The Association Between Chronic Hepatitis C And Type 2 Diabetes Mellitus

Section 1 Study on blood glucose level and its influencing factors of male drug users with different HCV infection statusType 2 diabetes mellitus(T2DM)is a chronic non-communicable disease characterized by elevated blood sugar,which seriously affects the health of the population and brings a heavy economic burden.HCV is a hepatotropic virus that can cause liver damage after invading the body through direct liver toxicity or causing host immune response.According to WHO,about 71 million people are chronically infected with HCV worldwide,and about 399,000 people died of hepatitis C related diseases in 2016.CHC is not only one of the important causes of end-stage liver disease and hepatocellular carcinoma(HCC),but also the cause of other serious extrahepatic diseases.The liver is the main organ of glucose metabolism,so there is an inseparable association between CHC and abnormal glucose metabolism(AGM).To understand the fasting plasma glucose(FPG)level and average blood glucose(ABG)level in different HCV infection groups and their influencing factors can help to explore the impact of HCV infection on glucose metabolism and provide a theoretical basis for further revealing the association between HCV infection and glucose metabolism.[Objectives] The purpose of this study is to understand the FPG levels and ABG levels of male drug users with or without HCV infection and to explore the related factors affecting the FPG levels and ABG levels of male drug users to provide preliminary insights into the association between HCV infection and glucose metabolism.[Methods] This study selected all detoxification personnel who received treatment at the compulsory isolation detoxification center in Yixing City,Jiangsu Province from June to August in 2018 as the study subject.After obtaining informed consent,a faceto-face questionnaire survey was conducted using a self-designed questionnaire to obtain the basic information of study subjects and 10 m L of venous blood was collected from every subject for detection of related indicators.Based on the test results of antiHCV and HCV RNA,all study subjects were divided into three groups(HCV antibody negative,spontaneous HCV clearance,and chronic Hepatitis C)to explore the differences and influencing factors in FPG and ABG levels.[Results] A total of 788 male drug users were included in this study,all of whom were male.Among them,631 were anti-HCV negative,67 were spontaneous clearance,and 90 were chronically infected with HCV.The questionnaire used in this study had good reliability and validity(Cronbach’s α coefficient = 0.890;KMO value = 0.877).There were significant differences in FPG levels among the three groups(P = 0.017),but no differences in ABG levels were observed.And the FPG levels in the chronic infection group was higher than that in the spontaneous clearance group(P = 0.017),and there was no significant difference between the other groups.The results were still observed after propensity score matching(P < 0.001)and covariance analysis adjusted history of drug addicted(P < 0.001).The multiple linear regression model indicated that the FPG levels increased with increasing age.And for every 1-year increased in the age of Male drug users,FPG level increase by 0.026 mmol/L(P < 0.001)and ABG level increase by 0.029 mmol/L(P < 0.001).[Conclusion] The FPG levels of male drug users who are chronically infected with HCV are higher than those of spontaneous clearance,but no significantly different from those of anti-HCV negative males.FPG levels and ABG levels in male drug users are no associated to HCV infection but increased with age.Section 2 The Association between chronic hepatitis C and type 2 diabetes mellitus: a mendelian randomization studyType 2 diabetes mellitus(T2DM)is a chronic non-communicable disease that seriously affects the health of the population,and has brought a heavy burden on the global economy.Since it was first reported in 1994,the association between chronic hepatitis C(CHC)and T2 DM was studied by many researchers,but the conclusions were inconsistent.And the limitations,such as confounding factors and reverse causal associations,further increased the difficulty of causal inference.Recently,the rise of Mendelian Randomization(MR)research has provided another way to solve these problems,which is based on Mendelian genetic laws to clarify the time sequence of exposures and outcomes and uses single nucleotide polymorphisms(SNPs)as instrumental variables(IV)to ensure grouping like randomized controlled trials,effectively addresses the problems of reverse causation and confounding bias on causal inference.Therefore,MR study can be used to solve the difficulties in the causal inference of CHC and T2 DM.[Objectives] This study aimed to find SNPs which are associated with serum HCV RNA levels and CHC,and select SNPs that meet the requirements as IV to explore the causation of serum HCV RNA levels and abnormal glucose metabolism(AGM),and the impact of CHC on T2 DM,providing a theoretical basis for causal inference of CHC and T2 DM.[Methods] The study includes two parts,one-sample MR and two-samples MR.The first part of this study recruited 370 CHC patients from the department of infectious diseases of Jurong people’s hospital affiliated to Jiangsu university(Zhenjiang,Jiangsu).The general demographic information of the CHC patients was obtained through a face to face questionnaire survey,and the relevant information of the blood test before receiving treatment was obtained in the hospital medical record system.Five milliliters of venous blood were collected from each subject,and genomic DNA was extracted from peripheral blood by phenol-chloroform method.A total of 31 candidate SNPs were selected from 10 candidate genes including IFNL4,IFNLR1,HLA-DMA,HLADMB,HLA-DOA,HLA-DOB,PSMB8,TAP1,TAP2 and tapasin,and samples were genotyped by Taqman-MGB probe technology.SNPs that were closely related to serum HCV RNA levels and met the requirements of IV were selected as IV to further explore the association between HCV RNA levels and AGM by two-stage least squares(2SLS)method.The two sample MR analysis identified IV from existing GWAS,and extracted information such as the effect estimates and P-values of SNP-CHC,SNP-glycated hemoglobin(GHb)and SNP-T2 DM from the relevant GWAS.The SNP that was closely associated with CHC but not related to GHb/T2 DM,with potential biological function was chooesed as IV,and Mendelian randomized Egger Regression(MR-Egger)was used to explore the impact of CHC on GHb and T2 DM.[Results] In the first part of the study,two eligible SNPs(HLA-DOA rs1059288 and tapasin rs3128935)were selected as IV.The genotypes of HLA-DOA rs3128935(F = 5.85,P = 0.003)and tapasin rs1059288(F = 6.84,P = 0.001)were significantly associated with serum HCV RNA levels,but were not associated with AGM.The results of 2SLS estimation using rs3128935,rs1059288,SNPs combination(rs3128935 + rs1059288)or the genetic risk score as IV suggested that there was no significant association between HCV RNA levels and AGM.In the second part,a total of 6 qualified SNPs(rs111531283,rs73050457,rs10853728,rs4803223,rs10424607,and rs9469220)were selected as IV.The association of CHC on GHb and T2 DM was not observed by using MR-Egger regression(P > 0.05).In addition,IV had no significant pleiotropy(P > 0.05)and sensitivity analysis indicated that the final results were robust.[conclusion] Variants of HLA-DOA rs1059288 and tapasin rs3128935 are associated with high serum HCV RNA levels.There is no causation between CHC and T2 DM.The impact of CHC on the increased risk of T2 DM may be smaller than factors such as diet,exercise,and family genetics.