Single Nucleotide Polymorphisms In Interleukin Research Articles

Single nucleotide polymorphisms of Interleukin - 4, Interleukin-18, FCRL3 and sPLA2IIa genes and their association in pathogenesis of endometriosis.

Endometriosis is a complex gynaecological disorder that contributes to infertility, dysmenorrhea, dyspareunia, and other chronic issues. It is a multifactorial disease involving genetic, hormonal, immunological and environmental components. Endometriosis's pathogenesis remains unclear. was to analyse the polymorphisms in Interleukin 4, Interleukin 18, FCRL3 and sPLA2IIa genes to identify any significant association with the risk of endometriosis. This study evaluated the polymorphism of -590C/T in interleukin- 4(IL-4) gene, C607A in Interleukin - 18(IL-18) gene, -169T > C in FCRL3 gene and 763C > G in sPLA2IIa gene in women with endometriosis. The case-control study included 150 women with endometriosis and 150 apparently healthy women as control subjects. DNA was extracted from peripheral blood leukocytes and endometriotic tissue of cases and blood samples for controls and further analysed by PCR amplification and then sequencing was carried out to find the allele and genotypes of the subjects and then to analyse the relationship between the gene polymorphisms and endometriosis. To evaluate the association of the different genotypes, 95% confidence intervals (CI) were calculated. Interleukin - 18 and FCRL3 gene polymorphisms of endometriotic tissue and blood samples of endometriosis (cases) showed significantly associated (OR = 4.88 [95% CI = 2.31-10.30], P > 0.0001) and (OR = 4.00 [95% CI = 2.2-7.33], P > 0.0001) when compared with normal blood samples. However, there was no significant difference in Interleukin - 4 and sPLA2IIa gene polymorphisms between control women and patients with endometriosis. The present study suggests that the IL-18 and FCRL3 gene polymorphisms are associated with a higher risk for endometriosis, which delivers valuable knowledge of endometriosis's pathogenesis. However, a larger sample size of patients from various ethnic backgrounds is necessary to evaluate whether these alleles have a direct effect on disease susceptibility.

Association of Single-Nucleotide Polymorphisms in Interleukin Genes with Microbial Keratitis in a South Indian Population

To examine the relationship between single-nucleotide polymorphisms (SNPs) in interleukin (IL) genes and keratitis and its clinical manifestations. SNPs in IL1B, IL6, CXCL8, IL10, and IL12B were analysed. Differences in frequencies of alleles, genotypes and haplotypes between cases and controls as well as associations between SNPs and clinical variables were calculated by χ2 tests with odds ratios. The minor homologous genotype in IL1B rs16944 (p = 0.036; odds ratio (OR) = 2.063, 95% confidence interval (CI): 1.048-4.061) and CXCL8 rs4073 (p = 0.041; OR = 0.463, 95% CI: 0.224-0.956) and the heterologous genotypes in IL6 rs1800795 (p = 0.046; OR = 0.563, 95% CI: 0.326-0.972) and IL12B rs2569254 (p = 0.0446; OR = 0.557, 95% CI: 0.314-0.989) or rs730691 (p = 0.0051; OR = 0.451, 95% CI: 0.260-0.784) were associated with keratitis. The minor genotype of rs16944 was associated with severe infection (p = 0.046). The heterologous genotype in rs2569254 was associated with hospital admission, photophobia, and mode of contact lens wear (p ≤ 0.041). The heterologous genotype in rs730691 was associated with blurred vision, discharge, anterior chamber reaction, and mode of wear (p ≤ 0.047). This study demonstrates that SNPs in IL1B and CXCL8 are associated with risk of developing keratitis. The study also found relationships between SNPs and clinical measures of keratitis. The potential for ethnic differences in frequency of SNPs and their association with keratitis should be followed up using different populations.

