A functional polymorphism in the promoter region of the IL1B gene is associated with risk of multiple myeloma

The cytokine interleukin-1β (IL1B) is important for anti-tumour immune response. Genetic variation may modify the expression of IL1B and thereby influence the risk of disease. We investigated genetic variations with functional importance in the IL1B and NFKB1 genes in 348 population-based samples of multiple myeloma (MM) and a random sample of 1700 individuals. Carriers of the variant T-allele IL1B C-3737T and carriers of the TGT haplotype were at lower risk of MM [relative risk (RR) 0·58 (95% confidence interval (CI) = 0·41-0·84) and RR 0·59 (95%CI 0·40-0·85), respectively]. No association with risk of MM was found for the NFKB1- 94 ins/del polymorphism.     

The importance of a sub-region on chromosome 19q13.3 for prognosis of multiple myeloma patients after high-dose treatment and stem cell support: a linkage disequilibrium mapping in <Emphasis Type="Italic">RAI</Emphasis> and <Emphasis Type="Italic">CD3EAP</Emphasis>

The gene RAI was originally described as an inhibitor of RelA/p65 subunit of nuclear factor κB (NF–κB). Here, we analyse the association between genetic variation in the genes RAI and CD3EAP and outcome of 348 myeloma patients treated with high-dose treatment (HDT), 146 patients treated with interferon-α (INF-α) as maintenance treatment, 177 patients treated with thalidomide, and 74 patients treated with bortezomib at relapse and address if the effects of polymorphisms in CD3EAP and RAI are modified by a functional polymorphism in NFКB1. By linkage disequilibrium mapping, we found that variant alleles of several polymorphisms in a sub-region of 19q13.3 spanning the regions RAI-intron1-1 to RAI intron1-3 and the region exon1 to exon3–6 in CD3EAP were associated with prolonged time-to-treatment failure (TTF; p = 0.003) and overall survival (OS; p = 0.02). Haplotype analyses revealed that none of the haplotypes were more strongly associated to TTF or OS than the two strongly linked SNPs, RAI-intron1-1 (rs4572514) and CD3EAP G-21A (rs967591). The association of RAI-intron1-1 and CD3EAP G-21A with TTF was independent of NFKB1-94 ins/del, but homozygous ins-allele carriers which were also variant allele carriers of RAI-intron1-1 or CD3EAP G-21A had the longest OS. Among patients treated with INF-α or thalidomide, no effect was seen in relation to genotype. Our results indicate that polymorphism in RAI and CD3EAP are associated with outcome of myeloma patients treated with HDT. Combination analyses with the functional polymorphism in NFKB1 suggest that a possibly functional effect of RAI or CD3EAP could be related to NF–κB availability.     

Polymorphisms of tumor necrosis factor-�� promoter region for susceptibility to HLA-B27-positive ankylosing spondylitis in Korean population

This study designed to assess the relationship between tumor necrosis factor (TNF)-?? promoter polymorphisms and disease susceptibility to human leukocyte antigen (HLA)-B27-positive ankylosing spondylitis (AS). One hundred and nineteen HLA-B27⁺ AS patients, 95 HLA-B27⁺ healthy controls, and 135 random healthy controls were enrolled in this study. Six single nucleotide polymorphisms (SNPs) of the TNF-?? promoter at positions ?C1031T/C, ?C863C/A, ?C857C/T, ?C646G/A, ?C308G/A, and ?C238G/A were analyzed. Differences between groups were evaluated using the chi-square test or Fisher??s exact test. Haplotypes from each SNP were constructed, and differences in haplotypic frequencies between groups were evaluated. There were significant differences in the allelic and genotypic frequencies of 1031T/C, ?C863C/A, and ?C857C/T TNF-?? promoters polymorphisms between HLA-B27⁺ AS patients and random controls, but not between patients with AS and HLA-B27⁺ healthy individuals. TNF-?? polymorphisms did not influence the extra-spinal clinical features in patients with AS. The haplotypic sequence ?C1031T/?C863C/?C857C/?C308G increased the risk of susceptibility to AS compared to random controls (P _corr?<?0.001, OR?=?2.756, 95% CI?=?1.894?C4.010), whereas the sequence ?C1031C/?C863A/?C857C/?C308G appeared to be associated with decreased susceptibility to AS compared to random controls (P _corr?=?0.006, OR?=?0.396, 95% CI?=?0.231?C0.679). This study indicates that TNF-?? promoter polymorphism between controls and AS patients with HLA-B27⁺ genetic background is not associated with susceptibility to AS. However, TNF-?? polymorphism, irrespective of HLA-B27, increases risk of susceptibility to AS in general population.     

