Sp1-activated FGFR2 is involved in early-life exposure to nickel-induced craniosynostosis by regulating the ERK1/2 signaling pathway.

Nickel, a common environmental hazard, is a risk factor for craniosynostosis. However, the underlying biological mechanism remains unclear. Here, we found that early-life nickel exposure induced craniosynostosis in mice. In vitro, nickel promoted the osteogenic differentiation of human mesenchymal stem cells (hMSCs), and its osteogenic ability in vivo was confirmed by an ectopic osteogenesis model. Further mRNA sequencing showed that ERK1/2 signaling and FGFR2 were aberrantly activated. FGFR2 was identified as a key regulator of ERK1/2 signaling. By promoter methylation prediction and methylation-specific PCR (MSP) assays, we found that nickel induced hypomethylation in the promoter of FGFR2, which increased its binding affinity to the transcription factor Sp1. During pregnancy and postnatal stages, AZD4547 rescued nickel-induced craniosynostosis by inhibiting FGFR2 and ERK1/2. Compared with normal individuals, nickel levels were increased in the serum of individuals with craniosynostosis. Further logistic and RCS analyses showed that nickel was an independent risk factor for craniosynostosis with a nonlinear correlation. Mediated analysis showed that FGFR2 mediated 30.13% of the association between nickel and craniosynostosis risk. Collectively, we demonstrate that early-life nickel exposure triggers the hypomethylation of FGFR2 and its binding to Sp1, thereby promoting the osteogenic differentiation of hMSCs by ERK1/2 signaling, leading to craniosynostosis.

Association of air pollution exposure and increased coronary artery disease risk: the modifying effect of genetic susceptibility.

BACKGROUND: Both genetic factors and air pollution are risk factors for coronary artery disease (CAD), but their combined effects on CAD are uncertain. The study aimed to comprehensively investigate their separate, combined and interaction effects on the onset of CAD. METHODS: We utilized data from the UK Biobank with a recruitment of 487,507 participants who were free of CAD at baseline from 2006 to 2010. We explored the separate, combined effect or interaction association among genetic factors, air pollution and CAD with the polygenic risk score (PRS) and Cox proportional hazard models. RESULTS: The hazard ratios (HRs) [95% confidence interval (CI)] of CAD for 10-µg/m3 increases in PM2.5, NO2 and NOx concentrations were 1.25 (1.09, 1.44), 1.03 (1.01, 1.05) and 1.01 (1.00, 1.02), respectively. Participants with high PRS and air pollution exposure had a higher risk of CAD than those with the low genetic risk and low air pollution exposure, and the HRs (95% CI) of CAD in the PM2.5, PM10, NO2 and NOx high joint exposure groups were 1.56 (1.48, 1.64), 1.55(1.48, 1.63), 1.57 (1.49, 1.65), and 1.57 (1.49, 1.65), respectively. Air pollution and genetic factors exerted significant additive effects on the development of CAD (relative excess risk due to the interaction [RERI]: 0.12 (0.05, 0.19) for PM2.5, 0.17 (0.10, 0.24) for PM10, 0.14 (0.07, 0.21) for NO2, and 0.17 (0.10, 0.24) for NOx; attributable proportion due to the interaction [AP]: 0.09 (0.04, 0.14) for PM2.5, 0.12 (0.07, 0.18) for PM10, 0.11 (0.06, 0.16) for NO2, and 0.13 (0.08, 0.18) for NOx). CONCLUSION: Exposure to air pollution was significantly related to an increased CAD risk, which could be further strengthened by CAD gene susceptibility. Additionally, there were positive additive interactions between genetic factors and air pollution on the onset of CAD. This can provide a more comprehensive, precise and individualized scientific basis for the risk assessment, prevention and control of CAD.

Association of gut microbiota composition and craniosynostosis.

