Investigating the role of killer cell immunoglobulin-like receptors and human leukocyte antigen genetic variants in hepatitis C virus infection.

The genetic diversity of killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) genes influences the host's immune response to viral pathogens. This study aims to explore the impact of five single nucleotide polymorphisms (SNPs) in KIR3DL2 and HLA-A genes on hepatitis C virus (HCV) infection. A total of 2251 individuals were included in the case-control study. SNPs including KIR3DL2 rs11672983, rs3745902, rs1654644, and HLA-A rs3869062, rs12202296 were genotyped. By controlling various confounding factors using a modified logistic regression model, as well as incorporating stratified analysis, joint effects analysis, and multidimensional bioinformatics analysis, we analyzed the relationship between SNPs and HCV infection. The logistic regression analysis showed a correlation between KIR3DL2 rs11672983 AA, KIR3DL2 rs3745902 TT, and increased HCV susceptibility (p < 0.01). Stratified analysis indicated that KIR3DL2 rs1654644 and HLA-A rs3869062 also heightened HCV susceptibility in certain subgroups. A linear trend of rising HCV infection rates was observed when combining KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT (ptrend = 0.007). Bioinformatics analysis suggested these SNPs' regulatory potential and their role in altering messenger RNA secondary structure, implying their functional relevance in HCV susceptibility. Our findings indicate that KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT are significantly associated with increased susceptibility to HCV infection.

Association of Elongation Factor Tu GTP-binding Domain-containing 2 Gene (EFTUD2) Polymorphism with the Risk of Hepatitis B Virus Infection.

BACKGROUND: The elongation factor Tu GTP-binding domain-containing 2 gene (EFTUD2) participates in antiviral immune responses. However, the association between genetic polymorphisms of EFTUD2 and hepatitis B virus (HBV) infection susceptibility has not been well-studied. We analyzed the relationship between single nucleotide polymorphisms (SNPs) of EFTUD2 and HBV infection susceptibility and clarified the potential function. METHODS: In total, 448 control subjects and 379 patients with chronic HBV infection from Zhangjiagang First People's Hospital (Jiangsu, China) were enrolled. Sequenom iPLEX assay was used to detect genotypes of four SNPs (rs1071682, rs2277617, rs2289674, and rs3809756). Dual-luciferase reporter vectors with wild-type A and mutant-type C alleles of EFTUD2 rs3809756 were transfected into HepG2 cells to explore effects on transcription activity. RESULTS: Only rs3809756 was significantly associated with HBV infection susceptibility (P < .05). The risk of HBV infection was higher in individuals carrying the rs3809756-CC genotype than in those carrying the rs3809756-AA genotype (odds ratio [OR] = 1.945, 95% confidence interval [CI] = 1.129-3.351, P = .017). Subgroup analysis based on the dominant model revealed that rs3809756-AC and rs3809756-CC carriers had a significantly higher risk of HBV infection than rs3809756-AA carriers among patients who were male (OR = 1.732, 95% CI = 1.218-2.464, P = .002), were aged ≥47 years (OR = 1.502, 95% CI = 1.050-2.148, P = .026), or without liver cirrhosis (OR = 1.407, 95% CI = 1.077-1.838, P = .012). In the dual-luciferase reporter assay, the relative luciferase activity of rs3809756-C was significantly lower than that of rs3809756-A (P < .05). CONCLUSION: EFTUD2 rs3809756A>C was associated with HBV infection susceptibility and might be involved in the downregulation of promoter activity.

Genetic Variation on TNF/LTA and TNFRSF1A Genes is Associated with Outcomes of Hepatitis C Virus Infection.