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.     

Relevance of low viral load in haemodialysed patients with chronic hepatitis C virus infection

AIM: To identify predictors of sustained virological response in hemodialysed patients treated by PEGinterferon α for chronic hepatitis C, genotype 1.METHODS: The sustained virological response(SVR) rate, IL28 B genotype, IFNL4 genotype, initial viral load(IVL) and other pretreatment variables in 39 endstage renal disease patients(ESRD) on maintenance haemodialysis(HD) infected with hepatitis C virus(HCV), genotype 1b, were compared with a control group of 109 patients with normal kidney function treated within the same period. All the patients were treatment nave and had well compensated liver disease. The ESRD patients received 135 μg of PEGylated interferon α-2a(Peg IFN-α) weekly and a reduced dose of ribavirin(RBV) was administered to 23/39 patients with an initial haemoglobin level 10 g/d L. Control group patients were given standard doses of Peg IFN-α and RBV. SVR was assessed as HCV RNA negativity 24 wk post-treatment. A t-test or ANOVA were used for comparisons of the means and a χ2 testcompared the frequencies.Logistic regression was used to determine significant predictors of SVR.Cutoff values for continuous variables were obtained from Receiver Operating Characteristic analysis.RESULTS:The distribution of IL28B rs12979860 CC,CT and TT genotypes in the ESRD group was 28.2%,64.1%and 7.7%,respectively,and 19.3%,62.4%and18.3%in the controls.The IFNL4 genotype was in almost absolute linkage disequlibrium with IL28B.The proportion of patients with a low IVL(600000 IU/m L)was significantly higher in the ESRD group than in the controls(28/39,71.8%vs 51/109,46.8%,P=0.009),as was the proportion of patients with low IVL in IL28B CC carriers compared with non-CC carriers in the ESRD group(10/11,90.9%vs 18/28,64.3%,P=0.0035).This difference was not found in the controls(7/22,31.8%vs 44/87,50.6%,P=0.9).The overall SVR rate was 64.1%(25/39)in the ESRD group and 50.5%(55/109)in the control group(P=0.19).11/11(100%)and 19/22(86.4%)IL28B CC patients achieved SVR in the ESRD and control groups,respectively.A statistically significant association between SVR and IL28B and IFNL4 variants was found in both groups.The ESRD patients who achieved SVR showed the lowest IVL[median 21000,interquartile range(IQR):6000-23000IU/m L],compared with ESRD individuals without SVR(1680000,IQR:481000-6880000,P=0.001),controls with SVR(387000,IQR:111000-1253000)and controls without SVR(905000,IQR:451000-3020000).In ESRD,an IVL600000 IU/m L was strongly associated with SVR:24/28(85.7%)patients who achieved SVR had viraemia below this threshold.CONCLUSION:Haemodialysis decreases the viral load,especially in IL28B CC genotype carriers.A low IVL was the strongest predictor of SVR in ESRD patients identified in multivariate analysis.     

The Association of Genetic Variants with Hepatic Steatosis in Patients with Genotype 1 Chronic Hepatitis C Infection

Background

Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impacts remain to be determined.

Aim

We sought to validate these associations and to explore their impact on treatment response to peginterferon and ribavirin therapy.