Background: Gut microbiota has been reported to be associated with a series of metabolic diseases including metabolic bone disease. However, study about gut microbiota and craniosynostosis (CS) is very rare. We aim to investigate the gut microbiota composition in CS patients and assess the possible relationship. Methods: A total of 30 infants with CS and 30 infants with non-CS treated in Children's Hospital of Nanjing Medical University of Jiangsu Province from June 2021 to March 2022 were finally included in this study. All processing and analysis are carried out using 16S ribosomal RNA (rRNA) high-throughput gene sequencing. Results: The CS group have significantly lower levels of family, genus, and species than non-CS group (all P<0.05). Furthermore, Staphylococcales and Lactobacillales at the order level, Enterococcaceae and Staphylococcaceae at the family level, and Enterococcus and Staphylococcus at the genus level were significantly enriched in the CS group (all P<0.05). Additionally, functional prediction showed that six metabolic pathways significantly differed between the two groups (all P<0.05). Of those, pathways involving polycyclic aromatic hydrocarbon degradation (P=0.030) and penicillin and cephalosporin biosynthesis (P=0.027) were more abundant in CS group than in non-CS group. Conclusions: Gut microbiota was statistically associated with the development of CS, and several taxa and specific functional pathways with significantly altered abundance have been identified in CS patients. These findings can provide clues for the study on the mechanism and early diagnosis of CS.

The Association of Metabolomic Profiles of a Healthy Lifestyle with Heart Failure Risk in a Prospective Study.

Lifestyle has been linked to the incidence of heart failure, but the underlying biological mechanisms remain unclear. Using the metabolomic, lifestyle, and heart failure data of the UK Biobank, we identified and validated healthy lifestyle-related metabolites in a matched case-control and cohort study, respectively. We then evaluated the association of healthy lifestyle-related metabolites with heart failure (HF) risk and the added predictivity of these healthy lifestyle-associated metabolites for HF. Of 161 metabolites, 8 were identified to be significantly related to healthy lifestyle. Notably, omega-3 fatty acids and docosahexaenoic acid (DHA) positively associated with a healthy lifestyle score (HLS) and exhibited a negative association with heart failure risk. Conversely, creatinine negatively associated with a HLS, but was positively correlated with the risk of HF. Adding these three metabolites to the classical risk factor prediction model, the prediction accuracy of heart failure incidence can be improved as assessed by the C-statistic (increasing from 0.806 [95% CI, 0.796-0.816] to 0.844 [95% CI, 0.834-0.854], p-value < 0.001). A healthy lifestyle is associated with significant metabolic alterations, among which metabolites related to healthy lifestyle may be critical for the relationship between healthy lifestyle and HF. Healthy lifestyle-related metabolites might enhance HF prediction, but additional validation studies are necessary.

Association between NMR metabolomic signatures of healthy lifestyle and incident coronary artery disease.

AIMS: To identify metabolites associated with a healthy lifestyle and explore the possible mechanisms of lifestyle in coronary artery disease (CAD). METHODS AND RESULTS: The nuclear magnetic resonance metabolomics platform was applied to perform metabolomic profiling of baseline plasma samples from a randomly selected subset of 121 733 UK Biobank participants. Cox proportional hazards models with covariate adjustments were used to investigate the associations between validated lifestyle-associated metabolites and incident CAD and to estimate the accuracy of the inclusion of metabolites to predict CAD compared with traditional prediction models. The discriminatory ability of each model was evaluated using Harrell's C statistic, integrated discrimination improvement (IDI), and continuous net reclassification improvement (NRI) indexes. During a median of 8.6 years of follow-up, 5513 incident CAD cases were documented. Among the 111 lifestyle-associated metabolites, 65 were significantly associated with incident CAD after multivariate adjustment (Bonferroni P < 3.11 × 10-04). The addition of these metabolites to classic risk prediction models [Framingham Risk Score (FRS) using lipids; FRS using body mass index] improved CAD prediction accuracy as assessed by the C statistic (increasing to 0.739 [95% CI, 0.731-0.747] and 0.752 [95% CI, 0.746-0.758]), respectively; continuous NRI (0.274 [0.227-0.325] and 0.266 [0.223-0.317]) and IDI (0.003 [0.002-0.004] and 0.003 [0.002-0.004]). CONCLUSION: Healthy lifestyle-associated metabolites are associated with the incidence of CAD and may help improve the prediction of CAD risk. The use of metabolite information combined with the FRS model warrants further investigation before clinical implementation.

Interactions among maternal smoking, breastfeeding, and offspring genetic factors on the risk of adult-onset hypertension.

