blinded raters with good inter-rater reliability using a valid method. Additionally, Voxel-based Morphometry (VBM) analysis was performed using hippocampal mask. The IL-6 level was measured in blood plasma using ELISA technique. SNP rs1800795 was genotyped using PCR and DNA sequencing. Psychotic symptoms were assessed using Scale for Assessment of Positive Symptoms and Scale for Assessment of Negative Symptoms. Results Schizophrenia patients had significantly deficient left and right hippocampal volumes after controlling for the potential confounding effects of age, sex and total brain volume. Plasma IL-6 levels were significantly higher in patients than controls. There was a significant diagnosis by rs1800795 genotype interaction involving both right and left hippocampal volumes. Interestingly, this effect was significant only in men but not in women. Conclusion Our first time observations suggest a significant relationship between IL-6 rs1800795 and reduced hippocampal volume in antipsychotic-naïve schizophrenia. Moreover, this relationship was antithetical in healthy controls and this effect was observed in men but not in women. Together, these observations support a “differential susceptibility” effect of rs1800795 in schizophrenia pathogenesis mediated through hippocampal volume deficit that is of possible neurodevelopmental origin.
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Affiliation(s)
- Sunil Vasu Kalmady
- The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India
- Translational Psychiatry Laboratory, Cognitive Neurobiology Division, Neurobiology Research Centre, National Institute of Mental Health and Neuro Sciences, Bangalore, India
| | - Ganesan Venkatasubramanian
- The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India
- Translational Psychiatry Laboratory, Cognitive Neurobiology Division, Neurobiology Research Centre, National Institute of Mental Health and Neuro Sciences, Bangalore, India
- * E-mail:
| | - Venkataram Shivakumar
- The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India
- Translational Psychiatry Laboratory, Cognitive Neurobiology Division, Neurobiology Research Centre, National Institute of Mental Health and Neuro Sciences, Bangalore, India
| | - S. Gautham
- Translational Psychiatry Laboratory, Cognitive Neurobiology Division, Neurobiology Research Centre, National Institute of Mental Health and Neuro Sciences, Bangalore, India
| | - Aditi Subramaniam
- The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India
- Translational Psychiatry Laboratory, Cognitive Neurobiology Division, Neurobiology Research Centre, National Institute of Mental Health and Neuro Sciences, Bangalore, India
| | - Dania Alphonse Jose
- The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India
- Translational Psychiatry Laboratory, Cognitive Neurobiology Division, Neurobiology Research Centre, National Institute of Mental Health and Neuro Sciences, Bangalore, India
| | - Arindam Maitra
- National Institute of Biomedical Genomics, Kalyani, India
| | - Vasanthapuram Ravi
- Department of Neurovirology, National Institute of Mental Health and Neuro Sciences, Bangalore, India
| | - Bangalore N. Gangadhar
- The Schizophrenia Clinic, Department of Psychiatry, National Institute of Mental Health and Neuro Sciences, Bangalore, India
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Li X, Chai W, Ni M, Xu M, Lian Z, Shi L, Bai Y, Wang Y. The effects of gene polymorphisms in interleukin-4 and interleukin-6 on the susceptibility of rheumatoid arthritis in a Chinese population. BIOMED RESEARCH INTERNATIONAL 2014; 2014:265435. [PMID: 24707478 PMCID: PMC3953475 DOI: 10.1155/2014/265435] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 12/16/2013] [Accepted: 01/09/2014] [Indexed: 01/05/2023]
Abstract
BACKGROUND Interleukin-4 (IL-4) and interleukin-6 (IL-6) have been reported to associate with pathogenesis of rheumatoid arthritis (RA); however, the role of IL-4 and IL-6 genetic polymorphisms in RA remains unknown. METHOD A total of 752 unrelated Chinese patients with RA and 798 healthy Chinese volunteers with no family histories of any autoimmune diseases were recruited. The promoter IL-4-590 C/T and IL-6-174 G/C polymorphisms were genotyped. RESULT The genotype distributions and allele frequencies of IL-4-590 C/T and IL-6-174 G/C polymorphisms in RA patients were significantly different from healthy volunteers. Statistically significant differences were observed in genotypes for IL-4-590 and IL-6-174. The frequencies of both the T allele on the IL-4-590 and the C on the IL-6-174 were significantly increased in RA patients. CONCLUSION The IL-4-590 and IL-6-174 promoter polymorphisms may be associated with increased risk of RA and could be used as genetic marker for assessing the susceptibility and severity of RA in Chinese.