Hepatitis C virus (HCV) infections are a serious global-scaled public health problem. Tumor necrosis factor (TNF)/lymphotoxin alpha (LTA) has been found to play a crucial role in relation to the outcomes of HCV infection after it binds to TNF receptor superfamily member 1A (TNFRSF1A). Thus, we investigated whether or not the TNF/LTA gene cluster and TNFRSF1A gene polymorphisms were associated with the outcomes of HCV infection. 1103 control participants without HCV infection, 497 patients with spontaneous clearance of HCV infection, and 713 patients with persistent HCV infection were enrolled. Rs2229094, rs1041981, rs1799964, and rs767455 were genotyped using the ABI TaqMan allelic discrimination assay. After adjusting for age, gender, and after determining a high-risk population, we used logistic regression analyses for which results indicated that the rs767455-C allele was associated with a reduced risk of HCV infection compared to respective results for the wild-type T allele (dominant model: adjusted OR = 0.74, 95% CI = 0.60-0.92, P = .006; additive model: adjusted OR = 0.76, 95% CI = 0.62-0.91, P = .004). Results also indicated that the rs1041981-A allele was associated with a decreased risk of persistent HCV infection compared to respective results for the wild-type C allele (additive model: adjusted OR = 0.81, 95% CI = 0.68-0.96, P = .017). Genetic polymorphisms in the LTA and TNFRSF1A genes were found to have been potentially important in relation to the susceptibility and chronicity of HCV infection among Chinese Han population.

Vitamin D receptor genetic polymorphisms are associated with oral lichen planus susceptibility in a Chinese Han population.

BACKGROUND: Vitamin D receptor (VDR) is involved in multiple immune-mediated disorders including oral lichen planus (OLP). This study investigated the association between VDR gene polymorphisms and the risk of OLP. METHODS: In total, 177 OLP patients and 207 healthy participants were recruited from the Affiliated Hospital of Stomatology, Nanjing Medical University. Eight single nucleotide polymorphisms (SNPs: rs731236, rs739837, rs757343, rs2107301, rs2239185, rs7975232, rs11574129 and rs11568820) in the VDR gene were selected and genotyped. RESULTS: The results showed that OLP risk was increased in subjects with the rs2239185 TT genotype (Recessive model: adjusted Odd ratio(OR) = 2.68, 95% Confidence interval(CI) = 1.28-5.62, P = 0.009) and rs7975232 CC genotype (Recessive model: adjusted OR = 2.25, 95% CI = 1.10-4.58, P = 0.026). Moreover, rs2239185 and rs7975232 (P < 0.01) showed significant cumulative effects on OLP risk.Haplotype analysis showed that the CC haplotype (rs2239185-rs7975232) was associated with an increased risk of OLP (OR = 3.11, 95% CI = 1.42-6.83, P = 0.005), compared with the AC haplotype. CONCLUSION: The rs2239185 and rs7975232 variants of VDR may influence OLP susceptibility, and VDR gene polymorphisms may be candidate susceptibility regions for OLP in a Chinese Han population.

Genetic variants in IFIH1 and DDX58 influence hepatitis C virus clearance in Chinese Han population.

AIMS: To investigate the association between two RIG-I-like receptor gene polymorphisms and hepatitis C virus (HCV) infection in Chinese Han population. METHODS: The current study genotyped two selected SNPs (IFIH1 rs3747517 and DDX58 rs9695310) using TaqMan allelic discrimination assay to assess their association with the susceptibility and clinical outcome of HCV infection among 3065 participants (1545 non-HCV infection individuals, 568 spontaneous HCV clearance cases, and 952 persistent infection patients). RESULTS: IFIH1 rs3747517 (dominant model: Adjusted odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.07-1.68; P = 0.009) and DDX58 rs9695310 (dominant model: Adjusted OR = 1.43, 95% CI = 1.15-1.78; P = 0.001) were associated with chronic hepatitis C (CHC). And the risk of CHC increased when people were carrying more unfavorable rs3747517-GA/AA and rs9695310-GC/CC genotypes from zero to two with the chronic rates of 56.72%, 59.38%, and 69.01%, respectively (Ptrend < 0.001). CONCLUSION: Genetic variations at IFIH1 rs3747517 and DDX58 rs9695310 were independent predictors of chronic hepatitis C in Chinese Han population.

Effectiveness of ombitasvir/paritaprevir/ritonavir, dasabuvir for HCV in HIV/HCV coinfected subjects: a comprehensive analysis.