Association of three single nucleotide polymorphisms in interleukin 6 gene with risk of chronic obstructive pulmonary disease

BackgroundsExperimental studies have implicated the involvement of interleukin 6 (IL6) in chronic obstructive pulmonary disease (COPD), supporting the possible association between genetic alterations in IL6 gene and risk of COPD. ObjectivesWe aimed to examine the association of three polymorphisms in IL6 gene with COPD by integrating the summary results of available reports, and summarize the changes circulating IL6 concentrations across genotypes. MethodsTwo investigators independently searched medical literature, selected qualified publications, assessed study quality, and abstracted detailed information. STATA software v14.1 was applied for statistical analyses. ResultsTen articles, including 18 independent studies and 4 815 participants, were comprehensively pooled. When all studies were analyzed together, the association with COPD was not significant for rs1800795 and rs1800797, yet statistical significance was attained for rs1818879 (P < 0.05) across four genetic modes of inheritance. When analyses were restricted to preset subgroups, race, matched condition, and COPD diagnosis were identified as the factors attributed to heterogeneity between studies. Moreover, changes in circulating IL6 concentrations remained nonsignificant across the genotypes of rs1800795 and rs1818879 (P > 0.05). Funnel plots and related tests revealed a low likelihood of publication bias for three studied polymorphisms (P > 0.1). ConclusionsOur findings indicated that IL6 gene rs1818879 might be a COPD-susceptibility locus. Further validations in longitudinal studies are necessary.

Association of three single nucleotide polymorphisms of interleukin -35 for detection and prediction of women with breast cancer in Erbil city

Association of three single nucleotide polymorphisms of interleukin -35 for detection and prediction of women with breast cancer in Erbil city

Status of Gene Methylation and Polymorphism in Different Courses of Ulcerative Colitis and Their Comparison with Sporadic Colorectal Cancer.

The objective of this study is to explore the common genetic and epigenetic mechanism of ulcerative colitis (UC) and sporadic colorectal cancer (SCRC) by observing genes methylation level and single nucleotide polymorphisms (SNPs) of different disease courses in UC and SCRC. Two hundred subjects were enrolled, including 40 in the healthy control (HC) group, 50 in the short disease course UC group (SUC), 52 in the long disease course UC group (LUC), and 58 in the SCRC group. Methylation-specific polymerase chain reaction was used to detect the methylation of MINT1 and cyclooxygenase 2 (COX-2) gene. Single nucleotide polymorphisms of interleukin (IL)-23R rs10889677 and IL-1β rs1143627 were detected by Sanger sequencing. Compared with HCs (32.5%), methylation level of MINT1 was significantly increased in SCRC (67.2%; P = 0.001) and was a risk factor for CRC (odds ratio, [OR] 4.26). The methylation ratios of COX-2 were 95.0%, 58.0%, 23.1%, and 24.1% in HC, SUC, LUC, and SCRC, respectively, which were negatively correlated with the disease course of UC (r = -0.290). Hypermethylation of COX-2 was a protective factor for SUC (OR, 0.11), LUC (OR, 0.02), and SCRC (OR, 0.03; P < 0.05). Compared with HCs, rs10889677 allele A was a risk factor for SUC and LUC, and rs1143627 allele T was a protective factor for SUC and LUC. Genotype TT was a protective factor for SUC. The hypomethylation of COX-2 gene was a common risk factor and epigenetic modification for UC and SCRC, which might be one of the mechanisms through which UC patients were susceptible to CRC. The hypermethylation of MINT1 was a risk factor for SCRC but not for UC; alleles of IL-23Rrs10889677 and IL-1βrs1143627 were related to UC but not to SCRC.

