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©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Interleukin-6-174G/C polymorphism is associated with a decreased risk of type 2 diabetes in patients with chronic hepatitis C virus
Cliviany Borges da Silva, Diego Alves Vieira, Luisa Freitas de Melo, Anna Luiza Soares Chagas, Adriana Dias Gomes, César Lúcio Lopes de Faria Jr, Rosângela Teixeira, Dulciene Maria de Magalhães Queiroz, Gifone Aguiar Rocha, Maria Marta Sarquis Soares, Juliana Maria Trindade Bezerra, Luciana Diniz Silva
Cliviany Borges da Silva, Sciences Applied to Adult Health Care Post-Graduate Programme, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
Cliviany Borges da Silva, Diego Alves Vieira, Luisa Freitas de Melo, Anna Luiza Soares Chagas, Rosângela Teixeira, Luciana Diniz Silva, Outpatient Clinic of Viral Hepatitis, Instituto Alfa de Gastroenterologia, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
Diego Alves Vieira, Luisa Freitas de Melo, Anna Luiza Soares Chagas, Medical undergraduate student, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
Adriana Dias Gomes, César Lúcio Lopes de Faria Jr, Dulciene Maria de Magalhães Queiroz, Gifone Aguiar Rocha, Laboratory of Research in Bacteriology, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
Rosângela Teixeira, Luciana Diniz Silva, Department of Internal Medicine, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
Maria Marta Sarquis Soares, Division of Endocrinology, Department of Internal Medicine, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
Juliana Maria Trindade Bezerra, Epidemiology of Infectious and Parasitic Diseases Laboratory, Department of Parasitology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte 30130100, Minas Gerais, Brazil
Author contributions: da Silva CB and Silva LD designed research (project conception, development of overall research plan, and study oversight); da Silva CB, Vieira DA, de Melo LF, Chagas ALS, Gomes AD, Faria Jr CLL conducted research (hands-on conduct of the experiments and data collection); Soares MMS, Teixeira R, Rocha GA and de Magalhães Queiroz DM provided essential reagents or provided essential materials; da Silva CB, de Bezerra JMT and Silva LD analysed data or performed statistical analysis; da Silva CB, de Bezerra JMT, Rocha GA and Silva LD wrote paper; da Silva CB, de Bezerra JMT, Rocha GA and Silva LD had primary responsibility for final content. All authors critically revised the manuscript, agree to be fully accountable for ensuring the integrity and accuracy of the work, and read and approved the final manuscript.
Supported by Fundação de Amparo à Pesquisa do Estado de Minas Gerais, No. APQ-02320-18.
Institutional review board statement: The protocol was approved by the Federal University of Minas Gerais Ethical Board (ETIC 0404.0.203.000-10).
Informed consent statement: The primary version (PDF) of the Informed Consent Form that has been signed by all subjects and investigators of the study, prepared in Portuguese was uploaded.
Conflict-of-interest statement: Authors declare no conflict of interests.
Data sharing statement: Technical appendix, statistical code and dataset available from the corresponding author at lucianadinizsilva@ufmg.br.
STROBE statement: The authors have read the STROBE statement-checklist of items and the manuscript was prepared and revised according to the strobe guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Luciana Diniz Silva, MD, PhD, Academic Research, Associate Professor, Attending Doctor, Research Scientist, Department of Internal Medicine, Faculdade de Medicina, Universidade Federal de Minas Gerais, Av Alfredo Balena 190 s/257, Belo Horizonte 30720030, Minas Gerais, Brazil. lucianadinizsilva@gmail.com
Received: December 29, 2019
Peer-review started: December 29, 2019
First decision: February 16, 2020
Revised: February 28, 2020
Accepted: March 22, 2020
Article in press: March 22, 2020
Published online: April 27, 2020
ARTICLE HIGHLIGHTS
Research background
Chronic hepatitis C (CHC) is associated with an elevated prevalence of type 2 diabetes mellitus. Although, some mechanisms underlying the modified glucose metabolism in hepatitis C virus (HCV) infection have been elucidated, several aspects remain unknown. Growing scientific evidence has suggested a role of pro-inflammatory immune response. Increased serum concentrations of interleukin-6 (IL-6) have been associated with insulin resistance, type 2 diabetes mellitus as well as advanced forms of liver disease in chronic hepatitis C infection.
Research motivation
Patients with CHC, with insulin resistance or type 2 diabetes mellitus are likely to have a more complicated course of the infection. Based on previous reports, it is important to keep in mind, if on the one hand insulin resistance is recognized as a risk factor for the progression of HCV-related liver disease, on the other hand, preceding HCV infection significantly increases the risk of developing type 2 diabetes mellitus. Additionally, diabetic patients are at an increased risk of acquiring HCV infection. Thus, this two-way interface, i.e., the relationship linking HCV and type 2 diabetes mellitus, is possibly determined by complex and multifaceted interactions among the hepatitis virus, the environment and the host.
Research objectives
The objectives of this study were therefore to investigate the frequency of IL-6-174G/C (rs1800795) single nucleotide polymorphism in CHC patients and in healthy subjects of the same ethnicity. Furthermore, the association between type 2 diabetes mellitus (dependent variable) and demographic, clinical, nutritional, virological and IL-6 genotyping data was also evaluated in patients chronically infected with HCV.
Research methods
Two hundred and forty-five patients with CHC and 179 healthy control subjects (blood donors) were prospectively included. Type 2 diabetes mellitus was diagnosed according to the criteria of the American Diabetes Association. Clinical, biochemical, histological and radiological criteria were applied to make the diagnosis and staging of the liver disease. IL-6-174G/C (rs1800795) genotyping was Taqman assayed by Real Time PCR System 7.500 by using oligonucleotide primers previously described by Fishman et al[44]. The Hardy-Weinberg equilibrium of alleles at individual loci was assessed by two-tailed chi-square test or Fisher’s exact test. The associations of each variable including IL-6-174G/C, sex, increasing age, blood hypertension, nutritional status, liver fibrosis stage (chronic hepatitis and cirrhosis) with type 2 diabetes mellitus were tested in univariate analysis. All variables with P values < 0.20 were included in the full model of logistic regression. Odds ratio (OR) and 95%CI were used as an estimate of the risk. P values ≤ 0.05 were considered significant.
Research results
Type 2 diabetes mellitus, blood hypertension and liver cirrhosis were observed in 20.8% (51/245), 40.0% (98/245) and 38.4% (94/245) of the patients, respectively. The frequency of the studied IL-6 single nucleotide polymorphism did not differ between the CHC patients and controls (P = 0.81) and the alleles were in Hardy-Weinberg equilibrium (P = 0.38). In the multivariate analysis, type 2 diabetes mellitus was inversely associated with GC and CC genotypes of IL-6-174 (OR = 0.42; 95%CI = 0.22-0.78; P = 0.006) and positively associated with blood hypertension (OR = 5.56; 95%CI = 2.79-11.09; P < 0.001).
Research conclusions
In the current study, we demonstrated for the first time that the IL-6-174G/C gene promoter polymorphism is inversely associated with type 2 diabetes mellitus in patients with CHC. This finding reinforces the need for additional investigations focusing on the biological mechanisms of diabetes mellitus in patients chronically infected with HCV.
Research perspectives
The identification of potential inflammatory mediators involved in the crosstalk between HCV and the axis pancreas-liver remains important issues that deserve further investigations. Moreover, better understanding of these processes may positively affect the management strategies for reducing the extra-hepatic manifestations and their negative impact on health status in CHC patients.