Methods

A total of 972 G1 HCV-infected Caucasian patients were genotyped for the SNPs rs12979860 (IL28B) and rs2896019 (PNPLA3). Multivariable analysis tested IL28B and PNPLA3 for association with the presence of any steatosis (>0 %); clinically significant steatosis (>5 %); steatosis severity (grade 0–3/4); and the interacting associations of the SNPs and hepatic steatosis to sustained viral response (SVR).

Results

IL28B and PNPLA3 polymorphisms were associated with the presence of any steatosis (rs12979860, p = 1.87 × 10^?7; rs2896019, p = 7.56 × 10^?4); clinically significant steatosis (rs12979860, p = 1.82 × 10^?3; rs2896019, p = 1.27 × 10^?4); and steatosis severity (rs12979860, p = 2.05 × 10^?8; rs2896019, p = 2.62 × 10^?6). Obesity, hypertriglyceridemia, hyperglycemia, liver fibrosis, and liver inflammation were all independently associated with worse steatosis. Hepatic steatosis was associated with lower SVR, and this effect was attenuated by IL28B. PNPLA3 had no independent association with SVR.

Conclusions

IL28B and PNPLA3 are associated with hepatic steatosis prevalence and severity in Caucasians with G1 HCV, suggesting differing potential genetic risk pathways to steatosis. IL28B attenuates the association between steatosis and SVR. Remediable metabolic risk factors remain important, independently of these polymorphisms, and remain key therapeutic goals to achieve better outcomes for patients with HCV-associated hepatic steatosis.     

Development of depressive symptoms post hip fracture is associated with altered immunosuppressive phenotype in regulatory T and B lymphocytes

Hip fracture is a common physical trauma in older adults that is also associated with a high incidence of new onset depression. The immune system declines with age and is also compromised by physical and psychological stress. This study examined whether hip fracture and depressive symptoms had additive effects upon the aged immune system that might contribute to poor health outcomes after hip fracture. We assessed the frequency of regulatory T cells, T_regs (CD4⁺ CD25⁺ Foxp3⁺) and IL10 production by CD4 T cells, and the frequency and IL10 production by regulatory B cells, B_regs (CD19⁺ CD24^hi CD38^hi) in 101 hip fracture patients (81 female) 6 weeks after injury and 43 healthy age-matched controls (28 female). 38 hip fracture patients (37 %) developed depressive symptoms. Hip fracture did not have an effect on circulating T_regs frequency but a significant reduction in the frequency of B_regs was observed in patients who developed depression compared with non-depressed patients (p = 0.001) or healthy controls (p < 0.001). B_regs also showed a significant decline in IL10 production in depressed hip fracture patients compared with controls (p = 0.04) and non-depressed patients (p = 0.01). In contrast, there was an increase in IL10 production by CD4 T cells in hip fracture patients with new onset depression compared to hip fracture patients without depression (p = .04) and healthy controls (p = .02). We conclude that the reduced immunity associated with new onset depression post hip fracture could include a contribution by heightened T_regs function.     

CKS1B nuclear expression is inversely correlated with p27Kip1 expression and is predictive of an adverse survival in patients with multiple myeloma

Background

CKS1B is a member of the highly conserved cyclin kinase subunit 1 (CKS1) family that interacts with cyclin-dependent kinases and plays an important role in cell cycle progression. We and others have shown that CKS1B amplification located on chromosome 1q21 is an adverse prognostic factor in multiple myeloma, but its relationship with CKS1B nuclear protein expression, is unclear. The aim of this study was to correlate nuclear CKS1B protein immunoreactivity, 1q21 amplification status, p27^Kip1 expression and survival in patients with newly-diagnosed multiple myeloma.

Design and Methods

Nuclear expression of CKS1B and p27^Kip1 was evaluated by immunohistochemistry in decalcified, paraffin-embedded bone marrow biopsies from 94 patients with newly diagnosed multiple myeloma. Clonal plasma cells of the bone marrow aspirates from the same cohort were examined for CKS1B gene status by interphase cytoplasmic fluorescence in situ hybridization.