The correlation between total immunoglobulin-E levels and interleukin-13 gene polymorphism in asthmatic children treated with inhaled corticosteroids or montelukast

Background: The aim of this research was to study the possible correlation between single-nucleotide polymorphism of interleukin (IL)-13-1112 C/T with specific parameters in asthmatic children (total serum immunoglobulin-E [TSIgE] levels and asthma severity) treated with montelukast or inhaled corticosteroid. Methods: The study included one hundred asthmatic patients attending Karbala Teaching Hospital for children and similar numbers of healthy unrelated age-matched controls from the same locality of Iraq. TSIgE levels were determined by ELISA technique. DNA was extracted and processed by the allele-specific polymerase chain reaction technique for characterization of genetic variants of IL-13-1112 C/T gene polymorphisms. Results: Iraqi children with asthma showed a lower frequency of the IL-13-1112 CC genotype (13% vs. 16%) for control cases with a higher frequency of the heterozygous IL-13-1112 CT genotype (78% vs. 75%). IL-13-1112 showed significantly negative association with asthma in the dominant, codominant, and overdominant models of inheritance. On the other hand, comparing genotypes of subgroups related to gender, asthma severity, and asthma control showed a nonsignificant difference (P > 0.05). Homozygous wild types of IL-13-1112 TT might be considered protective to Iraqi asthma children. Conclusion: The IL-13 gene may be associated with the level of control in treated asthmatic patients. There is no correlation between TSIgE and the SNP.

Retraction: Novel Single Nucleotide Polymorphisms in Interleukin 6 Affect Tacrolimus Metabolism in Liver Transplant Patients.

Retraction: Novel Single Nucleotide Polymorphisms in Interleukin 6 Affect Tacrolimus Metabolism in Liver Transplant Patients.

Single-Nucleotide Polymorphisms in Interleukin 6 (IL-6) Gene Are Associated with Suicide Behavior in an Iranian Population.

Previous association studies have demonstrated the association between immune regulatory genes and suicide behavior. Among these genes are those coding for cytokines. In the present study, we genotyped two interleukin 6 (IL-6) variants (rs2069845 and rs1800795) in 320 suicide attempters, 236 suicide completers, and 341 individuals without any history of psychiatric disorders or suicide ideation. The rs2069845 was not associated with suicide behavior. The rs1800795 C allele was significantly more common among suicide completers compared with suicide attempters (OR (95% CI) = 1.33 (1.04-1.71)), adjusted P = 0.04). Besides, the rs1800795 was associated with the lethality of suicide attempt in recessive model (adjusted P value = 0.01). Consequently, the present study supports the role of IL-6 in suicide behavior and warrants further researches to confirm its effect and explain the underlying mechanism.

Association Between the IL-6 rs1800795 Polymorphism and the Risk of Cervical Cancer: A Meta-Analysis of 1210 Cases and 1525 Controls.

Cervical cancer is the second most common cancer and the third leading cause of cancer-related death among females in less developed countries. Studies have shown that the single-nucleotide polymorphisms of interleukin 6 might be associated with cervical cancer risk. A total of 710 articles from EMBASE, EBSCO, Web of science, PubMed, Springer link, and Chinese National Knowledge Infrastructure databases were reviewed in our study. A meta-analysis on the associations between interleukin 6 rs1800795 polymorphism and cervical cancer risk was carried out by comparison using 5 genetic models. In this systematic review, 5 studies were analyzed. The pooled population included 2735 participants (1210 cases and 1525 controls). The overall odds ratio (G vs C alleles) using fixed-effects model was 0.85 (95% confidence interval 0.75-0.97), P = .02. Our results show that the C genotype of interleukin 6 rs1800795 is associated with higher cervical cancer risk. Our results indicate that interleukin 6 rs1800795 polymorphism might be associated with susceptibility to cervical cancer.

The prognostic value of IL10 and TNF alpha functional polymorphisms in premenopausal early-stage breast cancer patients.

