IL28B polymorphisms predict the virological response to standard therapy in patients with chronic hepatitis C virus genotype 4 infection

Background

Genome-wide association studies have recently revealed that several single-nucleotide polymorphisms (SNPs) in the interleukin (IL) 28B genes can predict the sustained virological response (SVR) to pegylated interferon-α2a/b plus ribavirin in hepatitis C virus (HCV)-genotype 1 patients. However, data for patients infected with HCV genotype 4 (HCV-G4) are limited.

Aim

We analyzed the association of IL28B SNPs (hematological, biochemical, virological, and pathological factors) with SVR in the HCV-G4 monoinfected cohort of patients.

Patients and methods

One hundred twenty-nine treatment-naïve HCV-G4 patients undergoing treatment were recruited from three tertiary care centers in Saudi Arabia. Five IL28B SNPs (rs12979860, rs12980275, rs8105790, rs8099917, and rs72486680) were identified by polymerase chain reaction and DNA sequencing. SVR was statistically correlated with various clinical, histopathological, virological, and genetic parameters.

Results

SVR was significantly associated with the CC and AA alleles of rs12979860 (p = 0.008) and rs12980275 (p = 0.004), respectively. Moreover, albumin levels (p = 0.002) and platelet count (p = 0.039) showed significant differences in the SVR and No SVR groups. On multivariate analysis, the CC allele of rs12979860 (OR, 2.89; 95 % CI 1.6–6.2, p = 0.006) and albumin levels (OR, 1.2; 95 % CI 1.1–1.4, p = 0.001) independently predicted SVR.

Conclusions

IL28B polymorphism (CC allele of rs12979860) predicts the sustained response to antiviral therapy in HCV-G4.     

Association of two polymorphisms of the IL28B gene with viral factors and treatment response in 1,518 patients infected with hepatitis C virus

Background

Two nucleotide polymorphisms of the interleukin-28B (IL28B) gene, at rs8099917 and rs12979860, influence the response to interferon (IFN)-based therapies in patients infected with hepatitis C virus (HCV) of genotype 1. We aimed to investigate whether these polymorphisms showed complete linkage in Japanese patients.

Methods

A total of 1,518 Japanese patients infected with HCV were genotyped for the two IL28B loci, and the two sets of genotypes were compared.

Results

TT at rs8099917 and CC at rs12979860 were detected in 77.7 and 76.8%, respectively, of the 1,518 patients and TG/GG and CT/TT were detected in 22.3 and 23.2%. These two sets of IL28B genotype stood in strong linkage disequilibrium (r ²?=?0.98). Discordance between the two IL28B polymorphisms occurred in 16 (1.1%) patients, and 13 (0.9%) of them possessed IFN-sensitive TT at rs8099917 and IFN-resistant CT at rs12979860. Three of these 13 patients had HCV of genotype 1b and had received pegylated-interferon and ribavirin, and none of them gained a sustained virological response. At rs8099917, IFN-resistant TG/GG were more frequent in patients infected with HCV of genotype 1 than in those infected with HCV of genotype 2 [258/1,046 (24.7%) vs. 75/441 (17.0%), p?=?0.001]. The response to pegylated-interferon/ribavirin in 279 patients who were infected with HCV-1 and the response to IFN monotherapy in 361 patients who were infected with HCV-1 , was higher in those with TT than in those with TG/GG at rs8099917, as well as being higher in those with CC than in those with CT/TT at rs12979860 (p?Conclusions Linkage disequilibrium between two IL28B polymorphisms at rs8099917 and rs12979860 is strong in Japanese HCV patients, but there are some discrepancies between the two sets of genotypes.     

Combinations of simple baseline variables accurately predict sustained virological response in patients with recurrent hepatitis C after liver transplantation

Background

The efficacy of antiviral therapy in patients with hepatitis C recurrence after liver transplantation (LT) is far from optimal and a careful selection of candidates with the best chances to achieve sustained virological response (SVR) is relevant. Moreover, investigating the effects of sustained viral clearance on clinical outcomes is particularly significant. We aimed to identify and combine the best baseline predictors of SVR and to assess the clinical outcomes of antiviral therapy after LT.

Methods

We studied 144 hepatitis C virus (HCV)-infected LT recipients who underwent antiviral therapy following transplantation. Baseline predictors of SVR including donor and recipient interleukin IL28B (IL28B) rs12979860 genotype were evaluated, and the long-term effects of antiviral therapy on clinical outcomes were assessed.

