Possible Relevance of PNPLA3 and TLL1 Gene Polymorphisms to the Efficacy of PEG-IFN Therapy for HBV-Infected Patients

Abstract

Lifestyle changes have led to an increase in the number of patients with nonalcoholic fatty liver disease (NAFLD). However, the effects of NAFLD-associated single-nucleotide gene polymorphisms (SNPs) in HBV-infected patients have not been adequately investigated. Methods: We investigated the association of the NAFLD-related SNPs patatin-like phospholipase domain-containing protein 3 (PNPLA3; rs738409), transmembrane 6 superfamily member 2 (TM6SF2; rs58542926), 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13; rs72613567, rs6834314 and rs62305723), membrane-bound O-acyltransferase domain containing 7 (MBOAT7; rs641738) and glucokinase regulatory protein (GCKR; rs1260326) with the presence of histologically proven hepatic steatosis (HS) in HBV-infected patients (n = 224). We also investigated tolloid-like 1 (TLL1) SNP (rs17047200), which has been reported to be involved in the disease progression in Japanese NAFLD patients, and evaluated the association of HS and various SNPs with the treatment efficacy of pegylated-interferon (PEG-IFN) monotherapy following nucleotide/nucleoside (NA) treatment (NA/PEG-IFN sequential therapy; n = 64). Among NAFLD-associated SNPs evaluated, only the PNPLA3 SNP was significantly associated with the presence of hepatic steatosis in a total of 224 HBV-infected patients (P = 1.0 × 10−4). Regarding the sequential therapy, PNPLA3 SNP and TLL1 SNP were related to the treatment efficacy, and patients without minor alleles of these SNPs showed favorable results with a high virologic response and significant reduction in their HBsAg titer. A multivariate analysis showed that HBeAg positivity (odds ratio 5.810, p = 0.016) and the absence of a risk allele in PNPLA3 and TLL1 SNPs (odds ratio 8.664, p = 0.0042) were significantly associated with treatment efficacy. The PNPLA3 SNP might be associated with the presence of HS, and the combination of the PNPLA3 and TLL1 SNPs might be related to the efficacy of PEG-IFN monotherapy following NA treatment.

Association between Interferon-Lambda-3 rs12979860, TLL1 rs17047200 and DDR1 rs4618569 Variant Polymorphisms with the Course and Outcome of SARS-CoV-2 Patients

“…TLL1 rs17047200 SNP may produce catalytically highly active short isoform (TLL1 isoform 2) [16]. Of note, we evaluated a SNP of Tolloid Like-1 (TLL-1) as a complementary activating protease and also as potentially able to stimulate the spike protein of SARS-CoV-2 [17].…”

A Missense Variant in Granulysin is Associated with the Efficacy of Pegylated-Interferon-Alpha Therapy in Chinese Patients with HBeAg-Positive Chronic Hepatitis B

“…Previous studies suggest that response-guided therapy or early on-treatment HBV RNA levels could be of great help in the management of patients treated with PegIFNα, 29 , 31 while it is unclear which indicators can predict that patients with CHB could benefit from earlier treatment. Although several SNPs have been proposed, 8 , 32 , 33 the effect of GNLY rs11127 on PegIFNα efficacy has never been reported before. Previously, GNLY rs11127 was regarded as an important factor in HBV clearance in patients infected with HBV in a Korean study.…”

“…Currently, predictive models of the efficacy for initial treatment with PegIFN were mainly reported on studies of some clinical baseline indicators 34 or SNPs. 32 , 33 , 35 Therefore, we compared the performance of clinical variables combined with PGS and that of clinical variables only, in predicting PegIFNα efficacy. The results demonstrated that the performance of the model including clinical variables combined with PGS in predicting PegIFNα efficacy was remarkably improved compared to that of the model including clinical variables only.…”

Implications of the Immune Polymorphisms of the Host and the Genetic Variability of SARS-CoV-2 in the Development of COVID-19

“…This enzyme can also activate SARS-CoV-2 S glycoprotein. rs17047200 (AA genotype) [19,212]. No data reported.…”