Single Nucleotide Polymorphisms Rs12979860 Research Articles

The impact of interleukin 28B rs12979860 single nucleotide polymorphism and liver fibrosis stage on response-guided therapy in HIV/HCV-coinfected patients

The impact of interleukin 28B rs12979860 single nucleotide polymorphism and liver fibrosis stage on response-guided therapy in HIV/HCV-coinfected patients

IL28B Polymorphism, Pretreatment CXCL10, and HCV RNA Levels Predict Treatment Response in Racially Diverse HIV/HCV Coinfected and HCV Monoinfected Patients

We sought to develop a score to predict sustained virological response (SVR) in racially diverse HIV/hepatitis C virus (HCV)-coinfected and HCV-monoinfected pegylated interferon/ribavirin-treated patients. We retrospectively evaluated 374 patients (259 monoinfected and 115 coinfected) treated at a single tertiary care center. The IL28B rs12979860 single nucleotide polymorphism genotyping was performed in 335 patients, and plasma CXCL10 levels were measured by enzyme-linked immunosorbent assay in 171 patients. Of the 374 patients, 64.9% were white, 17.2% were African American, 76.5% were HCV genotype 1 infected, and 49.3% had advanced fibrosis. Sustained virological response was achieved by 151 (40.4%) patients, 106 (40.9%) patients monoinfected, and 45 (39.1%) patients coinfected. Patients with IL28B C/C genotype were significantly more likely to achieve an SVR compared with non-C/C genotype patients, but only if they were infected with HCV genotypes 1/4 (59.1% vs 21.1%, P < 0.0001). No significant differences existed in IL28B predictive capacity between coinfected and monoinfected patients. Pretreatment CXCL10 levels were significantly higher in nonresponders, both monoinfected and coinfected, compared with SVR patients (P = 0.0018). Coinfected patients had higher CXCL10 levels compared with monoinfected patients (P = 0.03). The combination of IL28B genotype, pretreatment CXCL10 and HCV RNA levels, and HCV genotype had the best ability to predict treatment response in both patient groups (area under the receiver operating characteristic curve = 0.85). Among all patients, a cutoff score of -0.94 or more had a sensitivity of 0.93 and specificity of 0.59. In coinfected patients, a score of -0.55 or more had sensitivity of 0.81 and specificity of 0.80. IL28B genotype, pretreatment CXCL10, and HCV RNA levels have very good capacity to predict pegylated interferon/ribavirin-treatment outcome in both HIV/HCV coinfected and HCV monoinfected patients.

Su2084 Influence of Polymorphisms in the Cytokine Genes As Risk Factors for IBS and TMJD

Background: Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder with still unknown pathophysiology presumed to develop due to complex interactions between the sensitizing effects of inflammation, CNS dis-inhibition, gut immunity, psychosocial stressors and genetic influences. Prior studies have shown an increase of proinflammatory cytokines IL-6, IL-1β, and TNF-α from mononuclear cells within the cecum of subjects with IBS. IBS is also frequently associated with other chronic pain conditions such as temporomandibular disorders (TMD), which has an inflammatory influence and is found in 16% of patients with IBS. Objective: The aim of our study was to evaluate whether specific cytokine genes previously found to be associated with TMD are also associated with IBS. We hypothesized that if these two pain disorders share common pathophysiologic mechanisms, then they may show similar associations with polymorphisms in the proinflammatory cytokine genes. Methods: A total of 122 women were enrolled in this study (72 with IBS, 25 with TMD, and 25 controls). IBS subjects were diagnosed using Rome II criteria and those with TMD were evaluated using the research diagnosis criteria for TMD (RDC). Single nucleotide polymorphisms (SNPs) to be genotyped were selected based on results of prior identified risk loci for pain sensitivity in subjects with TMD analyzed by our group. Peripheral blood samples from all participants were analyzed using restriction fragment length polymorphisms of PCR chain products. A Chi-Square statistical analysis was used to compare allele frequencies across IBS, TMD and controls and haplotypes were constructed using EM algorithm and the association between haplotypes and test groups. Results: IL1 β, IL6 and TNFα SNPs were significantly associated with IBS compared to controls and TMD (p value ,.05). Two IL1 β SNPs (rs700518, rs 1143634), one TNF α SNP (rs1800629) and IL6 SNP were associated with IBS (p value , .05) versus controls. For IBS versus TMD, significant differences in allele frequencies emerged in the following SNPs, IL1 β (rs16944) and TNFα -(rs1800629 and rs1800683). The two-SNP haplotype of the TNF α gene was strongly associated with IBS compared with TMD and controls (p,0.0001). None of these polymorphisms were associated with TMD. Conclusion: Polymorphisms in specific cytokine genes may be a risk factor for IBS. The presence of the haplotype formed by SNPs rs1800629 and rs1800683 in the TNFα gene may increase the susceptibility to IBS in women. The lack of significance associations with TMD however may be due to our small sample size.