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Affiliation(s)
- Xiang Li
- Department of Orthopaedics, General Hospital of Chinese People's Liberation Army, Fuxing Road No. 28, Haidian District, Beijing 100853, China
| | - Wei Chai
- Department of Orthopaedics, General Hospital of Chinese People's Liberation Army, Fuxing Road No. 28, Haidian District, Beijing 100853, China
| | - Ming Ni
- Department of Orthopaedics, General Hospital of Chinese People's Liberation Army, Fuxing Road No. 28, Haidian District, Beijing 100853, China
| | - Meng Xu
- Department of Orthopaedics, General Hospital of Chinese People's Liberation Army, Fuxing Road No. 28, Haidian District, Beijing 100853, China
| | - Zijian Lian
- Department of Orthopaedics, General Hospital of Chinese People's Liberation Army, Fuxing Road No. 28, Haidian District, Beijing 100853, China
| | - Lewis Shi
- Department of Orthopaedics, University of Chicago Hospital, Maryland Avenue, Chicago, ll 60673, USA
| | - Yang Bai
- Department of Stomatology, General Hospital of Chinese People's Liberation Army, Fuxing Road No. 28, Haidian District, Beijing 100853, China
| | - Yan Wang
- Department of Orthopaedics, General Hospital of Chinese People's Liberation Army, Fuxing Road No. 28, Haidian District, Beijing 100853, China
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Liu Y, Gao SJ, Du BX, Wang JJ. Association of IL-6 polymorphisms with hepatocellular carcinoma risk: evidences from a meta-analysis. Tumour Biol 2013; 35:3551-61. [DOI: 10.1007/s13277-013-1469-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 11/25/2013] [Indexed: 12/16/2022] Open
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Giannitrapani L, Soresi M, Balasus D, Licata A, Montalto G. Genetic association of interleukin-6 polymorphism (-174 G/C) with chronic liver diseases and hepatocellular carcinoma. World J Gastroenterol 2013; 19:2449-2455. [PMID: 23674845 PMCID: PMC3646134 DOI: 10.3748/wjg.v19.i16.2449] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2012] [Revised: 03/06/2013] [Accepted: 03/22/2013] [Indexed: 02/06/2023] Open
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine which is expressed in many inflammatory cells in response to different types of stimuli, regulating a number of biological processes. The IL-6 gene is polymorphic in both the 5' and 3' flanking regions and more than 150 single nucleotide polymorphisms have been identified so far. Genetic polymorphisms of IL-6 may affect the outcomes of several diseases, where the presence of high levels of circulating IL-6 have been correlated to the stage and/or the progression of the disease itself. The -174 G/C polymorphism is a frequent polymorphism, that is located in the upstream regulatory region of the IL-6 gene and affects IL-6 production. However, the data in the literature on the genetic association between the -174 G/C polymorphism and some specific liver diseases characterized by different etiologies are still controversial. In particular, most of the studies are quite unanimous in describing a correlation between the presence of the high-producer genotype and a worse evolution of the chronic liver disease. This is valid for patients with hepatitis C virus (HCV)-related chronic hepatitis and liver cirrhosis and hepatocellular carcinoma (HCC) whatever the etiology. Studies in hepatitis B virus-related chronic liver diseases are not conclusive, while specific populations like non alcoholic fatty liver disease/non-alcoholic steatohepatitis, autoimmune and human immunodeficiency virus/HCV co-infected patients show a higher prevalence of the low-producer genotype, probably due to the complexity of these clinical pictures. In this direction, a systematic revision of these data should shed more light on the role of this polymorphism in chronic liver diseases and HCC.