Results

The presence of an IL28B CC genotype with either low viral load (VL), young donor age, or cyclosporine A (CsA)-based immunosuppression identified individuals with 69–80 % probabilities of SVR. In contrast, only 20 % of recipients with a CT/TT IL28B genotype and either high VL, old donor age, or non-CsA immunosuppression achieved an SVR (p = 0.004). Regarding clinical outcomes, the 5-year cumulative probability of graft loss was 2 % for the SVR patients and 48 % for non-responders (p < 0.001).

Conclusions

The use of simple combinations of baseline variables including IL28B polymorphisms identifies HCV-infected LT recipients with different probabilities of response to antiviral treatment. SVR is associated with improved clinical outcomes.     

Predictive value of FIB-4 and APRI versus METAVIR on sustained virologic response in genotype 1 hepatitis C patients

Purpose

Advanced liver fibrosis is a negative predictor of virologic response in genotype 1 chronic hepatitis C (CHC) patients. Biopsy, however, is invasive, costly, and carries some risk of complications.

Methods

Using data from the prospective, international cohort study PROPHESYS, we assessed two alternative noninvasive measures of fibrosis, the FIB-4 and AST-to-platelet ratio index (APRI), to predict virologic response in CHC patients.

Results

CHC genotype 1, monoinfected, treatment-naive patients prescribed peginterferon alfa-2a (40 KD)/ribavirin in accordance with country-specific legal and regulatory requirements and who had baseline METAVIR, FIB-4, and APRI scores (N = 1,592) were included in this analysis. Patients were stratified according to the baseline METAVIR, FIB-4, or APRI score to assess virologic response [hepatitis C virus (HCV) RNA <50 IU/mL] by week 4 of treatment (rapid virologic response) and 24 weeks after untreated follow-up ]sustained virologic response (SVR)]. Baseline predictors of SVR were explored by multiple logistic regression, and the strength of the association between each fibrosis measure and SVR was evaluated. Both FIB-4 and APRI scores increased with increasing levels of biopsy-assessed fibrosis. The association between FIB-4 and SVR (p < 0.1 × 10^?30) was stronger than that between METAVIR (p = 3.86 × 10^?13) or APRI (p = 5.48 × 10^?6) and SVR. Baseline factors significantly associated with SVR included male gender, lower HCV RNA, lower FIB-4 score, no steatosis, and higher alanine aminotransferase ratio.

Conclusion

The FIB-4 index provides a valuable, noninvasive measure of fibrosis and can be used to predict virologic response in patients treated with peginterferon alfa-2a (40  KD)/ribavirin.     

Ex vivo induction of IFN-λ3 by a TLR7 agonist determines response to Peg-IFN/Ribavirin therapy in chronic hepatitis C patients

Background

Genetic variation around interleukin-28B (IL28B), encoding IFN-λ3, predict non-responders to pegylated interferon-α/ribavirin (Peg-IFN/RBV) therapy in chronic hepatitis C (CHC). However, it remains unclear the expression and the role of IL28B itself. The aim of this study is to develop easy and useful methods for the prediction of treatment outcomes.

Methods

The mRNA and protein levels of IFN-λ3 induced by ex vivo stimulation of peripheral blood mononuclear cells (PBMC) or magnetically selected dendritic cells (DCs) with toll-like receptor agonists (TLR3; poly I:C, TLR7; R-837) were measured by the quantitative real-time polymerase chain reaction and our newly developed chemiluminescence enzyme immunoassays, respectively, and compared with the clinical data.

Results

We found that BDCA-4⁺ plasmacytoid and BDCA-3⁺ myeloid DCs were the main producers of IFN-λs when stimulated with R-837 and poly I:C, respectively. Detectable levels of IFN-λs were inducible even in a small amount of PBMC, and IFN-λ3 was more robustly up-regulated by R-837 in PBMC of CHC patients with favorable genotype for the response to Peg-IFN/RBV (TT in rs8099917) than those with TG/GG. Importantly, the protein levels of IFN-λ3 induced by R-837 clearly differentiated the response to Peg-IFN/RBV treatment (p = 1.0 × 10^?10), including cases that IL28B genotyping failed to predict the treatment response. The measurement of IFN-λ3 protein more accurately predicted treatment efficacies (95.7 %) than that of IL28B genotyping (65.2 %).