IL28B SNP screening and distribution in the French Canadian population using a rapid PCR-based test

Single nucleotide polymorphisms (SNPs) in the proximity of the interleukin-28B (IL28B) gene can predict spontaneous resolution of hepatitis C virus (HCV) infection and response to interferon therapy. Screening for this polymorphism has become part of the standard criteria for the management of HCV-infected patients, hence the need for a rapid, cost-effective screening method. Here, we describe a rapid PCR-based test to screen for two IL28B SNPs (rs12979860 and rs8099917). We used this test to investigate IL28B polymorphism and prevalence in a cohort of French Canadian injection drug users who are part of a unique population known to have a strong genetic founder effect. This population had lower linkage disequilibrium between the two tested SNPs as compared to other cohorts (|d′| = 0.68, r = 0.59). The special genetic makeup should be considered in the management of HCV-infected patients within that population.

TNF-α, IL6, and IL10 polymorphisms and the effect of physical exercise on inflammatory parameters and physical performance in elderly women

High levels of inflammatory mediators are associated with reduced physical capabilities and muscle function in the elderly. Single nucleotide polymorphisms (SNPs) may affect the expression and synthesis of these molecules, thus influencing the intensity of the inflammatory response and susceptibility to certain diseases. Physical exercise may attenuate age-related chronic inflammation and improve physical performance. This study evaluated the interaction between the SNP rs1800629 in TNF-α, rs1800795 in IL6, and rs1800896 in IL10 and the effect of physical exercise on physical performance and inflammation in elderly women. There was a significant interaction between rs1800629 and the effect of exercise on physical performance and between the combined 3-SNP genotype and changes in physical performance in response to exercise. These SNPs did not influence the effect of exercise on inflammatory parameters. Elderly women with a combination of genotypes associated with an anti-inflammatory profile (low TNF-α and IL-6 production, high IL-10 production) showed better physical performance independent of exercise modality, evidence of an interactive influence of genetic and environmental factors on improving physical performance in elderly women.

Meta-analysis of associations between TCF7L2 polymorphisms and risk of type 2 diabetes mellitus in the Chinese population

BackgroundAssociations between transcription factor 7-like 2 (TCF7L2) polymorphisms and type 2 diabetes mellitus (T2DM) have been evaluated extensively in multiple ethnic groups. TCF7L2 has emerged as the strongest T2DM susceptibility gene in Europeans, but the findings have been inconsistent in the Chinese population. The purpose of this meta-analysis was to evaluate the associations between TCF7L2 single nucleotide polymorphisms (SNPs) and T2DM risk in the Chinese population.MethodsWe performed searches in the PubMed, EMBASE, Cochrane, and Chinese databases (CNKI, CQVIP and Wanfang databases) for literature published from January 2007 to February 2012. We reviewed all relevant articles on TCF7L2 polymorphisms and susceptibility to T2DM in the Chinese population written in English and Chinese. Two reviewers extracted data independently using a standardized protocol, and any discrepancies were adjudicated by a third reviewer. Fixed-effects and random-effects meta-analyses were performed to pool the odds ratios (ORs). Publication bias and heterogeneity were examined.ResultsA total of 21 articles were confirmed to be eligible for and included in this meta-analysis: 7 (with 3942 cases and 3502 controls) concerning rs11196218 (IVS−/+4G>A), 8 (with 3377 cases and 2975 controls) concerning rs290487 (IVS3−/+C>T), and 14 (with 7902 cases and 7436 controls) concerning rs7903146 (IVS3−/+C>T). Overall, the results showed a significant association between rs7903146 and T2DM risk. The pooled ORs were 1.54 for the comparison of T and C alleles (95% CI [confidence interval]: 1.37–1.74, p = 1.47 × 10-12, I2 = 25.20%) and 1.56 for TC heterozygotes and CC homozygotes (95% CI : 1.38–1.76, p = 8.25 × 10-9, I2 = 21.00%). The rs11196218(IVS4G>A) and rs290487 (IVS3C>T) SNPs were not associated with T2DM risk.ConclusionsThe rs7903146 SNP of the TCF7L2 gene is associated with increased susceptibility to T2DM in the Chinese population as a whole as well as northern Chinese and southern Chinese as subgroups.

