Single Nucleotide Polymorphisms Rs12979860 Research Articles

A genetic variant in the IL-17 promoter is functionally associated with acute graft-versus-host disease after unrelated bone marrow transplantation.

Interleukin IL-17 is a proinflammatory cytokine that has been implicated in the pathogenesis of various autoimmune diseases. The single nucleotide polymorphism (SNP), rs2275913, in the promoter region of the IL-17 gene is associated with susceptibility to ulcerative colitis. When we examined the impact of rs2275913 in a cohort consisting of 438 pairs of patients and their unrelated donors transplanted through the Japan Marrow Donor Program, the donor IL-17 197A allele was found to be associated with a higher risk of acute graft-versus-host disease (GVHD; hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.00 to 2.13; P = 0.05). Next, we investigated the functional relevance of the rs2275913 SNP. In vitro stimulated T cells from healthy individuals possessing the 197A allele produced significantly more IL-17 than those without the 197A allele. In a gene reporter assay, the 197A allele construct induced higher luciferase activity than the 197G allele, and the difference was higher in the presence of T cell receptor activation and was abrogated by cyclosporine treatment. Moreover, the 197A allele displayed a higher affinity for the nuclear factor activated T cells (NFAT), a critical transcription factor involved in IL-17 regulation. These findings substantiate the functional relevance of the rs2275913 polymorphism and indicate that the higher IL-17 secretion by individuals with the 197A allele likely accounts for their increased risk for acute GVHD and certain autoimmune diseases.

Evidence for PTPN22 R620W Polymorphism As the Sole Common Risk Variant for Rheumatoid Arthritis in the 1p13.2 Region

The PTPN22 rs2476601 genetic variant has been associated with rheumatoid arthritis (RA) and other autoimmune diseases. Some reports suggest that this single-nucleotide polymorphism (SNP) may not be the only causal variant in the region of PTPN22. Our aim was to identify new independent RA-associated common gene variants in the PTPN22 region. We analyzed Wellcome Trust Case-Control Consortium genome-wide association study data for associations in the 397.2 kb PTPN22 region and selected 9 associated SNP (with p < 5 × 10(-3)) for replication and dependence analysis. The replication cohorts comprised 2857 patients with RA and 2994 controls from Spain, Netherlands, and Norway. We found that 6 of the 9 selected SNP were associated in the Spanish cohort. Of these, 4 were also associated in the Dutch and Norwegian cohorts, and all 6 were associated with RA in the combined analysis. Conditional analyses showed that none of these associations was independent of rs2476601. The SNP rs2476601 located in the PTPN22 gene is the sole common genetic variant associated with RA in the 1p13.2 region, suggesting that neighbor genes of PTPN22 do not have a major influence in RA.

Serum Level of IP-10 Increases Predictive Value of IL28B Polymorphisms for Spontaneous Clearance of Acute HCV Infection

Single nucleotide polymorphisms (SNPs) in IL28B and serum levels of interferon γ inducible protein 10 (IP-10) predict outcomes of antiviral therapy in patients with chronic hepatitis C. We associated IL28B SNPs rs12979860 and rs8099917, along with serum levels of IP-10, with outcomes of patients with acute hepatitis C (AHC). We studied 120 patients with AHC (64 male; 37 ± 16 years old) and 96 healthy individuals (controls). The IL28B SNPs rs12979860 and rs8099917 were detected using real-time polymerase chain reaction; serum concentrations of IP-10 were measured by enzyme-linked immunosorbent assays of 62 patients with AHC. Hepatitis C virus was cleared spontaneously from 59 patients (49.2%). The IL28B rs12979860 C/C genotype was more frequent among patients with AHC than controls (62.5% vs 39.6%; P < .001) and among patients with spontaneous clearance than those without (74.6% vs 51.7%; P = .02) (positive predictive value, 60.3%). Patients with IL28B rs12979860 C/C more frequently developed jaundice (53.2% vs 27.6%; P = .022) than carriers of the T allele. The median level of IP-10 was lower among patients with AHC and spontaneous clearance (764 [113-2470] pg/mL) than those without spontaneous clearance (1481 [141-4412] pg/mL; P = .006). Based on receiver operating characteristic analysis, 540 pg/mL IP-10 was set as the cutoff for patients most likely to have spontaneous clearance (positive predictive value, 71.4%; negative predictive value, 65.9%). Including data on IP-10 levels increased the ability of the IL28B rs12979860 C/C to identify patients most likely to have spontaneous clearance (83% of those who had an IP-10 level <540 pg/mL and 32% who had an IP-10 level >540 pg/mL) (P < .01). The combination of serum level of IP-10 and SNPs in IL28B can identify patients with AHC who are most likely to undergo spontaneous clearance and those in need of early antiviral therapy.