BACKGROUND: Previous studies have reported that maternal smoking during pregnancy and breastfeeding may affect the occurrence of hypertension, but whether early life factors modify the impact of the offspring's genetic risk on hypertension is still unknown. The aim of this study was to investigate the relationships among maternal smoking and breastfeeding with adult-onset hypertension and the modified impact of offspring genetic susceptibility. METHODS: This study included 437,185 participants from the UK Biobank who were initially free of hypertension and provided a prospective cohort of individuals aged 40 to 69 years. The association of maternal smoking during pregnancy and breastfeeding with hypertension was examined by using the Cox regression model. Then, a polygenic risk score (PRS) for hypertension was used to test the gene-environmental interaction on hypertension. RESULTS: During a median follow-up period of 8.7 years, a total of 68,148 cases of hypertension were identified in this study. The hazard ratios (HRs) and 95% confidence intervals (CIs) of hypertension for maternal smoking and breastfeeding were 1.11 (1.09, 1.13) and 0.96 (0.94, 0.98), respectively. However, no evidence of an interaction between maternal smoking and breastfeeding was observed. Across all levels of genetic risk, including high genetic risk, maternal smoking and nonbreastfeeding had higher hypertension hazards than nonmaternal smoking and breastfeeding, respectively. The adjusted HRs (95% CIs) of hypertension were 1.80 (1.73, 1.87) in those who had high genetic predisposition plus maternal smoking and 1.67 (1.60-1.74) in those with nonbreastfeeding and high genetic risk. There were significant additive interactions between maternal smoking or breastfeeding and genetic factors on the incidence of hypertension. CONCLUSIONS: Maternal smoking and nonbreastfeeding were associated with a higher risk of hypertension in adulthood and may attenuate the risk of hypertension related to genetic factors. These results suggested that adherence to nonmaternal smoking and breastfeeding was associated with a lower risk of hypertension among participants with all gradients of genetic risk.

Association of ambient air pollution exposure with low birth weight.

Increasing evidence has shown that exposure to air pollution is linked to adverse birth outcomes, but the results are not consistent. This study was performed on a subset of participants from the UK Biobank between 2006 and 2010. The land use regression (LUR) model was constructed to calculate the concentrations of particulate matter (PM2.5, PM2.5-10 and PM10), nitrogen oxides (NOx), and nitrogen dioxide (NO2). Binary logistic/multivariate linear regression models were applied to explore the potential linear relationships between air pollution exposure and newborn low birth weight (LBW) or BW. The Cochran-Armitage trend test was used to explore the possible association between the air pollution level and LBW. A restricted cubic spline (RCS) transformation of exposure variables was applied to visualize the relation of air pollutants to BW. Exposure to air pollutants, especially PM2.5 and PM10, was positively associated with LBW, and the odds ratios (ORs) and 95% confidence intervals (CIs) for each 10-µg/m3 increase in PM2.5 and PM10 were 1.25 ([1.03, 1.51], P = 0.025) and 1.12 ([1.02, 1.24], P = 0.021), respectively. A negative correlation was observed between the BW and PM2.5 (-0.05 [-0.08, -0.02], P = 0.001), PM10 (-0.03 [-0.05, -0.02], P < 0.001), PM2.5-10 (-0.04 [-0.07, -0.01], P < 0.001) and NOx (0.00 [0.00, 0.00], P = 0.021). Additionally, the BW changed dramatically up to a specific point (PM2.5 for 10.74 µg/m3, Pnonlinearity = 0.004; PM10 for 16.06 µg/m3, Pnonlinearity = 0.004; NO2 for 25.58 µg/m3, Pnonlinearity <0.001; and NOx for 39.88 µg/m3, Pnonlinearity <0.001), subsequently becoming relatively stable. PM2.5 and PM10 exposure were positively associated with LBW, and a negative correlation was observed between PM2.5, PM2.5-10, PM10 and NOx and BW.

Air pollution, genetic factors and the risk of depression.

Both genetics and ambient air pollutants contribute to depression, but the degree to which genetic susceptibility modifies the effect of air pollution on depression remains unknown. We aimed to investigate the effect of the modification of genetic susceptibility on depression. Notably, 490,780 participants who were free of depression at baseline in the UK Biobank study were recruited from 2006 to 2010. A land use regression (LUR) model was performed to estimate the concentrations of particulate matter with diameters ranging from ≤2.5-≤10 µm (PM2.5, PM2.5-10 and PM10), nitrogen dioxide (NO2), and nitrogen oxides (NOx). The International Classification of Diseases 10th Revision (ICD-10) code was used to identify depression cases. Cox proportional hazard models adjusted for covariates were used to investigate the association between ambient air pollutants and depression. Moreover, the polygenic risk score (PRS) was calculated to evaluate cumulative genetic effects, and additive interaction models were established to explore whether genetic susceptibility modified the effects of air pollutants on depression. PM2.5, PM10, NO2 and NOx exposure were significantly positively associated with the risk of depression, and the hazard ratios and 95 % confidence intervals for a 10-µg/m3 increase in PM2.5, PM10, NO2 and NOx concentrations were 2.12 (1.82, 2.47), 1.12 (1.03, 1.23), 1.07 (1.05, 1.10) and 1.04 (1.03, 1.05), respectively. Air pollutants and genetic variants exerted significant additive effects on the risk of depression (relative excess risk due to the interaction [RERI]: 0.15 for PM2.5, 0.12 for PM10, 0.10 for NO2, and 0.12 for NOx; attributable proportion due to the interaction [AP]: 0.12 for PM2.5, 0.10 for PM10, 0.08 for NO2, and 0.09 for NOx). Air pollution exposure was significantly associated with the risk of depression, and participants with a higher genetic risk were more likely to develop depression when exposed to high levels of air pollution.