Meta-analysis: implications of interleukin-28B polymorphisms in spontaneous and treatment-related clearance for patients with hepatitis C

BackgroundSince 2009, several studies have identified single-nucleotide polymorphisms (SNPs) near the gene encoding for interleukin (IL)-28 (IL28B) that are strongly associated with spontaneous and treatment-induced hepatitis C virus (HCV) clearance. Because this large amount of data includes some inconsistencies, we consider assessment of the global estimate for each SNP to be essential.MethodsRelevant studies assessing IL28B polymorphisms associated with sustained virologic response (SVR) and spontaneous clearance (SC) were identified from a literature search of PubMed up to 9 July, 2012. Studies were eligible studies if they included patients infected with HCV or HCV/HIV, or assessed any SNP located within or near the IL28B gene, SVR data available under standard treatment, and/or SC data in patients with acute HCV infection. Pooled odds ratios were estimated by fixed or random effects models when appropriate. Variables such as HCV genotype, ethnicity, and type of co-infection were studied.ResultsOf 282 screened studies, 67 were selected for SVR and 10 for SC. In total, 20,163 patients were studied for SVR and 3,554 for SC. For SVR, we found that all SNPs showed strong associations in patients with HCV genotypes 1 and 4, whereas the pooled ORs were almost three times lower for genotypes 2 and 3 (rs12979860 and rs8099917). Regarding ethnicity, the SNP most associated with SVR was rs12979860 in white patients, whereas in East Asians it seemed to be rs8099917. The most studied SNP (rs12979860) showed similar results for patients co-infected with HCV/HIV, as for those infected with HCV only. Finally, rs12979860 and rs8099917 both appeared to be associated with SC.ConclusionsIL28B polymorphisms influence both the outcome of interferon treatment and the natural clearance of HCV. However we did not identify a universal predictor SNP, as the best genetic markers differed depending on patient ethnicity, genotype, and type of infection. Nevertheless, our results may be useful for more precise treatment decision-making.

Association between polymorphism in STAT4 gene and risk of rheumatoid arthritis: A meta-analysis

Rheumatoid arthritis (RA) is a common chronic inflammatory autoimmune disease, affecting 1% of the population worldwide. Single nucleotide polymorphisms (SNPs) of signal transducer and activator of transcription 4 (STAT4) gene are suspected to have some relationship with the risk of RA. This meta-analysis aimed to evaluate the relationship between the polymorphism rs7574865 in STAT4 gene with RA and also examine whether the associations that have been reported in these studies differ between ethnic groups. We retrieved the relevant articles from PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) databases. The odds ratios (ORs) and their 95% confidence intervals (95% CIs) associated with the minor T allele of STAT4 rs7574865 SNP were extracted from the published studies and included in the analysis. Meta-analyses were performed on the total data set and separately for the major ethnic groups and RF and anti-CCP status. All analyses were performed using the Stata software. Twenty-three articles were included in the present analysis. Meta-analysis showed an association between the STAT4 polymorphism and RA in all subjects (OR=1.299, 95%CI=1.230-1.371, P<0.001). Stratified analyses indicated that the STAT4 rs7574865 T allele was significantly associated with RA in both Caucasians and Asians, in both positive and negative RF patients versus controls, also significantly in the presence of anti-CCP, both positive and negative. As for genotypes of rs7574865 polymorphism, all the results were significant, no matter in total subjects or stratified analyses by ethnic groups or by RF and anti-CCP status. Genetic polymorphism rs7574865 in STAT4 gene might be associated with RA susceptibility in total subjects, major ethnic groups and different status of anti-CCP or RF.