Conclusions

Genetic variations around IL28B basically affect IFN-λ3 production, but different amounts of IFN-λ3 protein determines the outcomes of Peg-IFN/RBV treatment. This study, for the first time, presents compelling evidence that IL28B confer a functional phenotype.     

Baseline factors and very early viral response (week 1) for predicting sustained virological response in telaprevir-based triple combination therapy for Japanese genotype 1b chronic hepatitis C patients: a multicenter study

Background

Genetic polymorphisms near Interleukin 28B (IL28B) (rs8099917) and a rapid virological response (RVR) have been reported as predictors for a sustained virological response (SVR) to telaprevir (TVR)-based triple combination therapy. However, the association between SVR and viral kinetics earlier than week 4 after initiation of therapy remains unclear. Thus, we evaluated the SVR prediction ability of baseline factors and reduced hepatitis C virus (HCV) RNA levels at week 1 after the initiation of TVR-based therapy in Japanese genotype-1b chronic hepatitis C (CHC) patients.

Methods

A total of 156 Japanese CHC patients received a 24-week regimen of TVR-based therapy. Baseline factors and reduction in HCV RNA levels at weeks 1 and 4 after the initiation of therapy were analyzed for SVR prediction.

Results

Multiple logistic regression analysis for SVR in TVR-based therapy identified the IL28B TT genotype, a reduction of ≥4.7 log₁₀IU/mL in HCV RNA levels at week 1, RVR, and treatment-naïve/relapse. Whereas the SVR rate was higher than 90 % regardless of the reduction in HCV RNA levels at week 1 in patients with the TT genotype, a reduction of ≥4.7 log₁₀IU/mL in HCV RNA levels at week 1 was the strongest predictor of SVR in patients with the non-TT genotype, as determined by multiple logistic regression analysis (P = 0.0043).

Conclusions

The IL28B TT genotype is the most important baseline factor for predicting SVR, and a ≥4.7 log₁₀IU/mL reduction in HCV RNA at week 1 is a useful very early on-treatment predictor of SVR, especially in the non-TT genotype.     

The virological response in Koreans infected with HCV genotype 1 did not differ between groups treated with a full dose or reduced dose (≥80 % full dose) of peginterferon alfa-2a: a prospective randomized multicenter trial

Purpose

A high rate of sustained viral response (SVR) in Koreans with chronic hepatitis C (CHC) is related to a favorable IL28B genotype. We compared two dosing strategies for peginterferon alfa-2a in Koreans with CHC and defined the combined effect of polymorphisms and dosing on the virological response.

Methods

A total of 178 treatment-naïve patients with CHC genotype 1 were prospectively enrolled. All patients were randomly assigned to treatment with one of two peginterferon alfa-2a regimens: 180 μg per week for 48 weeks (full-dose group) or 180 μg per week during the first 12 weeks followed by 135 μg per week for the next 36 weeks (dose-reduction group). Polymorphisms related to IL28B, ITPA, C20orf194 and SLC29A1 were studied.

Results

SVR rates did not differ between the full-dose and dose-reduction groups (56.5 and 51.2 %, respectively, p = 0.474). The frequency of additional reductions of the peginterferon dose because of adverse events was higher in the full-dose group than in the dose-reduction group. SVR rates in patients homozygous for the IL28B major allele were higher than those in patients for the other IL28B alleles. For patients with unfavorable IL28B genotypes, SVR was less likely to be achieved in the dose-reduction group than in the full-dose group.

Conclusions

In Koreans with HCV genotype 1, the virological response to treatment did not differ between a full dose and reduced dose (≥80 % of full dose) of peginterferon alfa-2a. However, in the patients with unfavorable IL28B genotypes, the full-dose treatment of peginterferon alfa-2a may be beneficial.     

Prediction of response to pegylated interferon/ribavirin combination therapy for chronic hepatitis C genotype 1b and high viral load

Background

This study explores pretreatment predictive factors for ultimate virological responses to pegylated interferon-α (1.5?μg/kg/week) and ribavirin (600–1000?mg/day) (PEG-IFN/RBV) combination therapy for patients infected with hepatitis C virus (HCV)-1b and a high viral load.