BackgroundInterleukin-10 and tumor necrosis factor α play an important role in breast carcinogenesis. Genes, encoding those two cytokines, contain single nucleotide polymorphisms, which are associated with differential levels of gene transcription. This study analyzes single nucleotide polymorphisms in interleukin 10 and tumor necrosis factor α genes and their contribution to breast cancer phenotype, lymph node status and survival in a group of young Lithuanian women with early-stage breast cancer patients.ResultsWe genotyped 100 premenopausal Eastern European (Lithuanian) patients with stage I-II breast cancer, ≤50 years old at the time of diagnosis, for interleukin 10 -592A > C, −819C > T and -1082A > G and tumor necrosis factor α -308G > A single nucleotide polymorphisms in the gene promoter region. We used the polymerase chain reaction, namely a restriction fragment length polymorphism method, for a SNP analysis. All genotypes were in Hardy-Weinberg equilibrium and had the same distribution as the HapMap CEU population. Holders of IL10 -592A > C heterozygous IL10 -592 AC genotype had a higher probability of estrogen receptor positive breast cancer phenotype than homozygous variants (P = 0.017). Phased ACC haplotype of IL10 polymorphisms was associated with younger age of diagnosis (P = 0.017). Of all the tested single nucleotide polymorphisms, only TNFα -308G > A has revealed a prognostic capability for breast cancer survival. GA genotype carriers, compared to GG, showed a significant disadvantage in progression-free survival (P = 0.005, adjusted hazard ratio (HR) = 4.631, 95 % confidence interval (CI) = 1.587 – 13.512), metastasis-free survival (P = 0.010, HR = 4.708, 95 % CI = 1.445 – 15.345) and overall survival (P = 0.037, HR = 4.829, 95 % CI = 1.098 – 21.243).ConclusionsAccording to our data, IL10 -1082A > G, −819 T > C, −592A > C polymorphisms and phased haplotypes have not revealed a prognostic value for breast cancer. On the contrary, the TNFα -308 polymorphism might modulate the risk and contribute to the identification of patients at a higher risk of breast cancer recurrence, metastasis and worse overall survival among young Lithuanian early-stage breast cancer patients.

Potential genetic markers for prediction of treatment response in Egyptian children infected with HCV genotype 4

Background: Egypt has a high prevalence of hepatitis C virus (HCV) infection. Limitations of the current HCV treatment in children are low rate of sustained virological response, significant side effects and high expenses, making prediction of treatment response crucial. Aim: This study aimed to investigate association of single nucleotide polymorphisms (SNPs) in interleukins (IL) 10, 28 and 29 genes in predicting the response to therapy in HCV infected children. Methods: Sixty-six Egyptian children infected with HCV genotype 4, receiving pegylated interferon alpha 2b and ribavirin, were included. Genotyping of six SNPs in interleukin 10, 28B and 29 gene as well as HCV genotype were analyzed by real-time polymerase chain reaction. Results: The CC genotype in IL28B; rs12979860 had 8.547 folds higher chance to develop sustained virological response than CT and TT genotypes (P=0.014). Genotype distribution of rs8099917 in IL28B gene (TG and GG genotypes) was found to be 3.348 more likely not to respond to treatment than the TT genotype (P=0.018). In multivariate analysis, interleukin 28 gene single nucleotide polymorphisms rs 12979860, interleukin 10 single nucleotide polymorphisms −592A > C and basal viral load were independent variables that significantly improved prediction of response to HCV therapy. Conclusion: This association can be translated into clinical decision making for HCV treatment.

- 251 A/T Single Nucleotide Polymorphism of Interleukin 8 and Susceptibility to Acute Myocardial Infarction

Backg round: Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide A well - characterized IL8 gene single - nucleotide polymorphism (SNP) at position −251 A/T is the only one known to influence its expression and was associated with several diseases. Aim: To investigate the possible correlation of the − 251 A/T polymorphism of IL - 8 gene with susceptibility to Acute Myocardial infarction and its correlation with Plasma IL - 8 levels in two case control populations , the Saudi and Egyptian populations. Methods : 20 AMI patients and 20 asymptomatic controls from Saudi population in addition to 20 AMI patients and 20 asymptomatic controls from Egyptian population were included in the current study. The IL - 8 plasma level was assayed using the human IL - 8 Quantikine ELISA Kit . The IL - 8

A preliminary study on the association of single nucleotide polymorphisms of interleukin 4 (IL4), IL13, IL4 receptor alpha (IL4Rα) & Toll-like receptor 4 (TLR4) genes with asthma in Indian adults.