Effects of IL‐28B gene polymorphism on response to peginterferon plus ribavirin combination therapy for genotype 2 chronic hepatitis C

AimInterleukin (IL)‐28B gene polymorphism is closely linked with treatment response to peginterferon plus ribavirin combination therapy for hepatitis C virus genotype 1. However, few studies have reported its effects on therapy for genotype 2. We aimed to examine the effects of IL‐28B gene polymorphism on treatment response in hepatitis C virus genotype 2 patients.MethodsIn a retrospective study of 101 patients infected with either genotype 2a (n = 65) or 2b (n = 36) and treated with peginterferon plus ribavirin, we investigated predictive factors for a sustained virological response (SVR), including genetic variations near the IL‐28B gene (rs8099917, rs11881222 and rs8103142) and clinical variables such as age, sex, body mass index, stage of fibrosis and drug adherence.ResultsUltra‐rapid virological response, rapid virological response (RVR), end‐of‐treatment response, SVR and relapse rates were 22.2%, 61.4%, 95.0%, 87.1% and 7.9%, respectively. In univariate analysis, RVR and IL‐28B single nucleotide polymorphisms (SNP) (rs8099917, rs11881222 and rs8103142) were significantly associated with SVR. In subgroup analysis, IL‐28B SNP were significantly associated with SVR in genotype 2a patients but not in genotype 2b patients. In multiple logistic regression analysis, RVR and IL‐28B SNP (rs8099917) were independently associated with SVR. Furthermore, IL‐28B SNP was significantly associated with relapse but RVR was not.ConclusionIn genotype 2 patients treated with peginterferon plus ribavirin combination therapy, IL‐28B gene polymorphism was a significant independent predictor of SVR as well as RVR. IL‐28B major allele may favor reduced relapse rates in patients with genotype 2 chronic hepatitis C.

Scavenger Receptor Class B Type 1 Gene rs5888 Single Nucleotide Polymorphism and the Risk of Coronary Artery Disease and Ischemic Stroke: A Case-Control Study

Background: Our previous studies have showed that the rs5888 single nucleotide polymorphism (SNP) in Scavenger receptor class B type 1 (SCARB1) gene is associated with serum lipid levels in the general Chinese populations. The present study was undertaken to detect the associations between rs5888 SNP and the risk of coronary artery disease (CAD) and ischemic stroke (IS).Methods: A total of 1,716 unrelated subjects (CAD, 601; IS, 533; and healthy controls, 582) were included in this study. Genotyping of the rs5888 SNP were determined by polymerase chain reaction and restriction fragment length polymorphism.Results: The genotypic frequencies of SCARB1 rs5888 SNP were different between CAD patients and controls, the subjects with TT genotype had high risk of CAD (OR = 1.76, P = 0.038 for TT vs. CC; and OR = 1.75, P = 0.036 for TT vs. CC/CT). There was no significant association between genotypes and the risk of IS. Further analysis showed that the subjects with TT genotype in the total population had lower levels of high-density lipoprotein cholesterol than the subjects with CC/CT genotypes (P < 0.05), the subjects with TT genotype in controls but not in CAD or IS patients had higher levels of serum LDL-C and ApoB than those with CC genotype (P < 0.05 for each).Conclusions: The present study suggests that the SCARB1 rs5888 SNP influences serum lipid levels, and is associated with the risk of CAD.

Interleukin 28B-related polymorphisms: A pathway for understanding hepatitis C virus infection?

