Relevance of HLA-DP/DQ and INF-λ4 Polymorphisms to COVID-19 Outcomes.

Background: Single nucleotide polymorphisms provide information on individuals' potential reactions to environmental factors, infections, diseases, as well as various therapies. A study on SNPs that influence SARS-CoV-2 susceptibility and severity may provide a predictive tool for COVID-19 outcomes and improve the customized coronavirus treatment. Aim: To evaluate the role of human leukocyte antigens DP/DQ and IFNλ4 polymorphisms on COVID-19 outcomes among Egyptian patients. Participants and Methods: The study involved 80 patients with severe COVID-19, 80 patients with mild COVID-19, and 80 non-infected healthy volunteers. Genotyping and allelic discrimination of HLA-DPrs3077 (G/A), HLA-DQrs7453920 (A/G), and IFNλ4 rs73555604 (C/T) SNPs were performed using real-time PCR. Results: Ages were 47.9 ± 8, 44.1 ± 12.1, and 45.8 ± 10 years in severe, mild and non-infected persons. There was a statistically significant association between severe COVID-19 and male gender (p = 0.002). A statistically significant increase in the frequency of HLA-DPrs3077G, HLA-DQrs7453920A, and IFNλ4rs73555604C alleles among severe COVID-19 patients when compared with other groups (p < 0.001). Coexistence of these alleles in the same individual increases the susceptibility to severe COVID-19 by many folds (p < 0.001). Univariate and multivariate logistic regression analysis for the studied parameters showed that old age, male gender, non-vaccination, HLA-DQ rs7453920AG+AA, HLA-DPrs3077GA+GG, and IFNλ4rs73555604CT+CC genotypes are independent risk factors for severe COVID-19 among Egyptian patients. Conclusion: HLA-DQ rs7453920A, HLA-DPrs3077G, and IFNλ4rs73555604C alleles could be used as markers of COVID-19 severity.

Genetic polymorphisms of Endoplasmic reticulum amino peptidase 1 (ERAP1) and Interferon lambda 4 (IFN-λ4) in Egyptian patients with type 1 diabetes mellitus.

Different genetic and environmental factors are implicated in type I diabetes (T1DM) pathogenesis. About 50% of the genetic susceptibility for T1DM is related to human leukocyte antigen (HLA) genes. Other non-HLA genes have variable roles in the destruction of pancreatic ß cells. A highly variable gene called endoplasmic reticulum associated with antigen processing gene 1(ERAP1) shares in activating autoreactive CD8+ T lymphocytes, peptide trimming, and subsequent pancreatic ß cells destruction. Local production of inflammatory cytokines within the cells of islets of Langerhans is linked to T1DM progression. Different viral and autoimmune disorders have been linked to genetic variations in type III interferon (IFNλs). This study aimed to determine genetic polymorphisms of interferon lambda 4 (IFNλ4rs 73555604) and endoplasmic reticulum aminopeptidases 1 (ERAP1 rs26618) in Egyptian patients with T1DM. The study recruited 120 patients with T1DM from Kafrelsheikh University Hospital and 100 normal controls who were age and sex matched with the patients' group. Single-nucleotide polymorphism (SNP) genotyping of ERAP1(rs26618) and IFN-λ-4(rs73555604) was performed using real-time polymerase chain reaction. Patients with CC genotype were less likely to develop T1DM than those with TC and TT genotypes for both genes. In addition, T allele frequency in comparison to C allele frequency was significantly increased in T1DM patients when compared to control group (p < 0.001). There were positive correlations between studied SNPs for both genes, fasting and postprandial blood glucose levels which suggest the association of these genes with T1DM occurrence. We concluded that the studied SNPs of ERAP1gene (rs26618) and IFNλ-4 gene(rs73555604) may be associated with T1DM development. In addition, T alleles for both genes could be considered risk alleles while C alleles would be regarded as a protective allele. Patients with TC and TT genotypes would be at a higher risk for T1DM than those carrying CC genotype.

The impact of genetic variations in sofosbuvir metabolizing enzymes and innate immunity mediators on treatment outcome in HCV-infected patients.

Hepatitis C virus (HCV) is the leading cause of liver diseases worldwide. At present, combinations of different classes of direct-acting antiviral agents (DAAs) are used as treatment options for HCV, in which sofosbuvir (SOF) is the common DAA among different therapeutic regimes. In Egypt, SOF plus daclatasvir (DCV) is the widely used anti-HCV treatment protocol. Herein, we aimed to assess the association between 3 single-nucleotide polymorphisms (SNPs) at the genes coding for 2 SOF metabolizing enzymes: histidine triad nucleotide-binding protein 1 (HINT1) rs4696/rs7728773 and nucleoside diphosphate kinase 1 (NME1) rs3760468, together with the most potent anti-HCV innate molecule, i.e., interferon lambda 3 (IFNL3) rs12979860 and the response to SOF/DCV in Egyptian patients chronically infected with genotype 4 (GT4). SNPs were genotyped using real-time PCR in DNA from patients who achieved sustained virological response (SVR) at 12 weeks post-SOF/DCV treatment (i.e., responders; n = 188), patients who failed to achieve SVR12 (i.e., non-responders; n = 109), and healthy controls (n = 62). Our results demonstrated that patients bearing HINT1 rs7728773 CT/TT (odds ratio 2.119, 95% CI 1.263-3.559, p = 0.005) and IFNL3 rs12979860 CC (odds ratio 3.995, 95% CI 2.126-7.740, p = 0.0001) were more likely to achieve SVR12. However, neither HINT1 rs4696 nor NME1 rs3760468 seems to contribute to the responsiveness to SOF/DCV. Binary regression analysis defined 5 predictor factors independently associated with SVR12: age, bilirubin, hemoglobin, early stages of fibrosis, and combined HINT1 rs7728773 and IFNL3 rs12979860 favorable and mixed genotypes (odds ratio 3.134, 95% CI 1.518-6.47, p = 0.002), and that was confirmed by the combined ROC curve for the 5 predictor factors (AUC = 0.91, 95% CI 0.869-0.95, P = 0.0001). In conclusion, these data suggest that the two SNPs have the potential in predicting the response rate to SOF/DCV treatment in patients infected with HCV GT4. This study is the first to investigate the pharmacogenetics of SOF metabolizing enzyme and introduce HINT1 rs7728773 as a novel SNP that predicts the treatment efficacy.