Results

Fluorescence in situ hybridization detected the 1q21 amplification in 36 (38%) of the 94 patients and immunohistochemistry showed CKS1B protein expression in 37 (39%). Thirty-two (86%) of the 36 amplified (1q21) cases expressed CKS1B and 31 (84%) of the 37 CKS1B immunore-active cases had amplified 1q21. 1q21 amplification and CKS1B protein expression were strongly correlated (P<0.0001). CKS1B protein expression was inversely correlated with p27^Kip1 immunostaining (P<0.0001) and was associated with a shorter overall survival (median 44.5 versus 89.3 months, P<0.0001).

Conclusions

Immunohistochemistry for CKS1B is a simple, rapid method that appears to predict 1q21 amplification and adverse outcome for risk stratification of patients with multiple myeloma.     

Differences in intraprocedural ACTs with standardized heparin dosing during catheter ablation for atrial fibrillation in patients treated with dabigatran vs. patients on uninterrupted warfarin

Purpose

Effective intraprocedural anticoagulation for catheter ablation for atrial fibrillation is critical to minimize the risk of cerebral thromboembolism. The effect of dabigatran on anticoagulation with heparin during the procedure is unknown. This study compares heparin anticoagulation in patients treated with dabigatran vs. patients on uninterrupted warfarin.

Methods

Seventy-six consecutive patients (24 dabigatran and 52 warfarin) subjected to a standard intraprocedural heparin protocol were included. Heparin administration and rapidity and degree of anticoagulation were compared between the groups.

Results

Despite greater administration of heparin (52.5?±?22.0 vs. 33.2?±?10.1?units?kg^?1?h^?1; p?<?0.001), the mean (320.3?±?19.5?s) and peak (358.8?±?28.6?s) activated clotting time (ACT) for the dabigatran group were significantly lower than for the warfarin group (mean, 362.9?±?35.9 and peak, 410.4?±?49.7; p?<?0.001). The time from initial heparin bolus to first ACT of ??300?s in the dabigatran group was more than twice that observed in the warfarin group (45.0?±?30.4 vs. 20.9?±?14.5?min; p?<?0.001). The time to first ACT of ??350?s was similarly prolonged (109.1?±?60.0 vs. 55.2?±?51.1?min; p?<?0.001) in the dabigatran group, with eight patients (33?%) failing to reach this target. Outcome differences persisted following analysis using linear models and Cox proportional hazard regression with adjustment for propensity scores.

Conclusion

A standard intraprocedural heparin protocol results in delayed and lower levels of anticoagulation as measured by the ACT for patients treated with dabigatran compared with those on uninterrupted warfarin.     

ThaDD plus high dose therapy and autologous stem cell transplantation does not appear superior to ThaDD plus maintenance in elderly patients with de novo multiple myeloma

Objectives: With the aim to address the issue whether high‐dose therapy (HDT) is required after new drugs combinations to improve outcome of elderly newly diagnosed multiple myeloma (MM) patients, we compared the toxicity and the outcome of ThaDD plus maintenance to those of ThaDD plus HDT‐autologous stem cell transplantation (ASCT). Methods: Sixty‐two patients not eligible for HDT receiving six courses of ThaDD regimen plus maintenance with thalidomide were compared to 26 patients eligible for HDT treated with four courses of ThaDD followed by melphalan 100–200 mg/m² and ASCT. The two groups were matched for the main characteristics except for age favouring the HDT group. Results and conclusions: Complete remission (CR) obtained with ThaDD plus maintenance was 24% whereas it was 57% after ThaDD plus HDT‐ASCT (P = 0.0232). However, after a median follow‐up of 36 months, median time to progression (TTP) and progression free survival (PFS) of the group of patients undergone HDT were not significantly different to those of patients receiving ThaDD plus maintenance (32 vs. 31 months: P = 0.962; 32 vs. 29 months: P = 0.726, respectively). Five‐year overall survival (OS) was 49% in the first group and 46% in the latter one (P = 0.404). As expected, a significantly higher incidence of grade 3–4 neutropenia, thrombocytopenia, infections, mucositis and alopecia were observed in the ThaDD plus HDT group. Our results suggest that in elderly MM patients ThaDD plus HDT, albeit significantly increases CR rate, seems to be equivalent to ThaDD plus maintenance in terms of TTP, PFS and OS. These results challenge the requirement for HDT consolidation in this subset of patients.     

