Association of interleukin-8 (IL-8 or CXCL8) -251T/A and CXCR2 +1208C/T gene polymorphisms with breast cancer

A case-control study involving 257 breast cancer patients with invasive ductal carcinoma and 233 healthy women was carried out to explore if the IL-8 -251T/A polymorphism and the CXCR2 +1208 C/T polymorphism have a role in breast cancer susceptibility. Genotypic analysis showed an increased frequency of high producer IL-8 -251AA genotype (p=0.016) in the patient group as compared to controls while CXCR2 +1208 C/T polymorphism did not show any differences between studied groups. However, in contrast to IL-8 -251 polymorphism, the percentage of CXCR2 +1208 TT genotype was significantly lower in patients with NPI3.4 (2% and 12%, respectively; p=0.03). Also, ER- tumors showed an approximately significant higher CXCR2 +1208 TT genotype compared to ER+ tumors (18.6% and 7.1%, respectively; p=0.07). In conclusion, IL-8 -251T/A polymorphism is associated with development of invasive ductal carcinoma type of breast cancer while CXCR2 +1208C/T polymorphism may affect the disease progression.     

Pleural space elastance and changes in oxygenation after therapeutic thoracentesis in ventilated patients with heart failure and transudative pleural effusions

Background and objective: Therapeutic thoracentesis (TT) is required in patients with refractory pleural effusions and impaired oxygenation. In this study, the relationship between pleural space elastance (PE) and changes in oxygenation after TT was investigated in ventilated patients with heart failure and transudative pleural effusions. Methods: Twenty‐six mechanically ventilated patients with heart failure and significant transudative effusions, who were undergoing TT, were studied. The effusion was drained as completely as possible, with monitoring of pleural liquid pressure (Pliq) and chest symptoms. The volume of effusion removed, the changes in Pliq during TT, PE and arterial blood gases before and after TT were recorded. Results: The mean volume of effusion removed was 1011.9 ± 58.2 mL. The mean Pliq decreased from 14.5 ± 1.0 to 0.1 ± 1.5 cm H₂O after TT, and the mean PE was 15.3 ± 1.8 cm H₂O/L. TT significantly increased the mean ratio of PaO₂/fraction of inspired oxygen (FiO₂) from 243.2 ± 19.9 to 336.0 ± 17.8 mm Hg (P < 0.0001). The changes in PaO₂/FiO₂ ratio after TT were inversely correlated with PE (r = ?0.803, P < 0.0001). The 14 patients (54%) with normal PE (≤14.5 cm H₂O/L) had significantly greater increases in PaO₂/FiO₂ ratio after TT than did the 12 patients with abnormal PE (>14.5 cm H₂O/L). Conclusions: Measurement of PE during TT may be valuable for predicting improvement in oxygenation in ventilated patients with heart failure and pleural effusions. Patients with lower PE showed greater improvement in oxygenation after TT.     

Impact of the peginterferon‐α 2a and ribavirin plasma levels on viral kinetics and sustained virological response in genotype 1 HCV/HIV‐co‐infected patients with the unfavourable non‐CC IL28B genotypes

Studies on the association between the peginterferon‐α and ribavirin levels and sustained virological response (SVR) have shown yielded conflicting results, but most of them were performed before the influence of IL28B polymorphisms was known. Our aim was to assess the effects of peginterferon‐α 2a and ribavirin plasma levels on viral kinetics and SVR in hepatitis C virus genotype 1 HCV‐1/HIV‐co‐infected patients according to IL28B genotype. This was a cohort study of HCV‐1/HIV‐co‐infected patients who were HCV‐treatment naïve and for whom the efficacy of peginterferon‐α 2a plus ribavirin was evaluated by per‐protocol analysis. The peginterferon‐α 2a and ribavirin levels were measured by ELISA and HPLC‐UV, respectively. The relationships among host and viral factors, the trough drugs levels and virological responses were analysed by multivariate regression analyses. A total of 131 Caucasian patients were included (cirrhosis:38.9%). Overall, SVR rate was 39.6%. In patients with CC IL28B genotype, SVR was related neither to peginterferon‐α 2a nor to ribavirin plasma levels, while higher levels of both drugs were the only variables independently associated with SVR in individuals with CT/TT IL28B genotypes (OR, 5.02; CI₉₅, 1.45–17.1; P = 0.001 and 4.0; CI₉₅, 1.08–14.7; P = 0.038, respectively). Moreover, faster viral declines were observed in CT/TT patients when pegIFN‐α 2a and ribavirin plasma levels were greater than 3400 pg/mL and 1.6 μg/mL, respectively. In contrast to the results for CC patients, the results in patients carrying the unfavourable CT/TT IL28B genotypes showed that plasma levels of both drugs have significant effects on viral kinetics and SVR.     