Methods

A total of 75 patients underwent PEG-IFN/RBV combination therapy for 48?weeks. HCV amino acid (aa) substitutions in non-structural protein 5a, including those in the IFN/RBV resistance-determining region (IRRDR) and the IFN sensitivity-determining region and the core regions, as well as the genetic variation (rs8099917) near the interleukin 28B (IL28B) gene (genotype TT) were analyzed.

Results

Of the 75 patients, 49?% (37/75) achieved a sustained virological response (SVR), 27?% (20/75) showed relapse, and 24?% (18/75) showed null virological response (NVR). Multivariate logistic regression analysis identified IRRDR with 6 or more mutations (IRRDR ≥6) [odds ratio (OR) 11.906, p?<?0.0001] and age <60?years (OR 0.228, p?=?0.015) as significant determiners of SVR and IL28B minor (OR 14.618, p?=?0.0019) and platelets <15?×?10⁴/mm³ (OR 0.113, p?=?0.0096) as significant determiners of NVR. A combination of IRRDR ≥6 and age <60?years improved SVR predictability (93.3?%), and that of IRRDR ≤5 and age ≥60?years improved non-SVR predictability (84.0?%). Similarly, a combination of IL28B minor and platelets <15?×?10⁴/mm³ improved NVR predictability (85.7?%), and that of IL28B major and platelets ≥15?×?10⁴/mm³ improved non-NVR (response) (97.1?%) predictability.

Conclusion

IRRDR ≥6 and age <60?years were significantly associated with SVR. IL28B minor and platelets <15?×?10⁴/mm³ were significantly associated with NVR. Certain combinations of these factors improved SVR and NVR predictability and could, therefore, be used to design therapeutic strategies.     

Association of glucokinase regulatory gene polymorphisms with risk and severity of non-alcoholic fatty liver disease: an interaction study with adiponutrin gene

Background

Recent genome-wide association studies demonstrated an association between single nucleotide polymorphisms (SNPs) on the glucokinase regulatory gene (GCKR) with hepatic steatosis. This study attempted to investigate the association of GCKR rs780094 and rs1260326 with susceptibility to non-alcoholic fatty liver disease (NAFLD) and its severity.

Methods

The genotypes were assessed on 144 histologically confirmed NAFLD patients and 198 controls using a Sequenom MassARRAY platform.

Results

The GCKR rs1260326 and rs780094 allele T were associated with susceptibility to NAFLD (OR 1.49, 95 % CI 1.09–2.05, p = 0.012; and OR 1.51, 95 % CI 1.09–2.09, p = 0.013, respectively), non-alcoholic steatohepatitis (NASH) (OR 1.55, 95 % CI 1.10–2.17, p = 0.013; and OR 1.56, 95 % CI 1.10–2.20, p = 0.012, respectively) and NASH with significant fibrosis (OR 1.50, 95 % CI 1.01–2.21, p = 0.044; and OR 1.52, 95 % CI 1.03–2.26, p = 0.038, respectively). Following stratification by ethnicity, significant association was seen in Indian patients between the two SNPs and susceptibility to NAFLD (OR 2.64, 95 % CI 1.28–5.43, p = 0.009; and OR 4.35, 95 % CI 1.93–9.81, p < 0.0001, respectively). The joint effect of GCKR with adiponutrin rs738409 indicated greatly increased the risk of NAFLD (OR 4.14, 95 % CI 1.41–12.18, p = 0.010). Histological data showed significant association of GCKR rs1260326 with high steatosis grade (OR 1.76, 95 % CI 1.08–2.85, p = 0.04).

Conclusion

This study suggests that risk allele T of the GCKR rs780094 and rs1260326 is associated with predisposition to NAFLD and NASH with significant fibrosis. The GCKR and PNPLA3 genes interact to result in increased susceptibility to NAFLD.     

Role of Interleukin-28B Genetic Polymorphisms in Korean Patients with Hepatitis C Virus Infection

Background/Aims

This study investigated the role of single nucleotide polymorphisms (SNPs) near the interleukin-28B (IL28B) gene with respect to clinical outcomes and the antiviral response in hepatitis C virus (HCV) infection to suggest the practical utility of IL28B genotyping in Korea.

Methods

Two SNPs near IL28B, rs12979860 and rs8099917, were analyzed using an allelic discrimination assay in a total of 454 individuals, including 147 health-check examinees and 307 patients with HCV infection.