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MESH Headings
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Fatty Liver/genetics
- Fatty Liver/immunology
- Genetic Predisposition to Disease
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/immunology
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/immunology
- Hepatitis, Autoimmune/genetics
- Hepatitis, Autoimmune/immunology
- Humans
- Interleukin-6/genetics
- Liver Cirrhosis/genetics
- Liver Cirrhosis/immunology
- Liver Diseases, Alcoholic/genetics
- Liver Diseases, Alcoholic/immunology
- Liver Neoplasms/genetics
- Liver Neoplasms/immunology
- Non-alcoholic Fatty Liver Disease
- Phenotype
- Polymorphism, Single Nucleotide
- Risk Factors
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Vasakova M, Sterclova M, Kolesar L, Slavcev A, Skibova J, Langova M, Striz I. Cytokine gene polymorphisms in idiopathic pulmonary fibrosis. World J Respirol 2013; 3:1-7. [DOI: 10.5320/wjr.v3.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Revised: 04/06/2013] [Accepted: 05/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To characterize cytokine gene polymorphisms in patients with idiopathic pulmonary fibrosis (IPF) compared to healthy controls.
METHODS: Fifty-six IPF patients were involved in the study. The control population consisted of 144 healthy volunteers without history of lung disease. All of the patients were diagnosed with IPF according to the American Thoracic Society/European Respiratory Society consensus statement. Polymorphisms in the interleukin (IL)-1, IL-1, IL-1R, IL-1RA, IL-2, IL-4, IL-6, IL-10, IL-12, tumour necrosis factor, interferon, transforming growth factor, IL-1, IL-2, IL-4 and IL-4RA genes were characterized by polymerase chain reaction with sequence-specific primers. Statistical analysis was performed using the MedCalc statistical software. A Bonferroni correction of significance at an alpha of 0.05 was used for multiple analyses. A corrected P value less than 0.0023 (0.05/22) was considered significant.
RESULTS: We found significant differences in the IL-4 promoter region polymorphisms between IPF patients and controls. Namely, polymorphisms of IL-4 (-590) [computed tomography (CT) in 32 of 56 patients vs 27 of 144 controls; P < 0.0001] and IL-4 (-33) (CT in 25 of 56 patients vs 27 of 144 controls; P = 0.0006) differed between both groups. With regard to haplotypes, we found differences in the frequencies for haplotype 1 of IL-4 (-1098) (-590) (-33) between IPF and controls (TCC in 23 of 56, TTC in 10 of 56, and TTT in 21 of 56 patients vs TCC in 112 of 144, TTC in 0 of 144, and TTT in 32 of 144 controls; P < 0.0001). We did not find significant differences in gene polymorphism frequencies of other cytokines in the IPF group vs the controls.
CONCLUSION: We hypothesize that IL-4 promoter polymorphisms could be involved in the pathogenesis of IPF, likely via enhancement of the Th2 cytokine milieu with exaggerated fibroproliferative healing.