Genotype rs8099917 near the IL28B gene and amino acid substitution at position 70 in the core region of the hepatitis C virus are determinants of serum apolipoprotein B-100 concentration in chronic hepatitis C

The life cycle of the hepatitis C virus (HCV) is closely related to host lipoprotein metabolism. Serum levels of lipid are associated with the response to pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy, while single nucleotide polymorphisms (SNPs) around the human interleukin 28B (IL28B) gene locus and amino acid substitutions in the core region of the HCV have been reported to affect the efficacy of PEG-IFN/RBV therapy in chronic hepatitis with HCV genotype 1b infection. The aim of this study was to elucidate the relationship between serum lipid and factors that are able to predict the efficacy of PEG-IFN/RB therapy, with specific focus on apolipoprotein B-100 (apoB-100) in 148 subjects with chronic HCV G1b infection. Our results demonstrated that both the aa 70 substitution in the core region of the HCV and the rs8099917 SNP located proximal to the IL28B were independent factors in determining serum apoB-100 and low-density lipoprotein (LDL) cholesterol levels. A significant association was noted between higher levels of apoB-100 (P = 1.1 × 10(-3)) and LDL cholesterol (P = 0.02) and the subjects having Arg70. A significant association was also observed between subjects carrying the rs8099917 TT responder genotype and higher levels of apoB-100 (P = 6.4 × 10(-3)) and LDL cholesterol (P = 4.2 × 10(-3)). Our results suggest that apoB-100 and LDL cholesterol are markers of impaired cellular lipoprotein pathways and/or host endogenous interferon response to HCV in chronic HCV infection. In particular, serum apoB-100 concentration might be an informative marker for judging changes in HCV-associated intracellular lipoprotein metabolism in patients carrying the rs8099917 responder genotype.

IL28B Genotype Effects During Early Treatment with Peginterferon and Ribavirin in Difficult-to-Treat Hepatitis C Virus Infection

Mathematical models of hepatitis C virus (HCV) during therapy may elucidate mechanisms of action for antiviral therapy. In genome-wide association studies, IL28B gene polymorphisms are highly predictive of therapeutic clearance of HCV. We collected sera from 20 chronically infected HCV participants at 13 points during the first 28 days of therapy. We assessed the presence of the C allele at single-nucleotide polymorphism rs12979860 using the ABI TaqMan allelic discrimination kit. We estimated dynamic parameters from the entire population using the Neumann model for HCV infection. Statistical methods for repeated nonlinear measures compared model parameters by established predictors of response. The frequencies of IL28B genotypes were 6 (C/C), 11 (C/T), and 3 (T/T). The mean log decline in HCV RNA from 0 to 48 hours was more rapid among C/C genotype participants compared with C/T or T/T genotype participants (1.4 vs 0.7; P = .07), and from 2 days to 14 days (1.6 vs 0.7; P = .04). In the multivariate model, the C/C genotype predicted a steeper second-phase decline when adjusted for race (P = .01). The presence of the C/C genotype at IL28B rs12979860 exerts its antiviral effect by increasing the infected hepatocyte death rate. This suggests that an immune-mediated mechanism is responsible.