Genetic susceptibility to enteroaggregative Escherichia coli diarrhea: polymorphism in the interleukin-8 promotor region

Enteroaggregative Escherichia coli (EAEC) infection can be identified in 26% of travelers with diarrhea and is associated with fecal interleukin (IL)-8 production. We hypothesized that single-nucleotide polymorphisms (SNPs) in the IL-8 gene are associated with EAEC-related symptoms. Fecal IL-8 production and IL-8 SNPs at 5 loci were identified in 69 US students who remained in Mexico for 5 weeks; 23 subjects had EAEC-associated diarrhea, 7 were asymptomatic EAEC carriers, 22 had nonspecific diarrhea, and 17 were asymptomatic without an enteropathogen. The chances of having EAEC-associated diarrhea were significantly increased among those with the AA genotype at the -251 position (odds ratio [OR], 208.51; 95% confidence interval [CI], 28.5-1525.36) and among those with AT genotype (OR, 14.3; 95% CI, 1.98-105.74), compared with those with the TT genotype at the -251 position. Among subjects with EAEC-associated diarrhea, the AA genotype at the -251 position produced greater concentrations of fecal IL-8 than those with the AT or TT genotype (P=.0053). In the present study, the AA genotype at the -251 position was associated with the occurrence of EAEC-associated diarrhea and increased levels of fecal IL-8.     

IL‐28B polymorphisms and the response to antiviral therapy in HCV genotype 2 and 3 varies by ethnicity: a meta‐analysis

Studies of IL‐28B genotype in patients with hepatitis C virus (HCV) genotype 2/3 infection have yielded conflicting results. The aim of this meta‐analysis was to obtain a pooled odds ratio (OR) of the impact of IL‐28B genotype on achieving sustained virologic response (SVR) in patients with HCV genotype 2/3 infection treated with pegIFN and ribavirin. A meta‐analysis with a random effects model was performed, and study heterogeneity and publication bias were assessed. Forty‐three percent of the Caucasians (11 studies) and 86% of Asians (five studies) had the favourable IL‐28B genotype. In Caucasians, the pooled OR of SVR with the favourable IL‐28B genotype was 1.36 (95%CI: 0.98–1.88, P = 0.07) in all patients and 1.55 (95%CI: 1.10–2.18, P = 0.01) in patients treated with pegIFN and ribavirin for ≥24 weeks. In Asians, the pooled OR of SVR in patients with the favourable IL‐28B genotype was 1.99 (95%CI: 0.94–4.25, P = 0.07). The favourable IL‐28B genotype was also significantly associated with rapid virologic response (RVR) in both groups (Caucasians: OR: 1.82, 95%CI: 1.12–2.96, P = 0.02; Asians: 2.39, 95%CI: 1.39–4.11, P = 0.002), as well as the likelihood of an SVR in a subgroup of 350 Caucasian patients without an RVR (OR: 3.29, 95%CI: 1.67–6.51, P = 0.001). The favourable IL‐28B genotype is a statistically significant predictor of SVR and RVR in Caucasian patients treated with pegIFN and ribavirin for 24 weeks. In contrast, the favourable IL‐28B genotype is associated with RVR, but not SVR in Asian HCV genotype 2 patients.     

Association of interleukin‐6 and interleukin‐10 genotypes with radiographic damage in rheumatoid arthritis is dependent on autoantibody status

Objective

Recent evidence has highlighted a major genetic contribution to radiographic damage in rheumatoid arthritis (RA). The objective of this study was to determine whether genetic variants in the loci for interleukin‐1 (IL‐1), IL‐6, IL‐10, protein tyrosine phosphatase N22 (PTPN22), and selenoprotein S are associated with radiographic damage.