Results

The CC genotype frequency was significantly higher in the spontaneous recovery group than in the chronic infection group and was higher in the chronic hepatitis group than in the liver cirrhosis or hepatocellular carcinoma group, suggesting its favorable role in the clinical outcome. Multivariate analysis revealed that the rs12979860 CC genotype was an independent predictor of sustained virologic response (SVR) in genotype 1 HCV infection. During the currently used response-guided therapy, IL28B genotyping was most helpful for the patients who exhibit early virologic responses without rapid virologic responses, as those patients exhibiting the non-CC type did not achieve SVR, although they represented approximately one-third of the total patients.

Conclusions

The IL28B SNP is an independent predictor of SVR. Our results may be helpful if the findings are carefully applied to select patients in Korea.     

Using early viral kinetics to predict antiviral outcome in response-guided pegylated interferon plus ribavirin therapy among patients with hepatitis C virus genotype 1

Background

HCV kinetics during treatment demonstrated strong association with the antiviral outcome of patients treated with pegylated interferon (Peg-IFN) plus ribavirin. However, the relationship between HCV kinetics and pre-treatment factors remains unclear.

Methods

Of 547 patients with HCV genotype 1 treated with Peg-IFN alfa-2b plus ribavirin, 401 completed the response-guided therapy and were assessed for per protocol analysis.

Results

The sustained virologic response (SVR) rate was 53 % for all patients, 60 % for those with genotype TT, and 19 % for those with genotype TG/GG according to IL28B (rs8099917) single nucleotide polymorphisms. The SVR rates increased with HCV decrease at week 4; 4 % (2/56) with <1 log₁₀ decrease, 13 % (7/56) with 1–2 log₁₀ decrease, 51 % (44/87) with 2–3 log₁₀ decrease, 64 % (56/87) with 3–4 log₁₀ decrease, 88 % (72/82) with more than 4 log₁₀ decrease but with detectable HCV RNA and 100 % (33/33) with undetectable HCV RNA (p < 0.001). Similarly, SVR rates increased step-by-step in proportion to HCV decrease in both IL28B TT and TG/GG groups, showing almost the same SVR rates for the same conditions. In multivariate analysis, age (p = 0.005) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with SVR. Advanced liver fibrosis (p = 0.004) and the magnitude of HCV decrease at week 4 (p < 0.001) but not IL28B were associated with non-response.

Conclusions

The magnitude of the HCV decrease at week 4 seems to be the most reliable marker for predicting antiviral outcome after starting Peg-IFN plus ribavirin therapy.     

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

Aims/hypothesis

The rs738409 C>G single-nucleotide polymorphism in PNPLA3 leads to a missense mutation (I148M) which increases liver fat but does not cause insulin resistance. We hypothesised that patients with non-alcoholic fatty liver disease (NAFLD) due to the PNPLA3 variant (‘PNPLA3 NAFLD’?=?PNPLA3-148MM) do not have adipose tissue (AT) inflammation in contrast with those with NAFLD due to obesity (‘obese NAFLD’).

Methods

Biopsy specimens of AT were taken, and PNPLA3 genotype and liver fat (¹H-magnetic resonance spectroscopy) were determined in 82 volunteers, who were divided into groups based on either median BMI (obese 36.2?±?0.7 kg/m²; non-obese 26.0?±?0.4 kg/m²) or PNPLA3 genotype. All groups were similar with respect to age and sex. The PNPLA3 subgroups were equally obese (PNPLA3-148MM, 31.1?±?1.3 kg/m²; PNPLA3-148II, 31.2?±?0.8 kg/m²), while the obese and non-obese subgroups had similar PNPLA3 genotype distribution. Gene expression of proinflammatory (MCP-1, CD68) and anti-inflammatory (Twist1, ADIPOQ) markers was measured using quantitative real-time RT-PCR.

Results

Liver fat was similarly increased in obese NAFLD (9.5?±?1.3% vs 5.1?±?0.9%, obese vs non-obese, p?=?0.007) and PNPLA3 NAFLD (11.4?±?1.7% vs 5.3?±?0.8%, PNPLA3-148MM vs PNPLA3-148II, p?<?0.001). Fasting serum insulin was higher in the obese than the non-obese group (76?±?6 vs 47?±?6 pmol/l, p?<?0.001), but similar in PNPLA3-148MM and PNPLA3-148II (60?±?8 vs 62?±?5 pmol/l, NS). In obese vs non-obese, MCP-1 and CD68 mRNAs were upregulated, whereas those of Twist1 and ADIPOQ were significantly downregulated. AT gene expression of MCP-1, CD68, Twist1 and ADIPOQ was similar in PNPLA3-148MM and PNPLA3-148II groups.