A high-risk signature for patients with multiple myeloma established from the molecular classification of human myeloma cell lines

Background

Multiple myeloma is a plasma-cell tumor with heterogeneity in molecular abnormalities and treatment response.

Design and Methods

We have assessed whether human myeloma cell lines have kept patients’ heterogeneity using Affymetrix gene expression profiling of 40 human myeloma cell lines obtained with or without IL6 addition and could provide a signature for stratification of patient risk.

Results

Human myeloma cell lines, especially those derived in the presence of IL6, displayed a heterogeneity that overlaps that of the patients with multiple myeloma. Human myeloma cell lines segregated into 6 groups marked by overexpression of MAF, MMSET, CCND1, FRZB with or without overexpression of cancer testis antigens (CTA). Cell lines of CTA/MAF and MAF groups have a translocation involving C-MAF or MAFB, cell lines of groups CCND1-1 and CCND1-2like have a t(11;14) and cell lines of group MMSET have a t(4;14). The CTA/FRZB group comprises cell lines that had no or no recurrent 14q32 translocation. Expression of 248 genes accounted for human myeloma cell line molecular heterogeneity. Human myeloma cell line heterogeneity genes comprise genes with prognostic value for survival of patients making it possible to build a powerful prognostic score involving a total of 13 genes.

Conclusions

Human myeloma cell lines derived in the presence of IL6 recapitulate the molecular diversity of multiple myeloma that made it possible to design, using human myeloma cell line heterogeneity genes, a high-risk signature for patients at diagnosis. We propose this classification to be used when addressing the physiopathology of multiple myeloma with human myeloma cell lines.     

Polymorphisms of inflammatory markers and risk of essential hypertension in Tatars from Russia

Abstract

Essential hypertension (EH) is a common disease with a clear genetic component. Inflammation and endothelial dysfunction play a prominent role in the development of persistent blood pressure elevation. The aim of the current study was to detect an association between EH and polymorphic markers in genes encoding for molecules involved in the control of intercellular interactions during the inflammation process. We analysed SNPs in SELE, SELP, SELL, ICAM1, VEGFA, IL1B, IL6, IL10 and IL12B genes in a group of 534 men of Tatar ethnicity (217 patients with EH and 317 controls). Using a Markov chain Monte-Carlo-based approach (APSampler), we found genotype and allelic combinations associated with EH. The most significant associations were observed for SELE rs2076059*C–SELP rs6131*A–VEGFA –2549*I–IL1B rs16944*C (p?=?3.42?×?10^?5, FDR q?=?0.035) and SELE rs2076059*C–SELP rs6131*A–IL12B rs3212227*C–IL1B rs16944*C (p?=?323?×?10^?4, FDR q?=?0.035).     

Effect of Aliskiren in Patients with Heart Failure According to Background Dose of ACE Inhibitor: A Retrospective Analysis of the Aliskiren Observation of Heart Failure Treatment (ALOFT) Trial

Aims

To compare the effect of the direct renin inhibitor aliskiren on neurohumoral activity in heart failure patients treated with low-dose and high-dose ACE inhibitor.

Methods

A retrospective analysis of the ALOFT trial. Comparison of the effects of 6 months treatment with aliskiren (versus placebo) in patients receiving n?=?109) with those receiving ?? recommended-dose (n?=?81). Neurohumoral measures included B-type natriuretic peptide (BNP), NT proBNP, plasma renin activity and urinary aldosterone excretion.