IL28B Genotype Does Not Correlate with HIV Control in African Americans

HIV-1 natural viral suppressors (NVS) are individuals that control HIV replication without antiretrovirals (also know as HIV elite controllers). We have recently shown that these individuals have an elevated rate of hepatitis C virus (HCV) clearance. Given the association of IL28B genotype, specifically the rs12979860 single nucleotide polymorphism (SNP) based CC genotype, with HCV clearance, we studied its association with HIV control in 172 African American HIV subjects and 173 race-matched controls. The frequency of the CC genotype was 12.5% in the NVS, 14.7% in the LVL ("low viral load" cohort with 400-20,000 HIV-1 RNA copies/mL), 17.8% in the MHVL ("medium/high viral load" cohort with >20,000 HIV-1 RNA copies/mL), and 11.6% in an HIV-negative cohort. There was no statistical significance in the CC genotype distribution between these cohorts (p= 0.48 between the NVS and non-NVS HIV positive controls, p= 0.85 between NVS and HIV-negatives). We also did not observe any association between CC genotype distribution and HIV RNA viral load, as a continuous measure. The IL28B CC genotype does not account for the noted HIV control in our specific NVS cohort. Further studies will be needed to determine if a common genetic factor can primarily account for any joint clearance of HCV and control of HIV.

IL28BPolymorphism Associated with Spontaneous Clearance of Hepatitis C Infection in a Southern Brazilian HIV Type 1 Population

About one-third of people infected with human immunodeficiency virus-1 (HIV-1) are coinfected with hepatitis C virus (HCV) because of shared transmission routes. Studies report that HIV-1 complicates hepatitis C infection by increasing HCV viral load and reducing spontaneous clearance. Single nucleotide polymorphisms (SNPs) upstream of the IL28B gene have been associated with spontaneous and treatment-induced clearance of HCV infection. The aim of this study was to evaluate the association between the SNP rs12979860 of the IL28B gene and spontaneous clearance of HCV infection in a Brazilian HIV-1 population. The SNP was analyzed by polymerase chain reaction (PCR) followed by restriction digestion in 138 anti-HCV-positive patients. Spontaneous clearance was observed in 34 subjects (24.6%). Genotype distribution was significantly different between spontaneous clearance and HCV chronic patients. The CT/TT genotypes conferred a nearly 3-fold increased odds to chronic HCV infection relative to the CC genotype (odds ratio, 2.78; 95% confidence interval, 1.16-6.64; p=0.011). In conclusion, the rs12979860 polymorphism is associated with spontaneous clearance of HCV in HIV-1 Brazilian infected patients.

Genetic background of hepatocyte cell lines: Are in vitro hepatitis C virus research data reliable?

The results of independent genome-wide association studies have recently been reported, describing the identification of single-nucleotide polymorphisms (SNPs) strongly associated with natural hepatitis C virus (HCV) clearance during acute infection and cure of chronic HCV infection on antiviral therapy with pegylated interferon (IFN)-α and ribavirin.1-4 These SNPs, in chromosomal region 19q13 upstream of the interleukin-28B (IL28B; IFN-λ3) gene, appear to be markers of cell responsiveness to type 1 IFNs. Nevertheless, the underlying mechanisms remain unknown. Several articles have been subsequently published that confirmed the association and provided valuable information on the predictive value of the so-called “IL28B genotype” on the outcomes of acute HCV infection, antiviral treatment of chronic infection, and recurrence of HCV infection after liver transplantation. These findings have been recently reviewed by Afdhal et al.5 To date, most of the current knowledge on HCV biology and new HCV drug development is based on in vitro studies using hepatoma cell lines, principally Huh7 cells and their derivatives. These cells are permissive for HCV entry, and harbor replication of subgenomic and genomic replicons of various genotypes, as well as the full life cycle of the genotype 2a JFH1 (Japanese fulminant hepatitis 1) infectious clone and derivatives. Nevertheless, their IL28B genotype remains uncharacterized, despite its likely effects on numerous intracellular biological processes relevant to HCV infection. We therefore genotyped the IL28B rs12979860 SNP of hepatoma cell lines used in HCV research, including Huh7, Huh7.5, Huh7.5.1, and HepG2 cells, as well as the commonly used non-hepatoma HEK293 (human embryonic kidney 293) and Hela cell lines. We used ultra-deep pyrosequencing to sequence 292 nucleotides flanking the rs12979860 locus, using a GS FLX Titanium Sequencing Kit in conjunction with a Genome Sequencer FLX (Roche Molecular Systems, Pleasanton, CA). Data was analyzed using two original in-house softwares: Pyroclass and Pyromute, with the results shown in Table 1. Huh7 cells and derivatives, and even two Huh7 cell lines originating from different laboratories, demonstrated different allelic frequencies. The “non-Mendelian” distribution of these polymorphisms is likely a consequence of the polyploidal nature of hepatoma cells, but may indicate the presence of multiple clonal populations arising under different environmental pressures. Data obtained from in vitro cell culture systems may often be related to the genetic background of the cell line(s) used. Our results emphasize the need for the genetic characterization of hepatoma cell lines used for HCV research, especially when these studies involve innate immunity, IFN responsiveness, the assessment of antiviral compound efficacy, or experiments aimed at cell cure. This conclusion may be extended to a number of other in vitro experiments in which the genetic background of the cell line has an influence on the properties studied. Paul Bensadoun M.D.*, Christophe Rodriguez M.D.* , Alexandre Soulier M.D.* , Martin Higgs M.D.*, Stéphane Chevaliez Pharm.D., Ph.D.* , Jean-Michel Pawlotsky M.D., Ph.D.* , * Institut National de la Santé et de la Recherche Médicale, Unité U955, Créteil, France, National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Henri Mondor Hospital, University of Paris-Est, Créteil, France.