Methods

Modified Larsen scores of radiographic damage were determined in a cross‐sectional population of patients with RA (n = 964). Rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti‐CCP) were also assayed. The Kruskal‐Wallis nonparametric test was used to compare median radiographic damage scores across genotype groups, followed by the Cuzick nonparametric test for trend to assess gene‐dose effects.

Results

An allele‐dose association of IL‐6 −174G with increasing radiographic damage was present (P = 0.005), but only in patients who were RF positive (P = 0.004) or anti‐CCP positive (P = 0.01). Patients with the IL‐10 −592CC genotype had more extensive radiographic damage than did those with the AC or AA genotype (P = 0.006), but this was observed only among patients who were RF negative (P = 0.002) or anti‐CCP negative (P = 0.002). However, RF status and anti‐CCP status were not associated with the IL‐6 or IL‐10 genotype. No other genetic associations were detected, apart from a marginal association of PTPN22 +1858T with increased radiographic damage.

Conclusion

The reported associations of IL‐6 −174G with high IL‐6 production and IL‐10 −592 with low IL‐10 production and our own results support a role of genetically determined dysregulated cytokine production in disease severity. The lack of association of these genotypes with RF and anti‐CCP antibody status suggests that they act downstream of autoantibody production. We conclude that IL‐6 and IL‐10 genotypes may be useful in predicting disease severity in autoantibody‐positive and autoantibody‐negative patients, respectively.

     

Elevated soluble IL‐2Rα, IL‐8, and MIP‐1β levels are associated with inferior outcome and are independent of MIPI score in patients with mantle cell lymphoma

Mantle cell lymphoma (MCL) is a unique type of lymphoma with a prognosis intermediate between indolent and aggressive types. The purpose of this study was to study blood cytokine levels in newly diagnosed and relapsed MCL patients with respect to patterns of abnormalities and relationship to the MCL International Prognostic Index (MIPI) score. We analyzed blood levels of 30 cytokines using a multiplex ELISA in 88 patients with newly diagnosed MCL (pre‐treatment levels) and 20 with relapsed MCL and compared them with controls without known lymphoma. Elevated cytokine levels were compared with clinical outcome and the MIPI score. In the 88 newly diagnosed MCL patients, we found significantly elevated levels compared with controls of IL‐12, IP‐10, sIL‐2Rα, MIG, IL‐1RA, IL‐8, MIP‐1α, and MIP‐1β (all P < 0.05). Of these elevated cytokines, sIL‐2Rα, IL‐8, MIG, MIP‐1α, and MIP‐1β were predictive of inferior event‐free survival, and sIL‐2Rα (HR = 1.94; P = 0.038), IL‐8 (HR = 2.17; P = 0.015), and MIP‐1β (HR = 2.10; P = 0.016) were independent of MIPI score; only sIL‐2Rα (HR = 2.35; P = 0.041) was associated with overall survival after adjustment for MIPI. In the relapsed MCL patient group, the only significantly elevated plasma cytokines that predicted EFS were sIL‐2Rα (HR = 2.90; P = 0.04) and IL‐8 (HR = 3.75; P = 0.02). Elevated blood levels of sIL‐2Rα and the pro‐inflammatory cytokines IL‐8 and MIP‐1β are poor prognostic factors in MCL patients and independent of MIPI score. These factors, if validated, will provide important additions to the MIPI and guide the development of new therapies for patients with elevated levels of these cytokines. Am. J. Hematol. 89:E223–E227, 2014. © 2014 Wiley Periodicals, Inc.     

Protective role of IL‐22 against Schistosoma mansoni soluble egg antigen‐induced granuloma in Vitro