Results

Patients in each ACE inhibitor-dose group were generally similar (those in the ?? recommended ACE inhibitor-dose had higher baseline blood-pressures and LVEF and were more often female and diabetic). In the p-value 0.94. The pattern of results for other neurohumoral markers was similar.

Conclusions

Aliskiren causes neurohumoral suppression in heart failure, even in patients treated with ??recommended-dose of ACE inhibitor.     

A polymorphism in NFKB1 is associated with improved effect of interferon-α maintenance treatment of patients with multiple myeloma after high-dose treatment with stem cell support

Background

Maintenance therapy with interferon-α after high-dose treatment with stem cell support in multiple myeloma has been intensively debated. In this study, we evaluated the response to treatment with interferon-α in relation to genetic variation in genes related to inflammation.

Design and Methods

In a retrospective study of 296 patients with multiple myelom undergoing high-dose therapy between 1994 and 2004, 146 patients were treated with interferon-α as maintenance therapy. We tested the polymorphisms IL1B T-31C, IL6 G-174C, NFKB1-94ins/delATTG, CD3EAP G-21A and PPP1R13L IVS1 A4364G for associations with time to treatment failure and overall survival with and without interferon-α treatment.

Results

The wild type ins-allele of polymorphism NFKB1-94 ins/delATTG was, by multivariate Cox analysis, associated with longer time to treatment failure (p=0.01) and overall survival (p=0.0084) when tested between treatment arms and in the subgroup of patients treated with interferon-α the wild type ins-allele was associated with longer overall survival (p=0.002). In the absence of interferon-α treatment, there was no association between the polymorphisms and treatment outcome, except for patients homozygous for the wild type G allele of IL6 G-174C who survived longer (p= 0.0074) than variant allele carriers. There was no association between the polymorphisms IL1B T-31C, CD3EAP G-21A and PPP1R13L IVS1 A4364G and treatment outcome for interferon-α.

Conclusions

Patients who are homozygous carriers of the wild type ins-allele of the NFKB1 -94ins/delATTG polymorphism may benefit from treatment with interferon-α, in contrast to patients carrying the variant allele. This result may indicate that the effect of interferon-α treatment is dependent on the availability of nuclear factor-κB and the polymorphism in NFKB1 may, therefore, be a good prognostic marker for multiple myeloma patients on maintenance treatment with interferon-α after high-dose therapy. A prospective study of interferon-α treatment in relation to NFKB1 -94ins/delATTG is highly warranted.     

Clinical features and prognosis of hepatocellular carcinoma in Mongolia: a multicentre study

Purpose

Hepatocellular carcinoma (HCC) is the most common cancer in Mongolia. We aimed to investigate the clinical features, therapeutic modalities, overall survival and prognostic factors for Mongolian patients with HCC.

Method

One hundred ninety-five patients with HCC were consecutively enroled in our study.

Results

The mean age was 61.7?years. The most common etiology for HCC was HCV infection (n?=?89, 45.6%), followed by HBV infection (n?=?67, 34.4%). The mean tumor diameter was 6.0?±?2.6?cm. Only 29 (14.9%) patients had a single lesion, while 39 (20.2%) had >3 lesions. Extrahepatic metastasis to lung (n?=?23), bone (n?=?10) and lymph node (n?=?3) were detected in 36 (18.5%) patients. Most patients had advanced HCC??88 (45.1%) in stage III and 57 (29.2%) in stage IV. Surgical resection was performed in 27 (13.8%) patients, RFA in 23 (11.8%) and TACE in 107 (54.9%). When all the patients were categorized as ??treated?? (n?=?156) and ??not treated?? (n?=?39), the 3-year survival was significantly lower in the ??not treated?? group than in the ??treated?? group (11 vs. 0%, P?<?0.001). Tumor diameter (<3?cm vs. ??3?cm), extrahepatic metastasis, TNM stage (I/II vs. III/IV) and treatment (or supportive care) were selected as independent predictors for survival.

Conclusions

High proportion of patients with HCC in Mongolia is diagnosed at an advanced stage and survival of these patients is lower compared to other countries. A surveillance system and referral policy for high-risk groups should be urgently established and implemented in Mongolia.     