Background & objectives:Interleukin 4 (IL4) and IL13 genes are believed to be responsible for inflammation of the airways in asthmatics. These share a common receptor component called IL4Rα which is another potentially important candidate gene linked to asthma phenotypes. Another gene Toll-like receptor 4 (TLR4) might affect the incidence or progression of asthma through the expression of proinflammatory genes. Several single nucleotide polymorphisms (SNPs) in IL4, IL13, IL4Rα and TLR4 have been reported to be linked to asthma or related phenotypes in several ethnic populations using linkage studies and association studies. However, the results have not been consistent. We investigated five SNPs (C-589T and C-33T of IL4, G+2044A of IL13, A+1902G of IL4Rα, and A+896G of TLR4) in patients with adult onset asthma to evaluate their role in manifestation and severity of asthma.Methods:Adult (>18 yr of age) patients with asthma (n=100) and healthy controls (n=50) were included in the study. Genotyping was performed using sequenom MassARRAY technology.Results:The mutant alleles of the C-589T and C-33T SNPs in the promoter region of IL4 were present in 4 per cent patients with asthma but absent from the control group suggesting that the variations in IL4 may contribute to asthma occurrence. The SNPs of other genes were seen in both controls and patients.Interpretation & conclusions:The results suggest the possible association between the genetic distribution of C-589T and C-33T SNPs of IL4 with asthma in Indian adults.

The association between single nucleotide polymorphisms of interleukin (IL)-10, IL-10 receptor antagonist and IL-16 genes and endometriosis

The association between single nucleotide polymorphisms of interleukin (IL)-10, IL-10 receptor antagonist and IL-16 genes and endometriosis

Novel Single Nucleotide Polymorphisms in Interleukin 6 Affect Tacrolimus Metabolism in Liver Transplant Patients

BackgroundTacrolimus is the first-line immunosuppressant after organ transplantation. It is mainly metabolized by cytochrome P450, family 3, subfamily A (CYP3A) enzymes, but there are large individual differences in metabolism. Interleukin 6 (IL6) has been shown to cause a pan-suppression of mRNA levels of ten major CYP enzymes in human hepatocyte cultures. IL6 has been shown to provide hepatoprotection in various models of liver injury. Rs1800796 is a locus in the IL6 gene promoter region which regulates cytokine production. We speculated that IL6 rs1800796 polymorphisms may lead to individual differences in tacrolimus metabolism by affecting CYP3A enzymes levels and liver function after liver transplantation.Methodology/Principal FindingsNinety-six liver transplant patients receiving tacrolimus were enrolled in the study. Two single nucleotide polymorphisms (SNP), CYP3A5 rs776746 and IL6 rs1800796, were genotyped in both donors and recipients. The effects of SNPs on tacrolimus concentration/dose (C/D ratio) at four weeks after transplantation were studied, as well as the effects of donor IL6 rs1800796 polymorphisms on liver function. Both donor and recipient CYP3A5 rs776746 allele A showed association with lower C/D ratios, while donor IL6 rs1800796 allele G showed an association with higher C/D ratios. Donor CYP3A5 rs776746 allele A, IL6 rs1800796 allele C, and recipient CYP3A5 rs776746 allele A were associated with fast tacrolimus metabolism. With increasing numbers of these alleles, patients were found to have increasingly lower tacrolimus C/D ratios at time points after transplantation. Donor IL6 rs1800796 allele G carriers showed an association with higher glutamic-pyruvic transaminase (GPT) levels.ConclusionsCombined analysis of donor CYP3A5 rs776746, IL6 rs1800796, and recipient CYP3A5 rs776746 polymorphisms may distinguish tacrolimus metabolism better than CYP3A5 rs776746 alone. IL6 may lead to individual differences in tacrolimus metabolism mainly by affecting liver function.