BACKGROUND: Data on the treatment of patients with hepatitis C virus (HCV)/human immunodeficiency virus (HIV) coinfection remains limited. A comprehensive analysis was performed to evaluate the efficacy and safety of ombitasvir (OBV)/paritaprevir (PTV)/ritonavir(r) ± dasabuvir (DSV) ± ribavirin (RBV) for treatment in HCV/HIV coinfected patients. METHODS: We systematically searched and included studies that enrolled patients with HIV/HCV coinfection using the OBV/PTV/r ± DSV ± RBV regimens and reported sustained virological response after 12 weeks (SVR12) end-of-treatment. Heterogeneity of results was assessed and pooled SVR rates were computed with 95% confidence intervals (95%CI). Subgroup analysis and assessment of publication bias through Egger's test were further performed. RESULTS: Ten studies containing 1358 coinfected patients were included in this study. The pooled estimate of SVR12 was 96.3% (95%CI: 95.1-97.4). Subgroup analysis showed that pooled SVR12 rate was 96.2% (95% CI: 94.8-97.4) for patients with genotype (GT) 1 and 98.8% (95% CI: 95.1-100.0) for those with GT4. The SVR12 rates for the treatment-naïve (TN) and treatment-experienced (TE) patients were 96.8% (95% CI, 94.8-98.5) and 98.9% (95% CI, 96.4-100.0), respectively. Pooled SVR12 rate was 97.8(95%CI: 94.6-99.8) for patients with cirrhosis and 96.7% (95%CI: 95.3-97.8) without cirrhosis. The pooled incidence of any adverse events (AEs) and serious adverse events (SAEs) was 73.9% (95%CI: 38.1-97.6) and 2.7% (95%CI: 0.0-9.5). Publication bias did not exist in this study. CONCLUSIONS: The comprehensive analysis showed high efficacy for the OBV/PTV/r ± DSV ± RBV regimen in patients coinfected with HIV and HCV, regardless of genotypes, history of treatment and the presence or absence of cirrhosis.

Impact of CYP2R1, CYP27A1 and CYP27B1 genetic polymorphisms controlling vitamin D metabolism on susceptibility to hepatitis C virus infection in a high-risk Chinese population.

CYP27A1, CYP2R1 and CYP27B1 hydroxylases are involved in the synthesis of 1, 25-hydroxyvitamin D3, which plays a role in the immune regulation and pathogenesis of hepatitis C virus (HCV) infection. The aim of the present study was to investigate the relationships between polymorphisms in vitamin D pathway genes and HCV infection outcomes in a Chinese population. Nine single-nucleotide polymorphisms (SNPs) of CYP27A1, CYP2R1 and CYP27B1 were genotyped in a high-risk Chinese population. The distributions of these SNPs were compared among groups with different outcomes of HCV infection, including 863 cases of persistent HCV infection, 524 cases of spontaneous clearance, and 1079 uninfected controls. The results showed that the CYP2R1 rs12794714-G, rs10741657-A, rs1562902-C, and rs10766197-G alleles were significantly associated with increased susceptibility to HCV infection (all PFDR < 0.05, in additive/dominant models), and the combined effect of the four unfavorable alleles was related to an elevated risk of HCV infection in a locus-dosage manner (Ptrend = 0.008). Moreover, haplotype analysis suggested that, compared with the most frequent haplotype (Ars12794714Grs10741657Trs1562902Ars10766197), the haplotype containing four unfavorable alleles, GACG, was associated with a higher risk of HCV infection. The results of our study suggest that genetic variants in CYP2R1 may be biomarkers for predicting the susceptibility to HCV infection in the Chinese population.

CD40 polymorphisms were associated with HCV infection susceptibility among Chinese population.