Low-density lipoprotein receptor genotyping enhances the predictive value of IL28B genotype in HIV/hepatitis C virus-coinfected patients

The aims of this study were to appraise the predictive value of variations in a single-nucleotide polymorphism (SNP) in the low-density lipoprotein receptor (LDLR) gene for sustained virological response (SVR) to pegylated interferon (Peg-IFN) and ribavirin (RBV), as well as to analyze the relationship between LDLR genotype and other predictors of SVR, particularly IL28B genotype, in patients coinfected with HIV and hepatitis C virus (HCV). One hundred and eighty-four HIV/HCV-coinfected, treatment-naive patients with chronic HCV infection, who received Peg-IFN and RBV, were included. Variations in the SNP rs14158 and rs12979860 were tested by Taqman PCR assay. Twenty-eight (38%) patients with rs14158 TT/TC and 61 (55%) with CC (P = 0.028) achieved SVR. The rates of SVR in patients with rs14158 TT/TC and with CC harboring HCV 1-4 were 20 and 41% (P = 0.020), respectively, and, in those with HCV genotype 2-3, 75 and 84% (P = 0.513), respectively. Patients with rs14158 CC showed less commonly plasma HCV-RNA load at least 600000 IU/ml (57 vs. 71%, P = 0.047) and lower likelihood of relapse (13 vs. 30%, P = 0.023). In patients with HCV genotype 1-4, the rates of SVR according to the combination of IL28B/LDLR genotypes were: CC/CC = 69%; CC/non-CC: 30%; non-CC/CC: 25%; non-CC/non-CC: 14% (P < 0.001). Variations in rs14158 are associated with SVR to Peg-IFN and RBV in HIV/HCV-coinfected patients harboring HCV genotype 1-4. LDLR and IL28B genotypes seem to have a synergistic effect on SVR. The combined use of LDLR and IL28B genotypes in routine clinical practice could enhance the predictive value of IL28B genotype alone.

Simple assay based on restriction fragment length polymorphism associated with IL28B in chronic hepatitis C patients

Objective. Several studies recently revealed that single nucleotide polymorphisms (SNPs) in the interleukin28B (IL28B) region are associated with the response to pegylated interferon-alfa (PEG-IFN-alfa) and ribavirin (RBV) treatment among hepatitis C virus (HCV)-infected individuals of European, African and Asian ancestry. The purpose of the study was to establish methods for determining the SNP rs8099917 associated with IL28B, which might be useful for further research of the treatment of HCV. Material and methods. Blood samples obtained from 93 consecutive patients with chronic hepatitis C were examined. On the basis of the sequence data, a new simple genotyping assay based on a PCR–restriction fragment length polymorphism (RFLP) with two enzymes, BsrDI and Tsp45I, was developed. Results. The proportion of null virological responders in the combined TG/GG group was higher than that in the TT group (p = 0.015), suggesting that minor allele is one of the important factors playing crucial roles in IFN-resistance. Genotyping of rs8099917 by our new method showed results identical to PCR and sequence in 98.9% and 98.9% by BsrDI and Tsp45I, respectively. Using two enzymes, BsrDI and Tsp45I, it was possible to distinguish IL28B SNP rs8099917. Conclusion. This simple method using RFLP will provide the framework for further studies of HCV.