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Szkandera J, Absenger G, Dandachi N, Regitnig P, Lax S, Stotz M, Samonigg H, Renner W, Gerger A. Analysis of functional germline polymorphisms for prediction of response to anthracycline-based neoadjuvant chemotherapy in breast cancer. Mol Genet Genomics 2012; 287:755-64. [PMID: 22903472 DOI: 10.1007/s00438-012-0715-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2012] [Accepted: 08/02/2012] [Indexed: 12/20/2022]
Abstract
To elucidate the role of predictive factors on individual's drug response, based on genetic variation, we examined the association between eight germline polymorphisms in genes involved in protection against oxidative stress, apoptosis, oncogenic transformation, proliferation, immune response and DNA repair (TP53, NQO1, IL6, TLR4 and XRCC1) and the pathological response to anthracycline-based neoadjuvant chemotherapy in 70 patients with breast cancer. The DNA was genotyped for eight polymorphisms in five genes (TP53, NQO1, IL6, TLR4 and XRCC1) by 5'-exonuclease (TaqMan™) technology. Fisher's exact test was used to evaluate the association between genotype, clinicopathological parameters and pathological response. A good pathological response, defined as a pathological complete response or residual isolated invasive tumor cells, was found significantly more frequently for estrogen (ER) and progesterone receptor (PR) negative breast carcinomas compared to ER and PR positive and ER or PR positive carcinomas, respectively (43.5 vs. 37.5 and 10.3 %, p = 0.006), and was significantly associated with high tumor grade (G3) (p = 0.002). A non-significant trend towards a good pathological response was shown in patients carrying the Arg/Arg or Arg/Pro TP53 codon 72 gene variant compared to those harboring the Pro/Pro variant (17.6 or 37.9 % vs. 0; p = 0.071). No association was found between NQO1 Pro187Ser, IL6 -174G>C, TLR4 Asp299Gly and Thr399Ile, and XRCC1 Arg194Trp, Arg399Gln and Arg280His and pathological response. The present study shows hormone receptor status and tumor grade as predictors for pathological response to neoadjuvant anthracycline-based chemotherapy. Among various functional germline polymorphisms, a potential predictive value was only found for the TP53 Arg72Pro gene variant.
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Affiliation(s)
- Joanna Szkandera
- Research Unit, Genetic Epidemiology and Pharmacogenetics in Oncology, Division of Clinical Oncology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria.
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Zakharyan R, Petrek M, Arakelyan A, Mrazek F, Atshemyan S, Boyajyan A. Interleukin-6 promoter polymorphism and plasma levels in patients with schizophrenia. ACTA ACUST UNITED AC 2012; 80:136-42. [DOI: 10.1111/j.1399-0039.2012.01886.x] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Cervello M, McCubrey JA, Cusimano A, Lampiasi N, Azzolina A, Montalto G. Targeted therapy for hepatocellular carcinoma: novel agents on the horizon. Oncotarget 2012; 3:236-60. [PMID: 22470194 PMCID: PMC3359882 DOI: 10.18632/oncotarget.466] [Citation(s) in RCA: 143] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Accepted: 03/31/2012] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer, accounting for 90% of primary liver cancers. In the last decade it has become one of the most frequently occurring tumors worldwide and is also considered to be the most lethal of the cancer systems, accounting for approximately one third of all malignancies. Although the clinical diagnosis and management of early-stage HCC has improved significantly, HCC prognosis is still extremely poor. Furthermore, advanced HCC is a highly aggressive tumor with a poor or no response to common therapies. Therefore, new effective and well-tolerated therapy strategies are urgently needed. Targeted therapies have entered the field of anti-neoplastic treatment and are being used on their own or in combination with conventional chemotherapy drugs. Molecular-targeted therapy holds great promise in the treatment of HCC. A new therapeutic opportunity for advanced HCC is the use of sorafenib (Nexavar). On the basis of the recent large randomized phase III study, the Sorafenib HCC Assessment Randomized Protocol (SHARP), sorafenib has been approved by the FDA for the treatment of advanced HCC. Sorafenib showed to be able to significantly increase survival in patients with advanced HCC, establishing a new standard of care. Despite this promising breakthrough, patients with HCC still have a dismal prognosis, as it is currently the major cause of death in cirrhotic patients. Nevertheless, the successful results of the SHARP trial underscore the need for a comprehensive understanding of the molecular pathogenesis of this devastating disease. In this review we summarize the most important studies on the signaling pathways implicated in the pathogenesis of HCC, as well as the newest emerging drugs and their potential use in HCC management.
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Affiliation(s)
- Melchiorre Cervello
- Institute of Biomedicine and Molecular Immunology, "Alberto Monroy" National Research Council (C.N.R), Palermo, Italy.