To analyze the role of rs12979860 and rs8099917 polymorphisms in hepatitis C virus (HCV) genotype 1 infection of Brazilians. A total of 145 adult patients diagnosed with genotype 1 chronic hepatitis C (CHC) who had completed a 48-wk regimen of pegylated-interferon α-2a or -2b plus ribavirin combination therapy were recruited from six large urban healthcare centers and 199 healthy blood donors (controls) from a single site between January 2010 and January 2012. Data on the patients' response to treatment was collected. Polymerase chain reaction-restriction fragment length polymorphism genotyping of the interleukin (IL)28B gene fragment encompassing the single nucleotide polymorphisms (SNPs) rs12979860 (C/T) and rs8099917 (T/G) was carried out for 79 of the CHC patients and 199 of the controls. Bi-directional amplicon sequencing of the two SNPs was carried out for the remaining 66 CHC patients. SNP rs12979860 genotyping was successful in 99.5% of the controls and 97.2% of the CHC patients, whereas the SNP rs8099917 genotyping was successful in 95.5% of the controls and 100% of the CHC patients. The genotype and allele distributions for both rs12979860 and rs8099917 were significantly different between the control and CHC patient groups, with significantly higher genotype frequencies of CC and TT in the controls (P = 0.037 and 0.046, respectively) and of TT and GG in the CHC patients (P = 0.0009 and 0.0001, respectively). Analysis of the CHC patients who achieved sustained virological response (SVR) to treatment (n = 55) indicated that the rs12979860 C allele and CC genotype were predictors of SVR (P = 0.02). No significant correlation was found between rs8099917 genotypes and treatment response, but carriers of the T allele showed significantly higher rates of SVR (P = 0.02). Linkage disequilibrium analysis of the group that achieved SVR showed a significant association between rs12979860 and rs8099917 (P = 0.07). The higher allele frequency of rs12979860 C and rs8099917 T observed in non-HCV-infected individuals may indicate a potential protective role for these IL28B-related polymorphisms.

IL28B Single-Nucleotide Polymorphism rs12979860 Is Associated With Spontaneous HIV Control in White Subjects

The single-nucleotide polymorphism (SNP) rs12979860 near the IL28B gene has been associated with the spontaneous clearance of hepatitis C virus. We sought to determine whether this SNP could be associated with the spontaneous control of human immunodeficiency virus (HIV) infection. We studied the prevalence of the IL28B CC genotype among 53 white HIV controllers, compared with the prevalence among 389 HIV-infected noncontrollers. We found that the IL28B CC genotype was independently associated with spontaneous HIV control (odds ratio [OR], 2.669; P = .017), as were female sex (OR, 7.077; P ≤ .001) and the presence of HLA-B57 and/or B27 (OR, 3.080; P = .017). This result supports the idea that common host mechanisms are involved in the spontaneous control of these 2 chronic infections.

Lack of clinical and histological progression of chronic hepatitis C in individuals with true persistently normal ALT: the result of a 17-year follow-up

Thirty to 40% of patients with chronic hepatitis C have persistently normal alanine aminotransferase (PNALT). Even though traditionally considered as healthy people, most PNALT carriers actually have some degree of clinical progression and histological liver damage. We evaluated the clinical and histological outcome of a 17-year follow-up on a cohort of patients with chronic HCV infection and PNALT. Between 1994 and 2011, 70 PNALTs and 55 Hyper-alanine aminotransferase (ALT) subjects underwent a clinical, biochemical, virological and histological follow-up. At the end of the follow-up, all patients were alive. In the PNALT group, none of the patients developed hepatic decompensation, while 14.5% of Hyper-ALTs were diagnosed as affected by decompensated cirrhosis. No significant variation of the Metavir grading and staging scores was observed among PNALTs by comparing pre- and post-follow-up liver specimens. On the contrary, a significant increase in both Metavir grading and staging scores was noticed within the Hyper-ALT group. Finally, the analysis of IL28B single-nucleotide polymorphism rs12979860 revealed no difference between Hyper-ALTs and PNALTs in terms of frequency of C/C genotype. In conclusion, progression of chronic hepatitis C among PNALTs is slow or even absent, because at the end of the 17-year follow-up histological and clinical parameters had not worsened significantly.

Hepatitis C virus kinetics by administration of pegylated interferon-α in human and chimeric mice carrying human hepatocytes with variants of the IL28B gene

ObjectiveRecent studies have demonstrated that genetic polymorphisms near the IL28B gene are associated with the clinical outcome of pegylated interferon α (peg-IFN-α) plus ribavirin therapy for patients with chronic hepatitis...