Association betweenTNF-αandIL-1βgenotypesvs Helicobacter pyloriinfection in Indonesia

To investigate the correlation between the Helicobacter pylori (H. pylori) infection and host genetic background of healthy populations in Indonesia. In March 2007, epidemiological studies were undertaken on the general population of a city in Indonesia (Mataram, Lombok). The participants included 107 men and 187 women, whose ages ranged from 6 to 74 years old, with an average age of 34.0 (± 14.4) (± SD). The H. pylori of subject by UBT method determination, and through the polymerase chain reaction with confronting two-pair primers (PCR-CTPP) method parsing the single nucleotide polymorphism of interleukin (IL)-8, IL-4, IL-1β, CD14, tumor necrosis factor (TNF-α) and tyrosine-protein phosphates non-receptor type 11 (PTPN11) genotypes. The experimental data were analyzed by the statistical software SAS. The H. pylori infection rates in the healthy Indonesian population studied were 8.4% for men and 12.8% for women; no obvious differences were noted for H. pylori infection rates by sex or age. TC genotypes of IL-4, TC and CC genotypes of TNF-α, and GA genotypes of PTPN11, were higher in frequency. Both CC and TC genotype of TNF-α T-1031C loci featured higher expressions in the healthy Indonesian population Indonesia studied of (OR = 1.99; 95%CI: 0.67-5.89) and (OR = 1.66; 95%CI: 0.73-3.76), respectively. C allele of IL-1β T-31C gene locus was at a higher risk (OR = 1.11; 95%CI: 0.70-1.73) of H. pylori infection, but no statistical significance was found in our study. We reveal that the association between the TNF-α and IL-1β genotypes may be the susceptibility of H. pylori in the studied population.

Burden of pediatric hepatitis C

Hepatitis C virus (HCV) is a major health burden infecting 170-210 million people worldwide. Additional 3-4 millions are newly-infected annually. Prevalence of pediatric infection varies from 0.05%-0.36% in the United States and Europe; up to 1.8%-5.8% in some developing countries. The highest prevalence occurs in Egypt, sub-Saharan Africa, Amazon basin and Mongolia. HCV has been present in some populations for several centuries, notably genotypes 1 and 2 in West Africa. Parenteral anti-schistosomal therapy practiced in the 1960s until the early 1980s had spread HCV infection throughout Egypt. Parenteral acquisition of HCV remains a major route for infection among Egyptian children. Insufficient screening of transfusions, unsterilized injection equipment and re-used needles and syringes continue to be major routes of HCV transmission in developing countries, whereas vertical transmission and adolescent high-risk behaviors (e.g., injection drug abuse) are the major routes in developed countries. The risk of vertical transmission from an infected mother to her unborn/newborn infant is approximately 5%. Early stages of HCV infection in children do not lead to marked impairment in the quality of life nor to cognitive, behavioral or emotional dysfunction; however, caregiver stress and family system strain may occur. HCV slowly progresses to serious complications as cirrhosis (1%-2%) and hepatocellular carcinoma (HCC) especially in the presence of risk factors as hemolytic anemias, obesity, treated malignancy, and concomitant human immune deficiency and/or hepatitis B virus co-infection. HCV vaccine remains elusive to date. Understanding the immune mechanisms in patients who successfully cleared the infection is essential for vaccine development. The pediatric standard of care treatment consists of pegylated interferon-α 2a or b plus ribavirin for 24-48 wk. The new oral direct acting antivirals, approved for adults, need further evaluation in children. Sustained virologic response varies depending on the viral load, genotype, duration of infection, degree of aminotransferase elevation, adiposity and single nucleotide polymorphisms of interleukin (IL)-28B locus. The goals of treatment in individual patients are virus eradication, prevention of cirrhosis and HCC, and removing stigmatization; meanwhile the overall goal is decreasing the global burden of HCV. IL-28B polymorphisms have been also associated with spontaneous clearance of vertically acquired HCV infection. The worldwide economic burden of HCV for children, families and countries is estimated to be hundreds of millions of US dollars per year. The United States, alone, is estimated to spend 199-336 million dollars in screening, monitoring and treatment during one decade. The emotional burden of having an HCV infected child in a family is more difficult to estimate.