BACKGROUND: CD40, encoded by TNFRSF5, participates in the survival of B cells, process of antigen presentation and generation of CD8+ T cell memory. It also has an important effect on HCV antiviral immune response. This study aims to investigate whether TNFRSF5 gene polymorphisms are associated with HCV infection outcomes among Chinese population. METHODS: Three single nucleotide polymorphism (SNPs) (rs1535045, rs1883832, rs4810485) on TNFRSF5 were genotyped by TaqMan assay among Chinese population, including 1513 uninfected subjects, 496 spontaneous viral clearance subjects and 768 persistent HCV-infected subjects. Logistic analysis was used to compare these SNPs among different groups in this cross-sectional study. Functional annotations of the identified SNPs were further evaluated by bioinformatics analysis. RESULTS: After adjusted by age, gender and routes of infection, the results of logistic analysis indicated that individuals carrying rs1535045 T allele had a higher risk to infect HCV compared with C allele (in recessive model, adjusted OR = 1.368, 95%CI = 1.070-1.749, P = 0.012). Subjects carried rs1535045 TT genotype were more likely to infect HCV than wild CC genotype (adjusted OR = 1.397, 95%CI = 1.078-1.809, P = 0.011). For rs1883832, T allele was significantly associated with an increased risk of HCV infection (in recessive model, adjusted OR = 1.337, 95%CI = 1.069-1.673, P = 0.011). Subjects with TT genotype had more possibility to infect HCV (adjusted OR = 1.351, 95%CI = 1.060-1.702, P = 0.015). In the stratified analysis, rs1535045 and rs1883832 were remained in various subgroups and the heterogeneity test showed no pronounced heterogeneity in any pairwise comparison (all P > 0.05). In addition, the results of the cumulative effects showed a tendency of that the more risk alleles (rs1535045 T and rs1883832 T) subjects carried, the more possibility of HCV infection exhibited (P<0.001). In haplotype analyses, compared with the CC haplotype, CT, TC and TT was correlated with an increased risk to infect HCV (P = 0.029, P = 0.047 and P<0.001, respectively). CONCLUSIONS: In conclusion, CD40 polymorphisms were significantly associated with the susceptibility to HCV among Chinese populations.

The development of hepatocellular carcinoma in HCV-infected patients treated with DAA: A comprehensive analysis.

It has been proven that hepatitis C virus (HCV) eradication after interferon-based treatment can reduce the risk of hepatocarcinogenesis. However, there were some arguments about whether the treatment of direct-acting antivirals (DAAs) boosts the development of hepatocellular carcinoma (HCC). We systematically review this crucial topic by combining all the relevant articles to calculate the pooled HCC density after DAA treatment. Studies reporting the recurrence or occurrence in chronic hepatitis C patients who received DAA regimen were selected from three retrieval library screening. Data on baseline and outcomes were extracted independently by three observers. Primary outcomes were incidence density of HCC. Pooled estimates of HCC occurrence and recurrence rate per 100 person-years (py) were undertaken by random-effects meta-analysis. Sixteen studies with 61334 patients, embracing 20 cohorts, were enrolled in this study and divided into two groups (HCC occurrence and HCC recurrence). In the pooled analysis, HCC developed at a rate of 3.5/100 py [95% confidence interval (CI): 2.4, 5.3] among patients without a history of HCC compared with 17.4/100 py (95% CI: 7.8, 39.0) among patients existed. Furthermore, HCC occurrence rate following DAA-induced sustained virological response (SVR) was 2.1/100 py (95% CI: 1.4, 3.4); however, the rate in patients without SVR was 9.1/100 py (95% CI: 5.4, 15.3). HCV cured after DAA therapy could induce a reduction of 78% in the risk of HCC occurrence compared with non-responders. There is no strong evidence for an increased risk of HCC occurrence or recurrence in patients treated by DAA. There was a significant decline in the incidence of HCC occurrence after SVR.

Genetic variants in chemokine CC subfamily genes influence hepatitis C virus viral clearance.

Chemokine genes may influence both hepatitis C virus (HCV) spontaneous clearance in acute infection and treatment response in chronic infection. We conducted this study to evaluate whether the genetic variants in several CC family genes influence HCV spontaneous clearance and treatment response. The current research genotyped eight SNPs, including CCR1 rs3733096, rs13096371, CCR5 rs746492, rs1800874, CCL3 rs1130371, CCL5 rs3817656, CCL8 rs1133763, CCL14 rs854625, to explore their associations with HCV spontaneous clearance and response to treatment in two populations. We identified that the CCR1 rs3733096 (dominant model: adjusted OR = 2.29, 95% CI = 1.49-3.53, additive model: adjusted OR = 2.21, 95% CI = 1.50-3.25) and CCL5 rs3817656 (dominant model: OR = 1.37, 95% CI = 1.10-1.70, additive model: OR = 1.33, 95% CI = 1.12-1.58) were associated with HCV spontaneous clearance in Chinese Han population, while we found no association with treatment response. Moreover, the expression quantitative trait loci (eQTL) analysis showed that the risk alleles of rs3817656 were significantly associated with downregulated expression of CCL5 in whole blood (P < 0.001). The polymorphism of CCR1 rs3733096 and CCL5 rs3817656 are associated with spontaneous clearance of HCV in Chinese Han population.