The role of T helper‐17 (Th17) lymphocytes in the regulation of Schistosoma mansoni soluble egg antigen (SEA)‐induced granuloma is unknown. This study examined the effect of Th17 cytokines (IL‐17 and IL‐22) on granulocyte recruitment and functions during SEA‐induced granuloma formation in vitro in Schistosoma‐infected and noninfected individuals. Granulocytes were isolated from 27 Schistosoma‐infected patients and 13 controls and were used for granuloma induction using SEA‐conjugated polyacrylamide beads in the presence of Th17 cytokines. Granuloma index was assessed, and granulocyte mediators such as tumour necrosis factor (TNF‐α), hydrogen peroxide (H₂O₂) and nitric oxide (NO) were measured in the culture supernatant at the 7th day using enzyme‐linked immunosorbent assay (ELISA). Schistosoma‐infected patients had significant larger SEA‐induced granuloma than controls. IL‐17 (125 pg/mL) induced the optimum size for granuloma within 3‐7 days. However, IL‐22 at different concentrations up to 300 pg/mL had no effect on granuloma formation. Using both cytokines simultaneously, IL‐22 suppressed the effect of IL‐17 and prevented granuloma formation. IL‐17 significantly decreased TNF‐α, H₂O₂ and NO levels in Schistosoma‐infected individuals. In contrast, IL‐22 increased TNF‐α and H₂O₂ levels. In conclusion, IL‐17 accelerates SEA‐induced granuloma formation and inhibits granulocytes functions in Schistosoma‐infected patients, while IL‐22 inhibited the granuloma formation, but enhanced granulocyte functions.     

Relationship between IL‐10 gene −1082A/G and −592C/A polymorphisms and the risk of hepatitis C infection: a meta‐analysis

Increasing evidence suggests that interleukin‐10 (IL‐10) gene promoter polymorphisms may be associated with chronic hepatitis C virus (HCV) infection and HCV clearance. To more precisely estimate the association between these variants and the risk of HCV infection, we performed a meta‐analysis of 26 studies describing the IL‐10–1082A/G, –819C/T, –592C/A genotypes, including 4039 chronic HCV infection cases and 2902 controls. When compared with a healthy population, the –1082GG allele had a 43% increased risk of chronic HCV infection in combined populations (GG vs GA + AA: odds ratio (OR) = 1.433, 95% confidence interval (CI) = 1.052–1.952, P = 0.023). In subgroup analysis by ethnicity, a significant increased risk was associated with the ?1082GG genotype in the Caucasian population (GG vs AA: OR = 1.390, 95% CI: 1.108–1.744, P = 0.004; GG vs GA + AA: OR = 1.621, 95% CI: 1.267–2.075, P = 0.000). However, no significant association was found in Asian, African or Chinese populations. Moreover, a higher distribution of ?592A was found in the spontaneously recovered population (AA vs CC: OR = 0.585, 95% CI = 0.387–0.884, P = 0.011; AA + AC vs CC: OR = 0.738, 95% CI = 0.551–0.988, P = 0.041; AA vs AC + CC: OR = 0.788, 95% CI = 0.664–0.935, P = 0.006) than that in the chronic HCV infection population. In conclusion, the IL‐10–1082GG allele may increase the risk of chronic HCV infection in Caucasian population, and people carrying the IL‐10–592A allele are more likely to clear HCV spontaneously.     

Prognostic significance of PaO2/PaCO2 ratio in normotensive patients with pulmonary embolism

Introduction: Risk stratification remains controversial in patients with normotensive pulmonary embolism (PE). The debate has recently focused right ventricular dysfunction detected by echocardiography or spiral computed tomography (CT) and cardiac biomarkers. Objectives: The utility of the PaO₂/PaCO₂ ratio to predict the short‐term prognosis of PE is not currently known and that is the aim of the present study. Materials and Methods: This study retrospectively enrolled 99 (34 males, 65 females, 67 ± 15 years) consecutive patients with acute PE, diagnosed by spiral chest tomography pulmonary angiography (CTPA).On admission, cardiac troponin T (cTn‐T) was measured and on CTPA both right ventricle diameter and left ventricle diameter was calculated (RV/LV ratio). During the first 24 h after admission, all the patients had initial arterial blood gas collected under room air. Receiver‐operating characteristic (ROC) analysis was performed to determine the optimal PaO₂/PaCO₂, RV/LV ratio and cTn‐T cutoff level with regard to prognosis. Results: In‐hospital mortality was 12.1% and all‐cause 90‐day mortality was 15.2%. Ten of 15 patients who died had a PaO₂/PaCO₂ ≤ 1.8 based on ROC analysis (P < 0.014).The cutoff level of PaO₂/PaCO₂ ≤ 1.8 had a high negative predictive value of 93% for mortality. Multivariable analysis revealed that PaO₂/PaCO₂ ≤ 1.8 Hazard Ratio (HR): 16.8 [95% CI: 2.6–108, P < 0.003] was the most significant independent predictor, whereas cTn‐T, pO₂ < 60 mmHg and cardiac failure were nonsignificant factors. In addition, PaO₂/PaCO₂ ≤ 1.8 showed significant survival differences for overall mortality rates in Kaplan–Meier analysis (P < 0.012). Conclusion: The PaO₂/PaCO₂ measurement is a highly useful and practical measurement to predict prognosis in patients with acute PE. Moreover, it appears to be a more accurate predictor than RV/LV ratio and cTn‐T levels in patients with normotensive PE. Please cite this paper as: Ozsu S, Abul Y, Yilmaz I, Ozsu A, Oztuna F, Bulbul Y and Ozlu T. Prognostic significance of PaO₂/PaCO₂ ratio in normotensive patients with pulmonary embolism. Clin Respir J 2012; 6: 104–111.     