Conclusions/interpretation

PNPLA3 NAFLD is characterised by an increase in liver fat but no insulin resistance or AT inflammation, while obese NAFLD has all three of these features.     

NOD2 Mutations Affect Muramyl Dipeptide Stimulation of Human B Lymphocytes and Interact with Other IBD-Associated Genes

Background

Genetic and functional studies have associated variants in the NOD2/CARD15 gene with Crohn’s disease.

Aims

This study aims to replicate the association of three common NOD2 mutations with Crohn’s disease, study its effect on NOD2 expression in B cells and its interaction with other IBD-associated genes.

Methods

A total of 294 IBD patients (179 familial IBD, 115 sporadic IBD) and 298 unrelated healthy controls were from central Pennsylvania. NOD2 mutations were analyzed by primer-specific amplification, PCR based-RFLP, and validated with the ABI SNPlex^M genotyping system. Gene–gene interaction was studied using a statistical model for epistasis analysis.

Results

Three common NOD2 mutations are associated with Crohn’s disease (p = 5.08 × 10^?7, 1.67 × 10^?6, and 1.87 × 10^?2 for 1007fs, R720W, and G908R, respectively), but not with ulcerative colitis (p = 0.1046, 0.1269, and 0.8929, respectively). For IBD overall, 1007finsC (p = 4.4 × 10^?5) and R720W (p = 9.24 × 10^?5) were associated with IBD, but not G908R (p = 0.1198). We revealed significant interactions of NOD2 with other IBD susceptibility genes IL23R, DLG5, and OCTN1. We discovered that NOD2 was expressed in both normal human peripheral blood B cells and in EBV-transformed B cell lines. Moreover, we further demonstrated that muramyl dipeptide (MDP) stimulation of B lymphocytes up-regulated expression of NF-κB-p50 mRNA.

Conclusion

NOD2 is expressed in peripheral B cells, and the up-regulation of NOD2 expression by MDP was significantly impaired by NOD2 mutations. The finding suggests a possible role of NOD2 in the immunological response in IBD pathogenesis.     

Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes

Aims/hypothesis

Latent autoimmune diabetes in adults (LADA) is phenotypically a hybrid of type 1 and type 2 diabetes. Genetically LADA is poorly characterised but does share genetic predisposition with type 1 diabetes. We aimed to improve the genetic characterisation of LADA and hypothesised that type 2 diabetes-associated gene variants also predispose to LADA, and that the associations would be strongest in LADA patients with low levels of GAD autoantibodies (GADA).

Methods

We assessed 41 type 2 diabetes-associated gene variants in Finnish (phase I) and Swedish (phase II) patients with LADA (n?=?911) or type 1 diabetes (n?=?406), all diagnosed after the age of 35 years, as well as in non-diabetic control individuals 40 years or older (n?=?4,002).

Results

Variants in the ZMIZ1 (rs12571751, p?=?4.1?×?10^?5) and TCF7L2 (rs7903146, p?=?5.8?×?10^?4) loci were strongly associated with LADA. Variants in the KCNQ1 (rs2237895, p?=?0.0012), HHEX (rs1111875, p?=?0.0024 in Finns) and MTNR1B (rs10830963, p?=?0.0039) loci showed the strongest association in patients with low GADA, supporting the hypothesis that the disease in these patients is more like type 2 diabetes. In contrast, variants in the KLHDC5 (rs10842994, p?=?9.5?×?10^?4 in Finns), TP53INP1 (rs896854, p?=?0.005), CDKAL1 (rs7756992, p?=?7.0?×?10^?4; rs7754840, p?=?8.8?×?10^?4) and PROX1 (rs340874, p?=?0.003) loci showed the strongest association in patients with high GADA. For type 1 diabetes, a strong association was seen for MTNR1B (rs10830963, p?=?3.2?×?10^?6) and HNF1A (rs2650000, p?=?0.0012).

Conclusions/interpretation

LADA and adult-onset type 1 diabetes share genetic risk variants with type 2 diabetes, supporting the idea of a hybrid form of diabetes and distinguishing them from patients with classical young-onset type 1 diabetes.     