Influence of IL28B and MxA gene polymorphisms on HCV clearance in Han Chinese population.

The high rate of chronic hepatitis C (CHC) was one of the key issues of global public health concern. Interferon (IFN)-λ relevant genes were in the antiviral treatment pathway, not only influenced hepatitis C virus (HCV) spontaneous clearance, but also affected the IFN-mediated viral clearance. The aim of this study was to identify the association of interleukin 28B (IL28B), myxovirus resistance A (MxA) gene polymorphisms with HCV spontaneous clearance and therapeutic response in Chinese CHC patients. IL28B and MxA gene genotypes were detected among 231 CHC carriers, 428 subjects with HCV spontaneous clearance and 662 CHC patients with pegylated IFN-α and ribavirin (pegIFN-α/RBV) treatment. Patients with MxA rs2071430 TT genotype were more likely to develop HCV infection chronicity (additive model: odds ratio (OR) 1.22, 95% confidence interval (CI) 1.01-1.48, P = 0.042). IL28B rs1298075 variant genotypes (additive model: OR 0.58, 95% CI 0.34-0.98, P = 0.040) and MxA rs17000900 variant genotypes (additive model: OR 0.54, 95% CI 0.30-0.99, P = 0.048) were less likely to achieve a sustained virological response. The life table indicated that patients with IL28B rs1298075 AG genotype were slower to achieve a viral load 106 copies/ml (all P < 0.05). This study illustrated that the carriage of IL28B rs12980275 AA had a positive effect on treatment response to pegIFN-α/RBV among Chinese CHC patients.

The relationship between human leukocyte antigen-DP/DQ gene polymorphisms and the outcomes of HCV infection in a Chinese population.

BACKGROUND: Recently, human leukocyte antigen (HLA) class-II gene polymorphisms have been reported to be related to Hepatitis C virus (HCV) infection and chronicity. The objective of this study was to explore the relationship of HLA-DP rs9277535 and HLA-DQ rs7453920 with the outcomes of HCV infection. METHODS: The rs9277535 and rs7453920 were genotyped in 370 subjects with chronic HCV infection, 194 subjects with spontaneous HCV clearance, and 973 subjects with non-HCV infection from the Chinese population using the ABI TaqMan allelic discrimination assay. RESULTS: Logistic regression analyses showed that the minor allele A of rs7453920 significantly increased the susceptibility of HCV infection in dominant model (adjusted OR = 1.33, 95% CI: 1.04-1.71, P = 0.026) and additive models (adjusted OR = 1.30, 95% CI: 1.06-1.60, P = 0.012). Rs9277535 A allele significantly increased the risk of chronic HCV infection in dominant model (adjusted OR = 1.52, 95% CI: 1.01-2.28, P = 0.046). Haplotype AA showed a higher risk of HCV infection than the most frequent haplotype GG (adjusted OR = 1.37, 95% CI: 1.05-1.78, P = 0.018). CONCLUSION: The HLA-DQ rs7453920 and -DP rs9277535 mutations were significantly associated with HCV infection susceptibility and chronicity, respectively.

Global, regional, and national time trends in the burden of epilepsy, 1990-2019: an age-period-cohort analysis for the global burden of disease 2019 study.

Background: Epilepsy is a non-communicable chronic brain disease that affects all age groups. There are approximately 50 million epilepsy patients worldwide, which is one of the most common neurological disorder. This study reports the time trends in the burden of epilepsy from 1999 to 2019. Methods: We evaluated the disease burden and its temporal trends of epilepsy using the prevalence and years lived with disability (YLDs), which was estimated based on the Global Burden of Disease (GBD) 2019 study. The age-period-cohort (APC) model was used to estimate the temporal trends of the epilepsy prevalence and YLDs rates, and to analyze the relative risks of age, periods and queues (age/period/queue effects). Results: In the past 30 years, the global age-standardized prevalence rate and age-standardized rate has increased by 29.61% and 27.02%, respectively. Globally, the APC model estimated the net drift of prevalence and YLDs were 0.88% (95% CI: 0.83-0.93) and 0.80% (95% CI: 0.75-0.85) per year. Among 204 countries and territories, the YLDs in 146 and prevalence 164 showed an increasing trend. And the risk of YLDs and prevalence increases with age, with the lowest risk among 0-4 years old and the highest risk among 75-79 years old. Unfavorable increasing period and cohort risks of YLDs and prevalence were observed. Conclusion: Over the past 30 years, the YLDs and prevalence of epilepsy have gradually increased globally and unfavorable increasing period and cohort risks were observed. Emphasizing epilepsy prevention, strengthening epilepsy health education, optimizing older adults epilepsy diagnosis and treatment plans, and actively promoting epilepsy diagnosis and treatment plans can effectively reduce new cases of epilepsy and related disabilities.