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Hernaez R. Genetic factors associated with the presence and progression of nonalcoholic fatty liver disease: a narrative review. GASTROENTEROLOGIA Y HEPATOLOGIA 2011; 35:32-41. [PMID: 22093607 DOI: 10.1016/j.gastrohep.2011.08.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2011] [Accepted: 08/04/2011] [Indexed: 12/25/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Whereas insulin resistance and obesity are considered major risk factors for the development and progression of NAFLD, the genetic underpinnings are unclear. Before 2008, candidate gene studies based on prior knowledge of pathophysiology of fatty liver yielded conflicting results. In 2008, Romeo et al. published the first genome wide association study and reported the strongest genetic signal for the presence of fatty liver (PNPLA3, patatin-like phospholipase domain containing 3; rs738409). Since then, two additional genome wide scans were published and identified 9 additional genetic variants. Whereas these results shed light into the understanding of the genetics of NAFLD, most of associations have not been replicated in independent samples and, therefore, remain undetermined the significance of these findings. This review aims to summarize the understanding of genetic epidemiology of NAFLD and highlights the gaps in knowledge.
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Affiliation(s)
- Ruben Hernaez
- Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
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Lepiller Q, Tripathy MK, Di Martino V, Kantelip B, Herbein G. Increased HCMV seroprevalence in patients with hepatocellular carcinoma. Virol J 2011; 8:485. [PMID: 22032643 PMCID: PMC3224784 DOI: 10.1186/1743-422x-8-485] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2011] [Accepted: 10/27/2011] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most common primary liver cancer, usually arising after years of chronic liver inflammation that could result from viral infections such as hepatitis B virus (HBV) and hepatitic C virus (HCV) infections. Human cytomegalovirus (HCMV) infects primary human hepatocytes and remains an important cause of morbidity in immunocompromised persons where it may manifest as symptomatic end-organ disease including hepatitis. The goal of the present study was to determine a potential correlation between HCMV infection and the appearance of HCC. METHODS First, we analyzed the seroprevalence of HCMV in a cohort of 11,318 patients hospitalized between 2003 and 2009 in different departments of a French University Hospital. Second, we studied HCMV seroprevalence in a cohort of 190 subjects who were stratified on the basis of age, gender, HCC, cirrhosis (Cir), and the exposition to hepatotropic viruses (HCV, HBV). We further determined whether HCMV DNA was present specifically in tumour area in liver biopsies from HCC-positive patients by using nested PCR. RESULTS We found that the HCMV seroprevalence was high in the Hepatology department. The HCMV seroprevalence was significantly higher in patients infected with HCV and/or HBV than in patients who were not infected by those later viruses (76.2% versus 56.5%, p < 0.001). The HCMV seroprevalence was significantly higher in patients with HCC (74%) and lower in patients without HCC (54% for HCC-/Cir+ patients, 57% for HCC-/Cir- subjects). We observed a positive correlation between serum IL-6 levels and HCMV seroprevalence in cirrhotic patients, but not in HCC patients. Serum IL-6 levels correlated positively with C-reactive protein (CRP) levels. Preliminary histological studies from liver biopsies from HCC-positive patients highlighted that HCMV DNA can be detected in tumour area of some of the patients studied. CONCLUSIONS Our results indicate that HCMV seroprevalence in patients with HCC is significantly higher than in patients without HCC, is positively correlated with serum IL-6 levels in cirrhotic patients, and is positively associated with the presence of other hepatotropic viruses such as HCV and HBV.
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Affiliation(s)
- Quentin Lepiller
- Department of Virology, University of Franche-Comte, EA 4266, IFR 133 INSERM, CHU Besancon, F-25030 Besançon, France
| | - Manoj K Tripathy
- Department of Virology, University of Franche-Comte, EA 4266, IFR 133 INSERM, CHU Besancon, F-25030 Besançon, France
| | - Vincent Di Martino
- Department of Hepatology, University of Franche-Comté EA 4266, CHU Besancon, F-25030 Besançon, France
| | | | - Georges Herbein
- Department of Virology, University of Franche-Comte, EA 4266, IFR 133 INSERM, CHU Besancon, F-25030 Besançon, France
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