Interleukin-17F gene polymorphism in patients with chronic immune thrombocytopenia

Introduction: IL‐17F is a novel inflammatory cytokine and plays an important role in some autoimmune diseases. We investigated the association between chronic ITP and the frequency of the single‐nucleotide polymorphism rs763780 (7488T/C), which causes a His‐to‐Arg substitution at amino acid 161. Patients and methods: We examined 102 patients (men/women, 40/62; median age, 42) diagnosed with chronic ITP and 188 healthy controls (men/women, 78/110; median age, 38). Genotyping was determined by the polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) technique. Results: Compared with the control group, patients with chronic ITP had a significantly lower frequency of the IL‐17F 7488CC genotype (0% vs. 4.8%, P < 0.05). The number of IL‐17F 7488C alleles among the patients with chronic ITP was also significantly lower than in the control group (8.7% vs. 15.2% OR = 0.48, 95%CI = 0.27–0.84, P = 0.016). Furthermore, patients with the IL‐17F 7488TT genotype showed a severe thrombocytopenic state (platelet count < 10×10⁹/L) at diagnosis than those with the IL‐17F 7488TC genotype (20.9% vs. 0%, P = 0.04). Conclusion: These findings suggest that the IL‐17F 7488 T allele is significantly associated with the development of chronic ITP, suggesting a role for IL‐17F in the pathogenesis of chronic ITP.     

A NOD2 gene polymorphism is associated with the prevalence and severity of chronic obstructive pulmonary disease in a Japanese population

Background and objective: Genetic background is thought to be one of the risk factors for development of COPD. Recently, it has been proposed that the innate immune system is involved in the pathophysiology of COPD. We hypothesized that polymorphisms in the nucleotide‐binding and oligomerization domain (NOD)1 and NOD2 genes would be associated with the pathogenesis of COPD. In addition, the associations between these single nucleotide polymorphisms (SNPs) and phenotypes of COPD were analysed. Methods: Japanese COPD patients (n = 228) and non‐COPD smokers (n = 101) were recruited from the outpatient clinic at Kyoto University Hospital, Kyoto, Japan. At entry into the study, a blood sample was taken and a pulmonary function test was performed. Genotyping was performed for 6 selected tag SNPs of NOD1 and 5 tag SNPs of NOD2. Further investigations were performed for SNP that were associated with COPD, including baseline gene expression, the relative proportions of splicing variants in whole blood, responses to ligand and enhancement of gene expression in peripheral blood neutrophils stimulated with pro‐inflammatory cytokines. Results: The distribution of NOD2 rs1077861 genotypes differed between Japanese COPD patients and non‐COPD smokers (P = 0.036). This SNP was also associated with a lower FEV₁ % predicted (57.2 ± 1.8 for TT vs 50.8 ± 2.3 for TA/AA, P = 0.03) and DL_CO/V_A (2.89 ± 0.1 in TT vs 2.53 ± 0.14 in TA/AA, P = 0.036) in COPD patients. NOD2 gene expression after stimulation with 10 ng/mL of tumour necrosis factor‐α for 4 h, was increased to a greater extent in TA/AA genotype than in TT genotype peripheral blood neutrophils (P = 0.015). Conclusions: The NOD2 rs1077861 SNP may influence the development and progression of COPD in Japanese subjects.     