A combined association of serum uric acid, alanine aminotransferase and waist circumference with non-alcoholic fatty liver disease: a community-based study.

Background: Increasing evidence has supported that serum uric acid (SUA), alanine aminotransferase (ALT) and waist circumference (WC) are associated with the occurrence of non-alcoholic fatty liver disease (NAFLD). However, the combined role of these factors in early screening of NAFLD has not been investigated. We aimed to de lineate this role in a community-based population. Methods: Binary logistic regression was used to explore the correlations of SUA, ALT and WC with NAFLD risk. The goodness of fit and discriminative ability of the model were evaluated by the Hosmer-Lemeshow test and area under the receiver operating characteristic curve (AUROC), respectively. Results: Logistic regression analysis indicated that elevated SUA (adjusted odds ratio (OR) = 2.44, 95% confidence interval (CI) [1.76-3.38]), ALT (adjusted OR = 4.98, 95% CI [3.41-7.27]) and WC (adjusted OR = 3.22, 95% CI [2.01-5.16]) were facilitating factors for incident NAFLD after fully adjusted for related confounders. In addition, the risk of NAFLD followed linear trend s with increasing levels of these three indicators (all P trend < 0.001). The risk assessment model consisting of SUA, ALT, WC and demographics showed useful discrimination by AUROC being 0.825 (95% CI [0.811-0.838]) and good performance of calibration (P = 0.561). Conclusions: SUA, ALT and WC were all associated with NAFLD, independent of known risk factors. The simple model composed of these indicators showed good performance in the Chinese population, which may be applicable for appraisal of NAFLD risk in primary healthcare.

Efficacy and Safety of Direct-Acting Antivirals in Kidney Transplantation From HCV-Viremic Donors to Negative Recipients: A Meta-Analysis.

Background: With the development of direct-acting antiviral agents (DAAs), the research on kidney transplantation from Hepatitis C virus (HCV)-viremic donors to HCV-negative recipients has grown. The objective of this comprehensive analysis was to evaluate the efficacy and safety of DAAs in kidney transplantation from HCV-viremic donors to negative recipients. Methods: Multiple databases were searched for a systematic and comprehensive up to March 2022. The primary outcomes included the percentage of sustained virological response at week 12 after the end of treatment (SVR12), adverse events (AEs; any grade), and severe adverse events (SAEs) as the endpoints. Publication bias was examined by using the funnel plots and Egger's test. Results: In total, 16 studies with 454 subjects were included in the study and the pooled estimate of SVR12, AEs, and SAEs rates were 100.0% (95% CI: 99.2-100.0), 1.9%(95%CI: 0.0-4.9), and 0.0% (95%CI: 0.0-1.5). Subgroup analysis showed that pooled SVR12 rates were 100.0% (95%CI: 99.6-100.0) for genotype (GT)1a and 96.3% (95%CI: 83.3-100.0) for GT2; 100.0% (95%CI: 98.9-100.0) for DAAs treatments; and 100.0% (95%CI: 98.2-100.0) for prophylaxis subgroup. Egger's tests showed that no publication bias was found in this study. Conclusion: This comprehensive analysis showed the high efficacy and safety of DAAs in kidney transplantation from HCV-viremic donors to HCV-negative recipients. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=246541.

Genetic Variants in KIR/HLA-C Genes Are Associated With the Susceptibility to HCV Infection in a High-Risk Chinese Population.