Association of PNPLA3 SNP rs738409 with liver density in African Americans with type 2 diabetes mellitus

AimNon-alcoholic fatty liver disease (NAFLD) is commonly diagnosed in patients with obesity and type 2 diabetes mellitus (T2DM), and has been associated with the single nucleotide polymorphism (SNP) rs738409 in the PNPLA3 gene. This association remains to be investigated in African Americans with T2DM, a group at lower risk for hepatic steatosis relative to European Americans with T2DM. MethodsWe examined 422 African Americans with T2DM (40.3% male; age: 56.4±9.6 years; Body Mass Index: 35.2±8.2kg/m2), all with measures of liver density reflecting hepatic fat content on abdominal computed tomography, and blood glucose and lipid profiles. Associations between rs738409 and phenotypes of interest were determined using SOLAR, assuming an additive model of inheritance with covariates age, sex, BMI and use of lipid-lowering medications. ResultsMean±SD liver density was 55.4±10.2 Hounsfield Units. SNP rs738409 in PNPLA3 was significantly associated with liver density (P=0.0075) and hepatic steatosis (P=0.0350), but not with blood glucose, HbA1c, total cholesterol, triglycerides, high-density or low-density lipoprotein levels or liver function tests (P=0.15–0.96). ConclusionThese findings provide evidence that the PNPLA3 SNP rs738409 contributes to risk for increased liver fat content in African Americans with T2DM, an effect that appears to be independent from serum lipids. Although African Americans are less susceptible to fatty liver than European Americans, PNPLA3 appears to be a risk locus for hepatic steatosis in diabetic African Americans.

Association of TCF7L2 Allelic Variations with Gastric Function, Satiation, and GLP‐1 Levels

Genetic variation in transcription factor 7-like 2 (TCF7L2), a regulator of proglucagon processing, is reproducibly associated with type 2 diabetes. GLP-1 alters gastric function and increases satiation. Genetic variation in TCF7L2 is associated with satiation, gastric motor function, and GLP-1 concentrations. In 62 adults, a single nucleotide polymorphism (SNP) of TCF7L2 (rs7903146) was genotyped and associations with gastric emptying (GE) of solids and liquids, gastric volume (GV), and satiation (maximum tolerated volume and symptoms after nutrient drink test) were explored using a dominant genetic model, with gender and BMI as covariates. In 50 of the participants, we also measured plasma GLP-1 during fasting and after ingestion of a nutrient drink. Presence of the T allele compared to CC genotype in rs7903146 SNP of the TCF7L2 gene was associated with reduced fasting GV (246.3 ± 11.4 mL for CC group, compared to 215.7 ± 11.4 mL for CT/TT group, p= 0.05) and accelerated GE t(1/2) of liquids (26.3 ± 2.0 minutes for CC compared to 17.7 ± 1.4 for CT/TT, p < 0.005). There was no significant association of rs7903146 SNP with GE of solids, gastric accommodation, satiation, fasting, or postprandial GLP-1. Our data suggest TCF7L2 is associated with altered gastric functions that may predispose to obesity.

Influence of Interleukin-28B Single-Nucleotide Polymorphisms on Progression to Liver Cirrhosis in Human Immunodeficiency Virus–Hepatitis C Virus–Coinfected Patients Receiving Antiretroviral Therapy