Genetic variation near interleukin 28B and the risk of hepatocellular carcinoma in patients with chronic hepatitis C

Background

We aimed to clarify the association between single nucleotide polymorphism (SNP) located near interleukin 28B and hepatocellular carcinoma (HCC).

Methods

A cohort comprising 792 patients treated with interferon for chronic hepatitis C was investigated. SNPs at rs8099917 and rs12979860 were determined. Cumulative incidence and HCC risk were analyzed by Kaplan–Meier and Cox proportional hazard analyses for a mean follow-up period of 4.9 years. Fibrosis progression rate (FPR) was determined in these patients with a known time of infection (n = 294).

Results

Cumulative HCC incidence was significantly higher in rs8099917 nonTT (minor homozygote or heterozygote) patients than in rs8099917 TT (major homozygote) patients (20.8 vs. 10.5 % over 10 years, logrank test, p = 0.002). This difference was notable in patients infected with genotype 1 and those treated with pegylated interferon and ribavirin. Among nonSVRs, interferon had a limited effect in suppressing alanine aminotransferase (ALT) and/or α-fetoprotein (AFP) levels in nonTT patients. The suppression of these values after interferon therapy was associated with a lower incidence of HCC. FPR were similar in TT and nonTT patients.

Conclusions

rs8099917 nonTT is related to higher HCC development in patients with HCV genotype 1 and those treated with pegylated interferon and ribavirin. Higher HCC incidence observed in nonTT patients partly results from the limited suppression of ALT and/or AFP by interferon in these patients.     

CCL4 is the only predictor for non-responder in GT-1 CHC patients with favorable IL28B genotype when treated with PegIFN/RBV

Background

Chemokines/cytokines play important roles in the pathogenesis of chronic hepatitis C (CHC). However, their clinical characteristics and implications in treatment responses to pegylated interferon plus ribavirin treatment (PegIFN/RBV) have not been fully illustrated yet. In this study, we intended to investigate the possible predictability of serum chemokines/cytokines on the treatment response in Taiwanese of CHC, genotype-1 (GT-1).

Methods

60 Patients with GT-1 CHC infection who had been treated with PegIFN/RBV were enrolled, including 27 (45%) with sustained virological response (SVR), 11 (18%) with relapse after 48 weeks of treatment and 22 (37%) non-response (NR). Clinical parameters, seven chemokines/cytokines, CCL3, CCL4, CXCL9, CXCL10, CXCL11, IL-10 and IFN-γ, and genotypes of rs12979860, the single nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) were analyzed for their relationship to treatment response.

Results

Baseline serum levels of CXCL10, CXCL11, CCL3 and CCL4 were significantly higher in NR group while comparing with non-NR group. (CXCL10: p =?0.001; CXCL11: p <?0.001; CCL3: p =?0.006; CCL4: p =?0.005). However, only rs12979860 CC genotype was the independent factors for NR in GT-1 CHC infection (OR, 8.985; p =?0.008). In addition, baseline serum level of CCL4 was found to be the only independent factor for NR in GT-1 CHC patients with favorable IL28B genotype (OR, 1.134; p =?0.039).

Conclusions

IL28B genotype is the predictor for NR in GT-1 CHC patients treated with PegIFN/RBV, while baseline serum level of CCL4 is the only predictor for NR in GT-1 CHC patients with favorable IL28B genotype.

     

Baseline risk factors for relapse in HIV/HCV co-infected patients treated with PEG-IFN/RBV

Purpose

Hepatitis C virus (HCV) viral relapse (VR) after end-of-treatment response (ETR) in human immunodeficiency virus (HIV) co-infected patients is observed in as many as one in three co-infected patients. The aim of the study was to identify baseline risk factors for VR in HIV/HCV co-infected patients treated with pegylated interferon plus ribavirin (PEG-INF/RBV).

Methods

A total of 212 Caucasian HIV-infected patients with chronic hepatitis C naïve for PEG-INF/RBV were followed prospectively. Patients were included in this prospective study if they had completed a full course of therapy with an ETR. We assessed the relationship between VR rate and potential predictors of relapse.