Genetic variation of the interleukin-1 family and nongenetic factors determining the interleukin-1 receptor antagonist phenotypes

The natural anti-inflammatory protein interleukin-1 receptor antagonist (IL-1Ra) inhibits the activity of IL-1 and is associated with vascular injury and metabolic disorders. We analyzed genetic and nongenetic determinants of the IL-1Ra phenotype. Fifteen haplotype-tagging single nucleotide polymorphisms (SNPs) in the IL-1α (IL1A), IL-1β (IL1B), and IL-1 receptor antagonist (IL-1RN) genes were determined in the Health 2000 survey (n = 6771) and European myocardial infarction (MI) survivors (n = 972). Three SNPs were genotyped in the FINRISK97 (FR97) study (n = 7222). We found 3 IL1RN variants that were associated with the IL-1Ra phenotype in the study populations and remained significant after Bonferroni correction with increasing significance in meta-analysis (P values for rs3213448,rs315952, rs315949, respectively: 5.5 x 10⁻¹¹, 1.5 x 10⁻¹¹, and 4.0 x 10⁻¹⁴). Minor allele of the rare IL1B variant rs1143642 was associated with decreased IL-1Ra levels in the Health 2000 and FR97 populations, and the association strengthened in the meta-analysis (P = 9.4 x 10⁻⁷). The proportion of variance explained by the IL1RN variant was larger in MI survivors (5.0%) than in the unselected population (0.5%). Body mass index was the strongest nongenetic predictor of the IL-1Ra phenotype, explaining 11.8% of the variance in Health 2000, 18.1% in FR97, and 25% in MI survivors. In conclusion, 3 IL1RN SNPs and 1 IL1B variant were determining IL-1Ra phenotype independently of body mass index and other metabolic phenotypes. The proportion of phenotypic variation in IL-1Ra explained by the genetic variants was, however, modest compared with the proportion explained by the body mass index.     

IL28B polymorphism genotyping as predictor of rapid virologic response during interferon plus ribavirin treatment in hepatitis C virus genotype 1 patients

AIM: To clarify the association of interleukin-28B (IL28B) single nucleotide polymorphisms (SNPs) with hepatitis C virus (HCV) viremia changes for assessment of interferon (IFN) response.METHODS: A cohort of 118 Caucasian treatment-naïve HCV-G1 infected patients, treated with pegylated-IFN alpha 2a or 2b associated with ribavirin (53 responders, 65 non-responders) during the period 2010-2012, were genotyped for IL28B SNPs rs12979860 C>T and rs8099917 T>G. Genotyping was performed by real-time allelic discrimination assay. Serum HCV RNA levels were assayed at 2, 4, 12, 24 and 48 wk during therapy. Correlation between IL28B genotypes and serum HCV RNA kinetics was investigated. Multivariable logistic regression analysis was performed to identify predictors of null-response.RESULTS: Twenty-six out of 118 patients (22%) had no HCV RNA decline ≥ 1 log IU/mL at therapy week 4 (null-responders). IL28B genotype was rs8099917 (G*)/rs1297860(**) in 21/26 (80%) of null-responder patients. Using multivariate analysis, it was shown that the presence of the rs8099917 G allele was the best predictor of null-response (OR = 7.9, 95%CI: 1.99-31.18). The presence of at least one favorable genotype showed a positive predictive value of above 90% for HCV RNA reduction ≥ log at week 4. Analysis of the HCV RNA kinetics during 12 wk of therapy in patients with IL28B rs12979860 CT heterozygosis (n = 73), according to their rs8099917 status, showed that the viremia reduction was significantly different in patients carrying the rs8099917 G allele compared to those with favorable homozygosis.CONCLUSION: Our findings emphasize the association of the IL28B rs8099917 G allele with HCV. Genotyping for both IL28B SNPs is useful in clinical practice for thorough patient risk stratification based on IFN responsiveness.     

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.