Single-nucleotide polymorphisms (SNPs) near the IL28B gene have recently been associated with spontaneous hepatitis C virus (HCV) clearance and response to interferon-based therapies in patients with chronic hepatitis C. Because human immunodeficiency virus (HIV) coinfection appears to accelerate HCV-related liver fibrosis progression, any influence of IL28B SNP on the risk of developing cirrhosis might be more easily recognized in the coinfected population. All HIV-HCV-coinfected patients who underwent hepatic elastography before initiating a course of pegylated interferon plus ribavirin therapy at 2 Spanish clinics were retrospectively identified. Liver cirrhosis was defined as >14.5 kPa by transient elastography. The IL28B rs12979860 SNP was examined in a blinded fashion. A total of 304 HIV-HCV-coinfected individuals were analyzed (mean age, 43 years; 80% were male; and 85% were receiving antiretroviral therapy), of whom 18% had cirrhosis. IL28B genotype distribution was as follows: CC, 46%; CT, 43%; and TT, 11%. Cirrhosis was more frequent in CC than CT/TT carriers (24% vs 13%; P = .01). Logistic regression analysis revealed that older age (odds ratio [OR], 1.05; 95% confidence interval [CI], 0.99-1.12]; P = .08), past alcohol abuse (OR, 1.97; 95% CI, 0.95-4.06; P = .07), and CC IL28B genotype (OR, 2.32; 95% CI, 1.22-4.41; P = .01) were predictors of cirrhosis. Interestingly, mean (SD) alanine aminotransferase (ALT) levels were greater (90 ± 53 vs 71 ± 33 IU/L;, P = .01) in IL28B CC than CT/TT carriers during the prior 4.8 ± 3.8 years. The IL28B rs12979860 CC genotype is associated with a higher prevalence of cirrhosis in HIV-HCV-coinfected patients than CT/TT genotypes, suggesting that IL28B CC carriers may experience a more rapid progression of HCV-related liver fibrosis, perhaps as result of increased liver inflammation. Thus, access to HCV treatment is of utmost importance in IL28B CC carriers, in whom treatment response is better and in whom progression to cirrhosis might occur more rapidly.

Detailed Analysis of Variants in FTO in Association with Body Composition in a Cohort of 70-Year-Olds Suggests a Weakened Effect among Elderly

BackgroundThe rs9939609 single-nucleotide polymorphism (SNP) in the fat mass and obesity (FTO) gene has previously been associated with higher BMI levels in children and young adults. In contrast, this association was not found in elderly men. BMI is a measure of overweight in relation to the individuals' height, but offers no insight into the regional body fat composition or distribution.ObjectiveTo examine whether the FTO gene is associated with overweight and body composition-related phenotypes rather than BMI, we measured waist circumference, total fat mass, trunk fat mass, leg fat mass, visceral and subcutaneous adipose tissue, and daily energy intake in 985 humans (493 women) at the age of 70 years. In total, 733 SNPs located in the FTO gene were genotyped in order to examine whether rs9939609 alone or the other SNPs, or their combinations, are linked to obesity-related measures in elderly humans.DesignCross-sectional analysis of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort.ResultsNeither a single SNP, such as rs9939609, nor a SNP combination was significantly linked to overweight, body composition-related measures, or daily energy intake in elderly humans. Of note, these observations hold both among men and women.ConclusionsDue to the diversity of measurements included in the study, our findings strengthen the view that the effect of FTO on body composition appears to be less profound in later life compared to younger ages and that this is seemingly independent of gender.

Genetic variation in interleukin 28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCV-infected children

The vertical transmission of hepatitis C virus (HCV-VT) is a major route of HCV infection in children, but the risk factors remain incompletely understood. This study analyzed the role of interleukin 28B (IL28B) in HCV-VT and in the spontaneous clearance of HCV among infected infants. Between 1991 and 2009, 145 mothers were recruited for this study: 100 were HCV-RNA+ve / human immunodeficiency virus negative (HIV-ve), with 128 children, and 33 were HCV-RNA-ve/HCV antibody+ve, with 43 children. The infants were tested for HCV-RNA at birth and at regular intervals until the age of 6 years. IL28B (single nucleotide polymorphism rs12979860) was determined in the mothers and children. HCV-VT was assumed when children presented HCV-RNA+ve in two subsequent blood samples. HCV-VT-infected infants were categorized as: (1) transient viremia with posterior HCV-RNA-ve and without serum-conversion; (2) persistent infection with serum-conversion. Of the 31 mothers with CC polymorphism, 19 (61%) were HCV-RNA+ve, whereas among the 68 mothers with non-CC polymorphism, 56 (82%) were HCV-RNA+ve. In all, 26 of 128 (20%) infants born to the HCV-RNA+ve mothers acquired HCV infection, but only 9 (7%) were chronically infected. The rate of HCV-VT was higher among the mothers with higher HCV viremia. No HCV-VT was detected in the HCV-RNA-ve women. Neither the mothers' nor the childrens' IL-28 status was associated with an increased risk of HCV-VT. The factors influencing viral clearance among the infected children were genotype non-1 and genotype CC of IL28B. In logistic regression, child CC polymorphism was the only predictor of HCV-clearance in HCV genotype-1. High maternal viral load is the only predictive factor of HCV-VT. IL28B plays no role in HCV-VT, but IL28B CC child polymorphism is associated independently with the spontaneous clearance of HCV genotype-1 among infected children.

