Single-nucleotide polymorphisms of HLA and Polygonum multiflorum-induced liver injury in the Han Chinese population

BACKGROUND Polygonum multiflorum is one of the leading causes of herb-induced liver injury in China.HLA-B*35:01 is reported to be a potential biomarker of Polygonum multiflorum-induced liver injury(PM-DILI).However,little is known about the relationship between single-nucleotide polymorphisms(SNPs) and PM-DILI.AIM To identify SNPs that indicate susceptibility to PM-DILI METHODS We conducted a systematic study enrolling 382 participants from four independent hospitals,including 73 PM-DILI patients,118 patients with other drug-induced liver injury(other-DILI) and 191 healthy controls.Whole-exome sequencing was performed for 8 PM-DILI patients and 8 healthy controls who were randomly selected from the above subjects.Nineteen SNPs that showed high frequencies in the 8 PM-DILI patients were selected as candidate SNPs and then screened in 65 PM-DILI patients,118 other-DILI patients and 183 healthy controls using the MassARRAY system.HLA-B high-resolution genotyping was performed for the 73 PM-DILI and 118 other-DILI patients.The Han-MHC database was selected as a population control for HLA-B analysis.P <6.25 x 103 after Bolferroni correction was considered significant.RESULTS The frequencies of rslll686806 in the HLA-A gene,rs1055348 in the HLA-B gene,and rs202047044 in the HLA-DRB1 gene were significantly higher in the PM-DILI group than in the control group [27.2% vs 11.6%,P=1.72×105,odds ratio(OR)=3.96,95% confidence interval(Cl):2.21-7.14;42.5% vs 8.6%,P=1.72×10-19 OR=13.62,95% CI:7.16-25.9;22.9% vs 8.1%,P=4.64×106,OR=4.1,95% CI:2.25-7.47].Only rs1055348 showed a significantly higher frequency in the PM-DILI group than in the other-DILI group(42.5% vs 13.6%,P=1.84×10-10,OR=10.06,95% Cl:5.06-20.0),which suggested that it is a specific risk factor for PM-DILI.rs1055348 may become a tag for HLA-B*35:01 with 100% sensitivity and 97.7% specificity in the PM-DILI group and 100% sensitivity and 98.1% specificity in the other-DILI group.Furthermore,HLA-B*35:01 was confirmed to be associated with PM-DILI with a frequency of 41.1% in the PM-DILI group compared with 11.9%(P=4.30×10-11,OR=11.11,95% CI:5.57-22.19) in the other-DILI group and 2.7%(P=6.22×10-166,OR=62.62,95% Cl:35.91-109.20) in the Han-MHC database.CONCLUSION rslll686806,rs1055348,and rs202047044 are associated with PM-DILI,of which,rs1055348 is specific to PM-DILI.As a tag for HLA-B*35:01,rs1055348 may become an alternative predictive biomarker of PM-DILI.

Prediction of hepatic inflammation in chronic hepatitis B patients with a random forest-backward feature elimination algorithm

BACKGROUND Persistent liver inflammatory damage is the main risk factor for developing liver fibrosis,cirrhosis,and even hepatocellular carcinoma in chronic hepatitis B(CHB)patients.Thus,accurate prediction of the degree of liver inflammation is a high priority and a growing medical need.AIM To build an effective and robust non-invasive model for predicting hepatitis Brelated hepatic inflammation.METHODS A total of 650 treatment-naïve CHB(402 HBeAg-positive and 248 HBeAgnegative)patients who underwent liver biopsy were enrolled in this study.Histological inflammation grading was assessed by the Ishak scoring system.Serum quantitative hepatitis B core antibody(qAnti-HBc)levels and 21 immunerelated inflammatory factors were measured quantitatively using a chemiluminescent microparticle immunoassay.A backward feature elimination(BFE)algorithm utilizing random forest(RF)was used to select optional features and construct a combined model.The diagnostic abilities of the model or variables were evaluated based on the estimated area under the receiver operating characteristics curve(AUROC)and compared using the DeLong test.RESULTS Four features were selected to predict moderate-to-severe inflammation in CHB patients using the RF-BFE method.These predictive features included qAnti-HBc,ALT,AST,and CXCL11.Spearman’s correlation analysis indicated that serum qAnti-HBc,ALT,AST,and CXCL11 levels were positively correlated with the histology activity index(HAI)score.These selected features were incorporated into the model to establish a novel model named I-3A index.The AUROC[0.822;95%confidence interval(CI):0.790-0.851]of the I-3A index was significantly increased compared with qAnti-HBc alone(0.760,95%CI:0.724-0.792,P<0.0001)in all CHB patients.The use of an I-3A index cutoff value of 0.41 produced a sensitivity of 69.17%,specificity of 81.44%,and accuracy of 73.8%.Additionally,the I-3A index showed significantly improved diagnostic performance for predicting moderate-to-severe inflammation in HBeAg-positive and HBeAgnegative CHB patients(0.829,95%CI:0.789-0.865 and 0.810,95%CI:0.755-0.857,respectively).CONCLUSION The selected features of the I-3A index constructed using the RF-BFE algorithm can effectively predict moderate-to-severe liver inflammation in CHB patients.