IL28B polymorphisms predict the response to chronic hepatitis C virus infection treatment in a Mexican population

Introduction. The treatment of hepatitis C virus (HCV) genotype 1 with ribavirin (RBV) and pegylated-interferon alpha (peg-IFNα) provides a low-level sustained virological response (SVR). Single nucleotide polymorphisms (SNPs) in the interleukin 28B (IL28B) gene have been identified as SVR predictors. Our aim was to establish an association between three IL28B SNPs (rs8099917, rs12979860, and rs8103142) and the peg-IFNα/RBV treatment response in a Mexican population cohort with chronic HCV.Material and methods. A cohort study was performed with 83 chronic HCV patients at the Fundación Clínica Médica Sur in Mexico City. All patients were treated with peg-IFNα and RBV. The data were analyzed by logistic regression, with adjustments for age, gender, and viral genotype, to determine any associations between the SNPs and the treatment response.Results. In the study group of 83 HCV patients, the main genotype was genotype 1 (70%, n = 58) and the overall SVR was 32.53% (n = 27). In the HCV-1 group, SVR was 27%, whereas SVR was 44% in the HCV-2 group. We found an association between rs12979860 CC and SVR in a codominant model (OR = 4.83, 95% CI = 1.12-20.8, P = 0.033). There was no statistically significant association between SVR and rs8099917 or rs8103142. rs12979860 polymorphisms of CC, CT, and TT, were present in 24%, 41%, and 35% of patients, respectively.Conclusion. A Mexican HCV-1-infected population treated with peg-IFNα and RVB had a low SVR rate, which was associated with the SNP rs12979860 (CC). SVR was not associated with the SNPs rs8099917 or rs8103142.

A single nucleotide polymorphism, rs129679860, in the IL28B locus is associated with the viral kinetics and a sustained virological response in a chronic, monoinfected hepatitis C virus genotype-1 Brazilian population treated with pegylated interferon-ribavirin

Single nucleotide polymorphisms (SNPs) in the interleukin (IL)28B locus have been associated with a sustained virological response (SVR) in interferon-ribavirin (IFN-RBV)-treated chronic hepatitis C virus (HCV)-infected patients in European and African populations. In this study, the genotype frequency of two IL28B SNPs (rs129679860 and rs8099917) in a cohort of chronic HCV-monoinfected patients in Brazil was evaluated and the SNP sufficient to predict the treatment response outcome was determined. A total of 66 naïve genotype-1 chronic HCV-infected patients were genotyped and the associated viral kinetics and SVR were assessed. The overall SVR was 38%. Both the viral kinetics and SVR were associated with rs129679860 genotypes (CC = 62% vs. CT = 33% vs. TT = 18%, p = 0.016). However, rs8099917 genotypes were only associated with SVR (TT = 53% vs. TG = 33% vs. GG = 18%; p = 0.032). In this population, the analysis of a single SNP, rs12979860, successfully predicts SVR in the IFN-RBV treatment of HCV.

Association of the rs7903146 single nucleotide polymorphism at the Transcription Factor 7-like 2 (TCF7L2) locus with type 2 diabetes in Brazilian subjects

To investigate the association of the T allele of the single nucleotide polymorphism (SNP) rs7903146 of TCF7L2 with the occurrence of T2D in a sample of subjects followed up at the Brasilia University Hospital. The SNP rs7903146 of TCF7L2 was genotyped by allele-specific PCR in 113 patients with known T2D and in 139 non-diabetic controls in Brasilia, Brazil. We found that the T allele of the SNP rs7903146 of TCF7L2 was significantly associated with T2D risk (odds ratio of 3.92 for genotype TT in the recessive genetic model, p = 0.004 and 1.5 for T allele, p = 0.032). These results reinforce previous findings on the consistent association of this genetic factor and the risk of T2D in populations of diverse ethnic backgrounds.

Optimum Ribavirin Exposure Overcomes Racial Disparity in Efficacy of Peginterferon and Ribavirin Treatment for Hepatitis C Genotype 1