Interleukin-28B Genotyping by Melt-Mismatch Amplification Mutation Assay PCR Analysis Using Single Nucleotide Polymorphisms rs12979860 and rs8099917, a Useful Tool for Prediction of Therapy Response in Hepatitis C Patients

Several studies have identified associations between single nucleotide polymorphisms (SNPs) occurring near the interleukin-28B (IL-28B) gene and response to antiviral treatment among hepatitis C virus (HCV) patients. Here, we describe a reliable melt-mismatch amplification mutation assay (melt-MAMA) PCR-based genotyping method for IL-28B which can be used in the management of HCV patients, helping to better define the course of therapy.

Core mutations, IL28B polymorphisms and response to peginterferon/ribavirin treatment in Swedish patients with hepatitis C virus genotype 1 infection

BackgroundPatients infected with hepatitis C virus (HCV) genotype 1 respond poorly to standard treatment with 50% or less achieving sustained virologic response. Predicting outcome is essential and could help avoid unnecessary treatment and reduce health cost. Recently, an association of amino acid substitutions in the core region and treatment outcome was observed in Japanese patients. In the present study, the impact of these mutations on response kinetics and treatment outcome was explored in Caucasian patients.MethodsThe core region of HCV pre-treatment samples obtained from 50 patients treated with peginterferon/ribavirin in a previous Swedish clinical trial with genotype 1 infection were sequenced. The alleles at rs12979860, a single nucleotide polymorphism (SNP), were assessed in order to identify any co-association with this strong response predictor.ResultsNo association between treatment response and substitutions of core residue 91 was found. In contrast, substitutions of core residue 70 were observed in 6/21 (29%) non-responders, but only in one of 29 responders (p = 0.03), and were more common in subgenotype 1b (R70Q in 6 of 13 strains) than in 1a (R70P in 1 of 37 strains, p = 0.004). The rs12979860 SNP upstream of the IL28B gene was overall the strongest response predictor (p = 0.0001). Core 70 substitutions were associated with poorer response kinetics in patients carrying the CT genotype at rs12979860.ConclusionsThe results indicate that substitutions of core residue 70 are related to treatment response in Caucasian patients with HCV-1b infection, but are of less importance than IL28B polymorphism.

Single nucleotide polymorphisms at the TRAF1/C5 locus are associated with rheumatoid arthritis in a Han Chinese population.

BackgroundGenetic variants in TRAF1C5 and PTPN22 genes have been shown to be significantly associated with arthritis rheumatoid in Caucasian populations. This study investigated the association between single nucleotide polymorphisms (SNPs) in TRAF1/C5 and PTPN22 genes and rheumatoid arthritis (RA) in a Han Chinese population. We genotyped SNPs rs3761847 and rs7021206 at the TRAF1/C5 locus and rs2476601 SNP in the PTPN22 gene in a Han Chinese cohort composed of 576 patients with RA and 689 controls. The concentrations of anti-cyclic citrullinated peptide antibodies (CCP) and rheumatoid factor (RF) were determined for all affected patients. The difference between the cases and the controls was compared using χ2 analysis.ResultsSignificant differences in SNPs rs3761847 and rs7021206 at TRAF1/C5 were observed between the case and control groups in this cohort; the allelic p-value was 0.0018 with an odds ratio of 1.28 for rs3761847 and 0.005 with an odds ratio of 1.27 for rs7021206. This significant association between rs3761847 and RA was independent of the concentrations of anti-CCP and RF. No polymorphism of rs2476601 was observed in this cohort.ConclusionsWe first demonstrated that genetic variants at the TRAF1/C5 locus are significantly associated with RA in Han Chinese, suggesting that TRAF1/C5 may play a role in the development of RA in this population, which expands the pathogenesis role of TRAF1/C5 in a different ethnicity.