白细胞介素8基因多态性与新疆汉族迟发型阿尔茨海默病关系的研究

目的探讨白细胞介素8(IL-8)基因-251A/T多态性与新疆汉族人群迟发性阿尔茨海默病(LOAD)遗传易感性的关系。方法选择老年患者80例为LOAD组,同期体检者80例为对照组。采用PCR-RFLP检测IL-8基因-251A/T多态性分布。结果 2组AA基因型分布及A等位基因频率比较,差异有统计学意义(16.3%vs 7.5%,P=0.035;41.3%vs 27.5%,P=0.010)。进一步分析显示,LOAD组A等位基因频率可能是LOAD的危险因素(OR=1.851,95%CI:1.159².957,P=0.010);AA基因型患LOAD的危险性是TT基因型的3.370倍(OR=3.370,95%CI:1.1432.957,P=0.010);AA基因型患LOAD的危险性是TT基因型的3.370倍(OR=3.370,95%CI:1.143⁹.939,P=0.023);AT基因型与LOAD发病风险不相关(OR=1.944,95%CI:0.9949.939,P=0.023);AT基因型与LOAD发病风险不相关(OR=1.944,95%CI:0.994³.803,P=0.051)。结论 IL-8基因-251A/T多态性与LOAD发病风险有一定关系。     

Analysis of whole genomic expression profiles of Helicobacter pylori related chronic atrophic gastritis with IL‐1B‐31CC/‐511TT genotypes

OBJECTIVE:   Many studies have linked cytokine interleukin‐1B gene polymorphisms to H. pylori‐related gastric cancer development. The current study evaluated the characterization of whole genomic expression profiles of the premalignant condition: H. pylori‐related chronic atrophic gastritis (CAG) with IL‐1B‐31CC/‐511TT genotypes. METHODS: IL‐1B‐31/‐511 gene polymorphisms were determined by DNA sequences. RNA was extracted and expression profiles were performed using Agilent human whole genomic oligonucleotide microarrays (G4112F). The expression of three samples with H. pylori infection was compared to that of three samples without H. pylori infection from samples of six CAG patients, all with IL‐1B‐31CC/‐511TT genotypes. Differentially expressed genes related to H. pylori‐induced CAG with IL‐1B‐31CC/‐511TT genotypes were screened and analyzed further by Gene Ontology (GO) and pathway. Validation of the microarray data was performed using qRT‐PCR. RESULTS: A total of 124 differentially expressed genes and 32 GO term annotations were identified between H. pylori positive and negative groups in the six CAG samples with IL‐1B‐31CC/‐511TT genotypes. The signaling pathways identified were oxidative phosphorylation and epithelial cell signaling in H. pylori infection. Five overlapping genes were contained in identified GO terms and pathways: ATP6V0B, NDUFS5, NDUFV2, ATP6V1F and ATP6V1G1. Comparisons of qRT‐PCR data and the previously reported data with the results of gene chips support the validity of our microarray data. CONCLUSION: The H. pylori‐related CAG with IL‐1B‐31CC/‐511TT genotypes has shown to be the more malignant phenotype than H. pylori negative CAG with IL‐1B‐31CC/‐511TT genotypes. Mitochondrial energy metabolism probably plays a crucial role as it is the molecular mechanism of host–bacterial interactions.     

The −509C/T polymorphism of transforming growth factor‐β1 is associated with increased risk for development of chronic idiopathic neutropenia