Peginterferon and ribavirin treatment is less effective for hepatitis C virus (HCV) genotype 1 infections in African Americans (AA) compared with Caucasian Americans (CA). Host genetic variability near the interleukin-28B (IL28B) gene locus is partly responsible. We investigated the relationship between ribavirin drug exposure and week 24 and 72 (sustained virologic response, SVR) responses (undetected serum HCV RNA) in 71 AA and 74 CA with HCV genotype 1 who received >90% of the prescribed peginterferon and weight-based ribavirin (1,000 or 1,200 mg per day) from week 1 to 24. Ribavirin plasma levels were measured at weeks 1, 2, 4, 8, 12 and 24; ribavirin area under the concentration vs. time curve (AUC) was calculated using the linear trapezoidal rule. Compared with CA, AA had lower week 24 (WK24VR) (57.8 vs. 78.1; P<0.05) and week 72 (SVR) (36.6% vs 54.8%; P<0.05) response rates. AA also had significantly lower ribavirin exposure (AUC) from week 1 to 12 (P<0.05). Ribavirin exposures ≥4,065 and ≥4,480 ng/ml/day in the first week (AUC(0-7)) were thresholds for WK24VR and SVR in receiver-operating characteristic curve analyses. AA were less likely to have a threshold ribavirin AUC(0-7) level than CA (P<0.05). There were no significant racial differences in WK24VR (AA: 77 vs. CA: 84%) and SVR (AA: 52 vs. CA: 60%) rates in patients who met the ribavirin AUC(0-7) thresholds. Ribavirin AUC(0-7) predicted WK24VR and SVR independently of IL28B single-nucleotide polymorphism rs12979860 genotype. Yet, achieving threshold AUC(0-7) levels increased response rates primarily in AA with the less favorable non-C/C genotypes. Standard weight-based dosing leads to suboptimal ribavirin exposure in AA and contributes to the racial disparity in peginterferon and ribavirin treatment efficacy for HCV genotype 1.

Genetic Variation in the TNF Gene Is Associated with Susceptibility to Severe Sepsis, but Not with Mortality

BackgroundTumor necrosis factor (TNF) and TNF receptor superfamily (TNFR)-mediated immune response play an essential role in the pathogenesis of severe sepsis. Studies examining associations of TNF and lymphotoxin-α (LTA) single nucleotide polymorphisms (SNPs) with severe sepsis have produced conflicting results. The objective of this study was to investigate whether genetic variation in TNF, LTA, TNFRSF1A and TNFRSF1B was associated with susceptibility to or death from severe sepsis in Chinese Han population.Methodology/Principal FindingsTen SNPs in TNF, LTA, TNFRSF1A and TNFRSF1B were genotyped in samples of patients with severe sepsis (n = 432), sepsis (n = 384) and healthy controls (n = 624). Our results showed that rs1800629, a SNP in the promoter region of TNF, was significantly associated with risk for severe sepsis. The minor allele frequency of rs1800629 was significantly higher in severe sepsis patients than that in both healthy controls (Padj = 0.00046, odds ratio (OR)adj = 1.92) and sepsis patients (Padj = 0.002, ORadj = 1.56). Further, we investigated the correlation between rs1800629 genotypes and TNF-α concentrations in peripheral blood mononuclear cells (PBMCs) of healthy volunteers exposed to lipopolysaccharides (LPS) ex vivo, and the association between rs1800629 and TNF-α serum levels in severe sepsis patients. After exposure to LPS, the TNF-α concentration in culture supernatants of PBMCs was significantly higher in the subjects with AA+AG genotypes than that with GG genotype (P = 0.007). Moreover, in patients with severe sepsis, individuals with AA+AG genotypes had significantly higher TNF-α serum concentrations than those with GG genotype (Padj = 0.02). However, there were no significant associations between SNPs in the four candidate genes and 30 day mortality for patients with severe sepsis.Conclusions/SignificanceOur findings suggested that the functional TNF gene SNP rs1800629 was strongly associated with susceptibility to severe sepsis, but not with lethality in Chinese Han population.

Alleles at rs4273729 in the chromosome 6 do not predict response to peg-interferon-α and ribavirin therapy in hepatitis C virus/HIV-1−coinfected patients