Background: KIR/HLA-C signaling pathway influences the innate immune response which is the first defense to hepatitis C virus (HCV) infection. The aim of this study was to determine the association between the genetic polymorphisms of KIR/HLA-C genes and the outcomes of HCV infection in a high-risk Chinese population. Methods: In this case-control study, four single nucleotide polymorphisms (SNPs) of KIR/HLA-C genes (KIR2DS4/KIR2DS1/KIR2DL1 rs35440472, HLA-C rs2308557, HLA-C rs1130838, and HLA-C rs2524094) were genotyped by TaqMan assay among drug users and hemodialysis (HD) patients including 1,378 uninfected control cases, 307 subjects with spontaneous viral clearance, and 217 patients with persistent HCV infection. Bioinformatics analysis was used to functionally annotate the SNPs. Results: After logistic regression analysis, the rs35440472-A and rs1130838-A alleles were found to be associated with a significantly elevated risk of HCV infection (OR = 1.562, 95% CI: 1.229-1.987, P < 0.001; OR = 2.134, 95% CI: 1.180-3.858, P = 0.012, respectively), which remained significant after Bonferroni correction (0.05/4). The combined effect of their risk alleles and risk genotypes (rs35440472-AA and rs1130838-AA) were linked to the increased risk of HCV infection in a locus-dosage manner (all Ptrend < 0.001). Based on the SNPinfo web server, rs35440472 was predicted to be a transcription factor binding site (TFBS) while rs1130838 was predicted to have a splicing (ESE or ESS) function. Conclusion: KIR2DS4/KIR2DS1/KIR2DL1 rs35440472-A and HLA-C rs1130838-A variants are associated with increased susceptibility to HCV infection in a high-risk Chinese population.

Vitamin D Level and Vitamin D Receptor Genetic Variation Were Involved in the Risk of Non-Alcoholic Fatty Liver Disease: A Case-Control Study.

Background: It has been demonstrated that vitamin D receptor (VDR), a key gene in the metabolism of vitamin D (VD), may affect the development of Non-alcoholic fatty liver disease (NAFLD) by regulating VD level and its biological effects. Objectives: To investigate the effects of serum VD level, VDR variation, and a combination of VDR SNP and environmental behavior factor on the risk of NAFLD. Methods: A total of 3023 subjects from a community in Nanjing were enrolled, including 1120 NAFLD cases and 1903 controls. Serum 25(OH)D3 levels were measured and eight single nucleotide polymorphisms (SNPs) in VDR gene were genotyped. Results: Logistic regression analyses indicated that VD sufficiency and VD insufficiency were significantly associated with a low risk of NAFLD (all P<0.05; all Ptrend<0.05, in a locus-dosage manner). After adjusting for gender and age, VDR rs2228570-A and rs11168287-A alleles were all reduced the risk of NAFLD (all PFDR=0.136, in dominant model; Ptrend =0.039, combined effects in a locus-dosage manner). The protective effects of two favorable alleles were more evident among subjects ≤40 years, non-hypertension, non-hyperglycemia and non-low high density lipoprotein-cholesterol (all P<0.05). The area under the receiver operating curve of the combination of VDR SNP and exercise time for assessing NAFLD risk was slightly higher than that of only including exercise time or neither (all P<0.05). Conclusion: High serum VD levels and VDR variants (rs2228570-A and rs11168287-A) might contribute to a low risk of NAFLD in Chinese Han population. The inclusion of VDR SNP and exercise time could improve the efficiency in assessment of NAFLD risk, which might provide a novel perspective for early screening and preventing NAFLD.

Genetic variant of RXR involved in the vitamin D metabolic pathway was linked to HCV infection outcomes among a high-risk Chinese population.