Objective: Impaired granulopoiesis in chronic idiopathic neutropenia (CIN) has been associated with an inflammatory bone marrow (BM) microenvironment consisting of pro‐inflammatory and pro‐apoptotic mediators, such as tumor necrosis factor (TNF)‐α, transforming growth factor (TGF)‐β1, and Fas‐Ligand (Fas‐L). In this study, we evaluated the frequency of TNF‐α, TGF‐β1 and Fas‐L gene polymorphisms in CIN patients and explored their role in excessive cytokine production and their association with CIN development. Methods: The TNF‐α?308G/A, TGF‐β1 ?509C/T, +869T/C, +915G/C, and Fas‐L ?844T/C polymorphisms were studied in 57 CIN patients, and 100 healthy controls from Crete, a well‐defined area with genetically homogeneous population, using a polymerase chain reaction‐based restriction fragment length polymorphism assay. Results: The mutant genotype C/T or T/T of TGF‐β1 ?509C/T polymorphism was more common in CIN patients than in controls (P = 0.033). Compared to wild‐type genotype, the TT genotype was associated with increased risk for CIN development (OR: 5.7; 95% CI: 1.18–27.26; P = 0.033). Compared to controls, patients with CT and TT genotypes displayed increased TGF‐β1 levels in serum (P < 0.0001 and P = 0.0002, respectively) and BM (P < 0.0001 and P = 0.0002, respectively). No significant difference was found between patients and controls in the frequency of TNF‐α?308G/A, TGF‐β1 +869T/C and +915G/C and Fas‐L ‐844T/C polymorphisms. Conclusions: The TGF‐β1 ?509C/T polymorphism is associated with increased risk for CIN and contributes to the pathophysiology of the disorder by inducing TGF‐β1 overproduction. This is the first study providing evidence that genetic factors may predispose to CIN and may have a role in the pathophysiology of the disorder.     

Interleukin‐1β and ‐10 polymorphisms influence erosive reflux esophagitis and gastritis in Taiwanese patients

Background and Aims: Helicobacter pylori (H. pylori) infection induces cytokine production and is associated with gastrointestinal diseases. This study examined the relationship of gene polymorphisms, including interleukin (IL)‐1β, ‐10, ‐8, and tumor necrosis factor‐α (TNF‐α), H. pylori infection, and susceptibility to gastrointestinal disorders in Taiwanese patients. Methods: IL‐1β?511/?31/+3953, ‐10?1082/?819/?592, ‐8?251, and TNF‐α?308 polymorphisms were assessed in 628 gastrointestinal disease patients, and 176 healthy controls were analyzed using the polymerase chain reaction?restriction fragment length polymorphism method. Results: IL‐1β?511 T/T and ?31 C/C genotypes, and IL‐1β?511 T and ?31 C alleles were associated with an increased risk of reflux esophagitis (P = 0.034, odds ratio [OR] = 1.384, 95% confidence interval [CI]: 1.023–1.871; P = 0.031, OR = 1.388, 95% CI: 1.028–1.873; P = 0.044, OR = 1.342, 95% CI: 1.008–1.786; and P = 0.040, OR = 1.349, 95% CI: 1.014–1.796, respectively). No relationship was found between H. pylori infection and the risk of reflux esophagitis. IL‐10?819 C/T and ‐10?592 A/C genotypes and IL‐10?1082/?819/?592 ATA/ACC and ATA/GCC haplotypes were associated with an increased risk of gastritis (P = 0.021, OR = 1.721, 95% CI: 1.084–2.733; P = 0.016, OR = 1.766, 95% CI: 1.112–2.805; P = 0.039, OR = 1.662, 95% CI: 1.024–2.697; and P = 0.035, OR = 1.600, 95% CI: 1.024–2.499, respectively). Conclusion: Among Taiwanese patients, IL‐1β and ‐10 polymorphisms were associated with an increased risk of erosive reflux esophagitis and gastritis, respectively.     

IL28RA polymorphism (rs10903035) is associated with insulin resistance in HIV/HCV‐coinfected patients

Hepatitis C virus (HCV) infection is associated with insulin resistance (IR), although mechanisms leading to IR in these patients are not completely understood. The aim of this study was to evaluate the association of interleukin 28B (IL28B) and interleukin 28 receptor alpha (IL28RA) polymorphisms with IR among human immunodeficiency virus (HIV)/HCV‐coinfected patients. We carried out a cross‐sectional study on 203 patients. IL28B (rs8099917) and IL28RA (rs10903035) polymorphisms were genotyped by GoldenGate^® assay. IR was defined as homeostatic model assessment (HOMA) values ≥3.00. Univariate and multivariate generalized linear models (GLM) were used to compare HOMA values and the percentage of patients with IR according to IL28B and IL28RA genotypes. In total, 32% (n = 65/203) of the patients had IR. IL28B rs8099917 TT was not significantly associated with HOMA values and IR. In contrast, rs10903035 AA was significantly associated with high HOMA values taking into account all patients (P = 0.024), as well as the subgroups of patients with significant fibrosis (P = 0.047) and infected with HCV genotype 3 (P = 0.024). Additionally, rs10903035 AA was significantly associated with IR (HOMA ≥3.00) in all patients (adjusted odds ratio (aOR) = 2.02; P = 0.034), in patients with significant fibrosis (aOR = 2.86; P = 0.039) and HCV genotype 3 patients (aOR = 4.89; P = 0.031). In conclusions, IL28RA polymorphism (rs10903035) seems to be implicated in the glucose homeostasis because AA genotype increases the likelihood of IR, but this association was different depending on hepatic fibrosis and HCV genotype.     