Four genome-wide association studies have demonstrated that several highly correlated, common, single nucleotide polymorphisms (SNPs) located near the interleukin 28B (IL28B) gene strongly predict a sustained viral response (SVR) to combined pegylated interferon-α (peg-IFNα) and ribavirin (RBV) therapy in hepatitis C virus (HCV)-infected patients [1–4]. The recent approval of direct-acting antiviral molecules, the NS3 protease inhibitors telaprevir and bocebrevir, which are active against HCV, will represent a major breakthrough for HCV patients. Because of the low genetic resistance of first-generation protease inhibitors, most failures of a triple combination of peg-IFN-a/RBV and either telaprevir or boceprevir will be due to a poor response to peg-IFNα/RBV. Predictors of SVR to former triple combinations will also include the IL28B genotype. A recent genome-wide association study showed that differences in allele frequency in chromosome 6 near human leukocyte antigen (HLA) DR*0301 were associated with spontaneous resolution of HCV infection [5]. This association was independent of race, HIV status, sex, cohort, HCV risk group, and which SNPs are near or within the IL28B gene. In particular, the association of rs4273729 (detected on chromosome 6 in a 100-kbp region comprising HLA class II genes) with spontaneous resolution was similar to those SNPs marking IL28B (e.g., rs12979860). We previously established the strong relationships between the IL28B rs12979860 and rs8099917 alleles and treatment failure in 197 patients from our HIV clinic unit who received a standard course of treatment with peg-IFN-α and RBV and exhibited a known viral response at 24 weeks post-treatment. Here, these 197 patients were genotyped for rs4273729. Genomic DNA was extracted from peripheral blood as previously described [6,7]. rs4273729 SNP genotyping was performed using the ABI TaqMan allelic discrimination kit and the ABI7500HT Sequence Detection System (Applied Biosystems, Foster City, California, USA). Chi-squared tests and contingency tables were used to assess host genetic associations and to calculate the p-values, odds ratios (ORs), and 95% confidence intervals (CIs). The above statistical analyses were performed using GraphPad Prism (San Diego, California, USA). In the study cohort of 197 patients, the overall respective genotype distributions of IL28B rs12979860 CC, CT, and TT were 50%, 39%, and 11%; the respective distributions of rs4273729 GG, GC, and CC were 45%, 43%, and 12%. rs12979860 and rs4273729 genotypes were in Hardy–Weinberg equilibrium (P = 0.2521 and P = 0.6948, respectively). Within the cohort, 83 patients (42%) had SVR (Table 1). HCV genotype, HCV RNA plasma level, fibrosis stage, age, and aspartate aminotransferase levels were significantly associated with SVR [7]. Respective SVR rates were 57%, 30%, and 18% for rs12979860 CC, CT, and TT, and 46%, 39%, and 39% for rs4273729 GG, CG, and CC (Table 1). As expected, single analysis of rs12979860 demonstrated that the CC genotype was highly associated with SVR (OR = 3.6, 95% CI = 2.0–6.5, P = 2.2 × 10−5; Table 1). In contrast, no significant association with SVR was observed when rs4273729 GG, GC, or CC were analyzed (GG: OR = 1.3, 95% CI = 0.7–2.2, P = 0.4397; GC: OR = 0.8, 95% CI = 05–1.5, P = 0.4890; CC: OR = 1.0, 95% CI = 0.4–2.5, P = 0.9828). Similarly, no association was observed when patients were stratified by HCV genotype (data not shown). These results demonstrated that rs4273729 alone is of limited clinical value because of its low positive predictive value for treatment success. We therefore tested whether both genotypes together, rs4273729, and rs12979860, provided additional power to predict SVR. In patients with the homozygous rs12979860 CC genotype, the additional determination of rs4273729 had no significant effect on the prediction of SVR (rs12979860 CC/rs4273729GG versus rs12979860 CC: OR = 1.3, 95% CI = 0.6–2.9, P = 0.4816; rs12979860 CC/rs4273729GC versus rs12979860 CC: OR = 0.8, 95% CI = 0.4–1.6, P = 0.8716). In total, 23 of 36 (64%) patients with rs12979860CC/rs4273729GG and 33 of 62 (53%) with rs12979860CC/ rs4273729GC achieved SVR. In addition, in patients with the heterozygous variant of the rs12979860 T nonresponder allele, the pattern of the rs4273729 SNP did not significantly affect the chances of achieving SVR (data not shown).Table 1: Association of rs12979860 and rs4273729 genotypes with sustained viral response to pegylated interferon-α and ribavirin therapy.To our knowledge, this is the only study to focus on the association of HLA class II gene variants and response to peg-IFNα/RBV therapy in HCV-infected patients. Our results clearly demonstrate that rs4273729 was not associated with a better response to therapy in the study cohort, and also that it did not improve the predictive value of the IL28B rs12979860 SNP. Whether HCV spontaneous clearance and treatment clearance are affected by different gene loci and innate mechanisms remains to be elucidated. Acknowledgements This study was supported by grants from the Spanish Ministry of Science and Innovation (BFU2010–15194 and SAF2010-21617). Conflicts of interest There are no conflicts of interest.