Genetic variation of related genes in Vitamin D (VD) metabolic pathway played an important role in antiviral immune response and chronic hepatitis C virus (HCV) infection. Retinoid X receptor (RXR) is one of the key genes in the metabolism pathway of VD. This study aims to investigate the effect of single nucleotide polymorphisms (SNPs) in RXR on the outcomes of HCV infection. Three SNPs (RXRɑ-rs4842194, rs1045570 and RXRß-rs2076310) were genotyped using Sequenom MassARRAY platform in 515 spontaneous clearance subjects, 830 persistent infection subjects, and 1062 uninfected subjects. Multivariate stepwise regression analyss was used to identify the prediction factors for HCV infection outcomes. The USCS Brower and RNAfold web serves were performed to further explore the potential biological functions of positive SNPs. The results of logistic regression analysis after adjusting for age, gender and types of high-risk population showed that subjects with RXRß rs2076310-T (recessive model: adjusted OR = 1.598, 95%CI = 1.126-2.267, P = 0.009; additive model: adjusted OR = 1.196, 95%CI = 1.011-1.416, P = 0.037) had a significantly increased possibility of HCV infection chronicity. Rs2076310, age, types of high-risk population and aspartate aminotransferase were independent predictors of chronic HCV infection (P < 0.05). And the area under the receiver operating characteristic curve of combined effects of these factors was 0.679. Bioinformatics analysis indicated that rs2076310 could affect the gene expression level by affecting the transcriptional regulatory activity of the corresponding gene region. These findings indicated that genetic variation of RXRß was associated with the risk of HCV infection chronicity among a high-risk Chinese population.

Genetic Variants in TNFSF4 and TNFSF8 Are Associated With the Risk of HCV Infection Among Chinese High-Risk Population.

BACKGROUND: The tumor necrosis factor superfamily (TNFSF) and TNF receptor superfamily (TNFRSF) play important roles in the immune responses to infections. The aim of this study was to determine the impact of single nucleotide polymorphisms (SNPs) of several TNFSF/TNFRSF genes on the risk of hepatitis C virus (HCV) infection in the Chinese high-risk population. METHODS: The TNFSF4-rs1234313, TNFSF4-rs7514229, TNFSF8-rs3181366, TNFSF8-rs2295800, TNFRSF8-rs2298209, and TNFRSF8-rs2230625 SNPs were genotyped in 2309 uninfected controls, 597 subjects with spontaneous HCV clearance and 784 patients with persistent HCV infection using the TaqMan-MGB assay. The putative functions of the positive SNPs were determined using online bioinformatics tools. RESULTS: After adjusting for gender, age, high-risk population, alanine transaminase (ALT), aspartate aminotransferase (AST), IL28B-rs12979860 and rs8099917 genotypes, the non-conditional logistic regression showed that rs7514229-T, rs3181366-T, and rs2295800-C were associated with an increased risk of HCV infection (all P FDR < 0.05). Combined analysis of rs7514229-T and rs3181366-T risk alleles showed that the subjects carrying 2-4 risk alleles were more susceptible to HCV infection compared with those lacking any risk allele (all P < 0.001). Furthermore, the risk of HCV infection increased with the number of risk alleles (P trend < 0.001). In silico analysis showed that rs7514229, rs3181366, and rs2295800 polymorphisms may affect the transcription of mRNA by regulating miRNA binding, TF binding, and promoter activation, respectively, which may have biological consequences. CONCLUSION: TNFSF4-rs7514229, TNFSF8-rs3181366, and TNFSF8-rs2295800 are associated with increased risk of HCV infection in the Chinese high-risk population.

Hemoglobin glycation index in relationship to the risk of cardiovascular complication in patients with type 2 diabetes: A systematic review and meta-analysis.

AIM: To estimate the association of hemoglobin glycation index (HGI) level with total mortality and cardiovascular complication risk among patients with T2DM. METHODS: Literatures evaluating the associations of HGI with the risk of cardiovascular outcomes and total mortality in patients with T2DM were systematically searched by using the PubMed and Embase databases from January 2002 to April 2019. Fixed-effects model and random-effects model meta-analyses were used to calculate pooled adjusted hazard ratios (HRs). RESULTS: Six prospective cohort studies and one nest case-control study (comprising n = 37,280) were included in this systematic review. T2DM patients with high HGI level had significant high HRs (95% confidence interval, 95% CI) for cardiovascular complication [1.25 (1.16, 1.36)] and total mortality [1.26 (1.14, 1.39)] compared to intermediate HGI level. For every 1-unit increment in HGI, the average HR (95% CI) were 1.20 (1.00, 1.41) for cardiovascular complication and 1.13 (1.06, 1.19) for total mortality. CONCLUSIONS: The findings suggested that a rising HGI level was associated with the increased risk for cardiovascular complication and total mortality among patients with T2DM.