Relation between microRNA-21, transforming growth factor ß and response to treatment among chronic hepatitis C patients.

BACKGROUND: Persistence of hepatitis C virus (HCV) infection and response to antiviral therapy has been shown to be associated with inappropriate levels of cytokines and microRNAs (miRNAs). miRNA levels have been reported to fluctuate during treatment. Thus they could be useful predictors for responses to treatment among HCV infected patients, thereby reducing ineffective treatments. AIM: The current study aimed to investigate the relation between miRNA-21 expression profiles, transforming growth factor ß (TGF-ß) serum levels and response to treatment with the new direct antiviral drugs (sofosbuvir + daclatasvir ± ribavirin), among HCV infected Egyptian patients. SUBJECTS AND METHODS: This prospective study was conducted on 50 HCV infected patients (before and after treatment) and 20 healthy volunteers. miRNA expression profiles were determined by real-time polymerase chain reaction and TGF-ß1 serum levels were measured by using enzyme-linked immunosorbent assay. RESULTS: There was a significant increase in serum albumin, platelets count and a significant decrease in liver enzymes, serum bilirubin, and prothrombin time after treatment. Significant reduction of viral load among HCV patients after receiving the treatment was reported. Concomitantly, there was an increase in the relative quantity of miRNA-21 (P = .001*) and serum levels of TGF-ß1 ( P = .337) among HCV patients after receiving treatment. CONCLUSION: Nearly all responders to direct antiviral drugs showed increased levels of both miRNA-21 and TGF-ß1. This may indicate an interplay between TGF-ß1 and miRNA-21 during remission or progression of viral infection. Thus miRNA-21 could be used as promising serum biomarker, for assessment of antiviral treatment efficacy and improvement of fibrosis among chronically infected HCV patients.

Association of interferon-γ inducible protein-10 pretreatment level and sustained virological response in HCV-positive Egyptian patients.

BACKGROUND: The response to antiviral therapy in HCV infected patients depends on several predictive factors; however, the ability to achieve sustained virological response is still limited to around 60% of the patients infected with the HCV-4 genotype. Increased serum and intrahepatic interferon -γ inducible protein 10 (IP-10) levels in patients with chronic hepatitis C have been described. The aim of the work was to study the impact of pretreatment serum IP-10 level on the antiviral treatment outcome in a group of Egyptian patients infected with HCV. MATERIALS AND METHODS: The study included 80 treatment naive HCV patients. Serum IP-10 levels were determined by an enzyme linked immunosorbent assay before therapy was introduced. Serum samples were examined twice by Real-Time PCR after complete course of therapy for detection of HCV RNA; at the end of the antiviral therapy and six months later to detect sustained virological response (SVR). RESULTS: 57 patients (71%) achieved SVR while 23 (29%) patients were non-responders (NR). Pretreatment serum IP-10 levels were significantly lower in patients who achieved SVR than in NR (p=0.000). CONCLUSION: Low pretreatment serum IP-10 is a favorable predictive of response to antiviral HCV therapy in Egyptian patients.

Can brucellosis influence the course of chronic hepatitis C in dual infection?

Hepatitis C and brucellosis are infectious diseases that occur worldwide, and both are endemic in Egypt. Co-infection with both agents is possible, and this can involve the liver in various ways. In this study, we investigated serum tissue inhibitor metalloproteinase-1 (TIMP-1), viral load, and liver functions in patients co-infected with hepatitis C virus (HCV) before and after brucellosis treatment. Over 3 years, 241 consecutive HCV patients (before interferon therapy was received) with recurrent fever who had occupational contact with animals were tested for brucellosis co-infection by a standard tube agglutination test. In patients with dual infection, viraemia (RT-PCR), TIMP-1 measured by ELISA, and liver functions were assessed and re-evaluated 2 months after brucellosis treatment. The number of patients with HCV/brucellosis co-infection was 32 out of 241 (13.3%). TIMP-1, viraemia, AST, ALT and bilirubin showed significant decrease (improvement) after brucellosis treatment (p < 0.001) but an insignificant difference (p > 0.05) with regard to serum albumin and prothrombin concentration. The study revealed that brucellosis is an important infection in HCV-infected patients and can aggravate the course of disease, suggesting that early treatment and prevention are important.