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.

High SVR12 With 8-Week Course of Direct-Acting Antivirals in Adolescents and Children With Chronic Hepatitis C: A Comprehensive Analysis.

Direct-acting antiviral (DAA) treatment for 8 weeks has a sustained virological response rate in adults with chronic hepatitis C. We have conducted a systematic review and meta-analysis to compare the efficacy and safety of the 8-week vs. 12/24-week DAA treatment in adolescents and children with CHC. The PubMed, Web of Science, and Cochrane databases were searched for the relevant articles from January 1, 2017 to August 28, 2020 and further screened for literature reviews on April 1, 2021. Pool proportions with 95% CIs for SVR12 were summarized with fixed/random effects models using Freeman-Tukey double arcsine transformation. Subgroup analysis was used to explore the source of heterogeneity. Thirty-six relevant publications were identified. For adolescents aged 12-17 years old, the pooled SVR12 and AE rate were 99.4% (95% CI: 98.7-99.9) and 34.7% (95% CI: 31.9-37.6). No one discontinued treatment due to drug intolerance. In addition, the SVR12 adolescents treated for 12 and 8/24 weeks were 99.3% (95% CI: 98.4-99.9) and 100%, respectively. The pooled SVR12 rate, AEs, and SAEs for children younger than 12 years were 98.9% (95% CI: 97.3-99.8), 51.6% (95% CI: 47.0-56.2), and 1.1% (95% CI: 0.4-2.5), respectively. The most common AE was fatigue (28.4%). The SVR12 was 98.8% (95% CI: 97.1-99.8) and 100% for the pediatric patients treated for 12 weeks and 8/24 weeks, respectively. Taken together, DAAs are generally effective against CHC and well-tolerated by the adolescents and children. A treatment duration of 8 weeks is equally effective and safe as 12/24 weeks in this demographic group.

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.

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.

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.

Efficacy and Safety of Glecaprevir/Pibrentasvir in HCV Patients With Previous Direct-Acting Antiviral Therapy Failures: A Meta-Analysis.

Background: Since a greater number of hepatitis C virus (HCV) patients have access to direct-acting antiviral (DAA) based therapies, the number of patients not properly responding to prior DAA regimens is increasing. The objective of this comprehensive analysis was to assess the efficacy and safety of glecaprevir/pibrentasvir (GLE/PIB) in HCV patients who experienced previous DAA therapy failures. Methods: Bibliographic databases were systematically searched for relevant articles published by November 2020. The main endpoints were sustained viral response after 12 weeks (SVR12), adverse events (AEs; any grade) and severe adverse events (SAEs). Publication bias assessment was performed using funnel plots and the Egger's test. Results: Fourteen studies consisting of a total of 1,294 subjects were included in this study and the pooled estimate of SVR12, AEs and SAEs rates were 96.8% (95%CI: 95.1-98.2), 47.1% (95%CI: 26.0-69.3), and 1.8% (95%CI: 0.7-3.4), respectively. Subgroup analysis showed that pooled SVR12 rates were 97.9% (95%CI: 96.7-98.9) for Japan and 91.1% (95%CI: 87.3-94.3) for the United States; 95.8% (95%CI: 93.9-97.4) for genotype (GT)1 and 100.0% (95%CI: 99.6-100.0) for GT2; 95.3% (95%CI: 92.4-97.2) for cirrhosis and 96.3% (95%CI: 94.2-97.7) for non-cirrhosis cases. There was no publication bias included this study. Conclusion: This comprehensive analysis revealed that GLE/PIB is an effective and secure retreatment option for patients who did not optimally respond to DAA treatment, especially the Asian population with GT1-2.

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.

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.