白细胞介素-8基因多态性与老年人非体外循环下冠状动脉旁路移植术预后的相关性

目的 研究白细胞介素-8(IL-8)在围手术期的变化及其与基因多态性关系,探讨心脏手术后炎性反应与预后的相关性.方法 术前分析IL-8(-251A>T)基因多态性.并于术前、术后4 h、24 h、72 h获取血液标本检测细胞因子.同时记录手术情况及对应时间点患者肌钙蛋白T(TnT)、肌酸激酶同工酶(CKMB)和血肌酐等生化指标.结果 145名患者首次接受择期非体外循环下冠状动脉旁路移植术,术后患者血浆IL-8水平上升,术后4 h水平最高(18.0[8.4,37.1]ng/L,P=0.000),术后3 d已下降至接近术前水平.其中-251AA基因型患者术后4 h IL-8水平产量升高(33.1[16.6,49.5]ng/L)(P=0.035).IL-8-251AA基因型患者,TnT和CKMB水平于术后4 h高于AT和TT基因型患者(TnT:0.53[0.43,4.92]ng/ml,P=0.037;CKMB:41.5[28.8,65.5]U/L,P=0.025);AA基因型患者血肌酐水平于术后24 h升高(93.1[76.4,121.5]μmol/L,P＝0.021).手术后呼吸机使用>1 d或术后住院时间>14 d患者,术后4 h IL-8水平升高(P=0.036,0.038).应用Logistic回归方法对术后出现呼吸机使用>1 d,术后住院>14 d等危险因素进行回归分析发现,IL-8-251AA患者呼吸机使用>1 d(OR＝11.80,95% CI:1.87～74.48),术后住院>14 d(OR=38.00,95% CI:4.15～347.87)风险增加.结论 非体外循环下冠状动脉旁路移植术会引起机体炎性反应.IL-8-251AA基因型患者术后炎性反应程度及预后风险增加,手术后炎性反应程度和预后与遗传背景有关.     

Early IL‐10 predominant responses are associated with progression to chronic hepatitis C virus infection in injecting drug users

Summary. The critical events in clearance or persistence of hepatitis C virus (HCV) infection are unknown but likely to be determined early in acute infection. Type 1 and type 2 cytokine production was assessed by HCV peptide ELISpot and multiplex in vitro cytokine production assays in longitudinally collected samples from 20 untreated participants enrolled in the Australian Trial in Acute Hepatitis C (ATAHC); a prospective cohort of acute HCV infection (77% injecting drug users, IDU). Significantly higher interleukin‐10 (IL‐10) production (P = 0.048), in the relative absence of interferon‐gamma (IFN‐γ) and IL‐2 production, was present early in HCV infection in those who progressed to chronic infection. In contrast, viral clearance was associated with a greater magnitude and broader specificity of IFN‐γ (magnitude P < 0.001, breadth P = 0.004) and IL‐2 responses, in the relative absence of IL‐10. Early IL‐10 production was correlated with higher HCV RNA level at baseline (P = 0.046) and week 12 (P = 0.018), while IFN‐γ and IL‐2 production was inversely correlated with HCV RNA level at baseline (IFN‐γP = 0.020, IL‐2 P = 0.050) and week 48 (IFN‐γP = 0.045, IL‐2 P = 0.026). Intracellular staining (ICS) indicated the HCV‐specific IFN‐γ response was primarily from CD8⁺ T cells and NK cells, whereas IL‐10 production was predominantly from monocytes, with a subset of IL‐10 producing CD8⁺ T cells present only in those who progressed to chronic infection. IL‐10, an immunoregulatory cytokine, appears to play a key role in progression to chronic HCV infection.