Results

Of the patients followed, 130 (61.3 %) attained ETR and 103 (79.2 %) achieved sustained virological response (SVR). Consequently, 27 (20.8 %) showed VR. Patients who relapsed were more often male (p = 0.036), carried the non-CC rs14158 genotype in the low-density lipoprotein receptor (LDLr) gene (p = 0.039), had higher baseline HCV RNA levels (p = 0.012), body mass index (BMI) ≥25 kg/m² (p = 0.034), significant liver fibrosis (p < 0.001), had been diagnosed with acquired immunodeficiency syndrome (AIDS)-defining criteria in the past (p = 0.001) and bore the HCV genotypes 1/4 (p = 0.046) when compared with SVR patients. The IL28B genotype was not associated with relapse. Multivariate binary logistic regression showed that high baseline HCV RNA, significant liver fibrosis, HCV genotypes 1/4, being overweight and being diagnosed with AIDS-defining criteria in the past were independently associated with relapse.

Conclusions

Our study shows that VR can be accurately predicted in HIV/HCV co-infected patients on the basis of risk factors which can be identified before treatment.     

Systematic evaluation of validated type 2 diabetes and glycaemic trait loci for association with insulin clearance

Aims/hypothesis

Insulin clearance is a highly heritable trait, for which few quantitative trait loci have been discovered. We sought to determine whether validated type 2 diabetes and/or glycaemic trait loci are associated with insulin clearance.

Methods

Hyperinsulinaemic–euglycaemic clamps were performed in two Hispanic-American family cohorts totalling 1329 participants in 329 families. The Metabochip was used to fine-map about 50 previously identified loci for type 2 diabetes, fasting glucose, fasting insulin, 2 h glucose or HbA_1c. This resulted in 17,930 variants, which were tested for association with clamp-derived insulin clearance via meta-analysis of the two cohorts.

Results

In the meta-analysis, 38 variants located within seven loci demonstrated association with insulin clearance (p?<?0.001). The top signals for each locus were rs10241087 (DGKB/TMEM195 [TMEM195 also known as AGMO]) (p?=?4.4?×?10^?5); chr1:217605433 (LYPLAL1) (p?=?3.25?×?10^?4); rs2380949 (GLIS3) (p?=?3.4?×?10^?4); rs55903902 (FADS1) (p?=?5.6?×?10^?4); rs849334 (JAZF1) (p?=?6.4?×?10^?4); rs35749 (IGF1) (p?=?6.7?×?10^?4); and rs9460557 (CDKAL1) (p?=?6.8?×?10^?4).

Conclusions/interpretation

While the majority of validated loci for type 2 diabetes and related traits do not appear to influence insulin clearance in Hispanics, several of these loci do show evidence of association with this trait. It is therefore possible that these loci could have pleiotropic effects on insulin secretion, insulin sensitivity and insulin clearance.     

IL28B minor allele is associated with a younger age of onset of hepatocellular carcinoma in patients with chronic hepatitis C virus infection

Background

IL28B polymorphisms were shown to be associated with a response to peg-interferon-based treatment in chronic hepatitis C (CHC) and spontaneous clearance. However, little is known about how this polymorphism affects the course of CHC, including the development of hepatocellular carcinoma (HCC). We evaluated the influence of IL28B polymorphisms on hepatocarcinogenesis in CHC patients.

Methods

We genotyped the rs8099917 single-nucleotide polymorphism in 351 hepatitis C-associated HCC patients without history of IFN-based treatment, and correlated the age at onset of HCC in patients with each genotype.

Results

Frequencies of TT, TG, and GG genotypes were 74.3 % (261/351), 24.8 % (87/351), and 0.9 % (3/351), respectively. The mean ages at onset of HCC for TT, TG, and GG genotypes were 69.9, 67.5 and 66.8, respectively. In multivariate analysis, IL28B minor allele (TG and GG genotypes) was an independent risk factor for younger age at onset of HCC (P = 0.02) in males (P < 0.001) with higher body mass index (BMI; P = 0.009). The IL28B minor allele was also associated with a lower probability of having aspartate aminotransferase-to-platelet ratio index (APRI) >1.5 (minor vs. major, 46.7 vs. 58.6 %; P = 0.01), lower AST (69.1 vs. 77.7 IU/L, P = 0.02), lower ALT (67.8 vs. 80.9 IU/L, P = 0.002), higher platelet count (12.8 vs. 11.2 × 10⁴/μL, P = 0.002), and higher prothrombin time (79.3 vs. 75.4 %, P = 0.002).

Conclusions

The IL28B minor allele was associated with lower inflammatory activity and less progressed fibrosis of the liver; however, it constituted a risk factor for younger-age onset of HCC in CHC patients.