IL28B SNP rs12979860 Is a Critical Predictor for On-Treatment and Sustained Virologic Response in Patients with Hepatitis C Virus Genotype-1 Infection

BackgroundSingle nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) have received considerable interest for their association with sustained virological response (SVR) when treating patients of genotype-1 hepatitis C virus (GT1-HCV) chronic infection with pegylated interferon and ribavirin (PegIFN/RBV). This study was to investigate the predictive power of IL28B SNPs for on-treatment responses and SVR in treatment-naïve patients with GT1-HCV chronic infection.Methodology/Principal FindingsWe analyzed ten SNPs of IL28B in 191 treatment-naïve patients with GT1-HCV chronic infection who received PegIFN/RBV. In these patients, rapid virological response (RVR), early virological response (EVR) and SVR were achieved in 69.6%, 95.8% and 68.6% of the patients, respectively. Multivariate analysis (odds ratio; 95% confidence interval; P value) indicated age (0.96; 0.93–0.99; 0.012), low baseline viral load (4.65; 2.23–9.66; <0.001) and CC genotype of rs12979860 (7.74; 2.55–23.53; <0.001) but no other SNPs were independent predictors for SVR. In addition, none of the ten SNPs examined were associated with baseline viral load and stages of liver fibrosis. Regarding RVR, low baseline viral load (2.83; 1.40–5.73; 0.004) and CC genotype of rs12979860 (10.52; 3.45–32.04; <0.001) were two critical predictors. As for EVR, only CC genotype of rs12979860 (36.21; 6.68–196.38; <0.001) was the predictor. Similarly, for end of treatment response (ETR), CC genotype of rs12979860 (15.42; 4.62–51.18; <0.001) was the only predictor. For patients with RVR, only low baseline viral load (3.90; 1.57–9.68; 0.003) could predict the SVR. For patients without RVR, only rs12979860 (4.60; 1.13–18.65; 0.033) was the predictor for SVR.Conclusions/Significancers12979860 is the critical predictor for RVR, EVR, ETR and SVR in treatment-naïve patients of GT1-HCV chronic infection. Furthermore, this SNP is the only predictor for SVR in patients without RVR. These results have provided evidence that rs12979860 is the ideal IL28B SNP for genetic testing in treating patients of GT1-HCV chronic infection.

Association between the PTPN22+1858 C/T polymorphism and psoriatic arthritis

IntroductionThe purpose of the present study was to investigate the frequency of the PTPN22 +1858 C/T single nucleotide polymorphism (SNP) (rs 2476601), previously shown to be associated with several autoimmune diseases, in patients with psoriatic arthritis (PsA) in comparison with population based controls.MethodsA total of 291 patients (145 male/146 female, mean age (± S.D.) 52.2 (± 13.1) years) with PsA were examined clinically, by standard laboratory tests and their DNA was genotyped for the SNP rs2476601 (PTPN22 +1858 C/T). Allelic frequencies were determined and compared with 725 controls.ResultsCarriage of the risk allele, PTPN22+1858T, showed a significant association with patients with PsA compared with controls (χ2 = 6.56, P = 0.010, odds ratio (OR) 1.49; 95% confidence interval (CI) 1.10 to 2.02). A significantly higher proportion of carriers of the risk allele (T) had significantly more deformed joints (n ± SEM) (5.9 ± 1.2 vs 2.8 ± 0.5; P = 0.005).ConclusionsIn this study the +1858T allele of the PTPN22 gene, known to be associated with several autoimmune diseases, was associated with PsA. The finding of significantly more joints with deformities among carriers of the T variant could indicate a more aggressive phenotype of disease.