Relevance of interleukin-10RB to chronic hepatitis B virus infection and biological activities of interferon-λ and interleukin-22

PurposeThe association of a single nucleotide polymorphism of interleukin (IL)-10RB codon 47 with the chronic hepatitis B virus (HBV) infection has been reported in two ethnic populations with different results, but not in a Korean population. IL-10RB is a subunit of receptor complexes for interferon-lambda (IFN-λ) and IL-22, which have antiviral and hepatocyte-protective activity, respectively. This study examined the association of IL-10RB K47E with the outcomes of HBV infection in Korean subjects and the cellular response to these cytokines.MethodsGenotypes of IL-10RB and the outcomes of HBV infection were analyzed in 1,000 Korean patients. The effect of IFN-λ or IL-22 on HBV replication and cell viability was assessed in hepatoma cells expressing IL-10RB K47 or E47. The transcript level of IL-10RB was examined in Epstein Barr virus-transformed B cells and hepatoma cells.ResultsIL-10RB K47E was associated with chronic HBV infection but not with hepatoma in the Korean population. IL-10RB K47E was associated with the transcript level of IL-10RB in transformed B cells but not with the responses in hepatoma cells to IFN-λ or IL-22. HBV replication or 5-fluorouracil-induced cell death was suppressed by treatment of IFN-λ or IL-22 in an IL-10RB K47E-independent manner.ConclusionsIL-10RB K47E is related to chronic HBV infection in a Korean population, but not to cellular responsiveness to IFN-λ and IL-22.Electronic supplementary materialThe online version of this article (doi:10.1007/s12072-012-9361-8) contains supplementary material, which is available to authorized users.

A Genome-Wide Association Study of Overall Survival in Pancreatic Cancer Patients Treated with Gemcitabine in CALGB 80303

Cancer and Leukemia Group B 80303 was a randomized, phase III study in patients with advanced pancreatic cancer treated with gemcitabine plus either bevacizumab or placebo. We prospectively collected germline DNA and conducted a genome-wide association study (GWAS) using overall survival (OS) as the endpoint. DNA from 351 patients was genotyped for more than 550,000 single-nucleotide polymorphisms (SNP). Associations between OS and SNPs were investigated using the log-linear 2-way multiplicative Cox proportional hazards model. The subset of 294 genetically European patients was used for the primary analysis. A nonsynonymous SNP in interleukin (IL)17F (rs763780, H161R) and an intronic SNP in strong linkage disequilibrium (rs7771466) were associated with OS using genome-wide criteria (P ≤ 10(-7)). Median OS was significantly shorter (P = 2.61 × 10(-8)) for the rs763780 heterozygotes [3.1 months; 95% confidence interval (CI), 2.3-4.3] than for the patients without this variant (6.8 months; 95% CI, 5.8-7.3). After adjustment by stratification factors, the P value for the association was 9.51 × 10(-7). The variant 161R form of IL-17F is a natural antagonist of the antiangiogenic effects of wild-type 161H IL-17F, and angiogenesis may play an important role in the metastatic spread of pancreatic cancer. In this preliminary study, we hypothesize that the angiogenetic potential of pancreatic cancers in patients with variant IL-17F is higher than that of tumors in patients with wild-type IL-17F, conferring worse prognosis. This exploratory GWAS may provide the foundation for testing the biology and clinical effects of novel genes and their heritable variants through mechanistic and confirmatory studies in pancreatic cancer.

IL28B polymorphism as a predictor of antiviral response in chronic hepatitis C

To evaluate the effect of single nucleotide polymorphisms of interleukin (IL)-28B, rs12979860 on progression and treatment response in chronic hepatitis C. Patients (n = 64; 37 men, 27 women; mean age, 44 ± 12 years) with chronic hepatitis C, genotype 1, received treatment with peg-interferon plus ribavirin. Genotyping of rs12979860 was performed on peripheral blood DNA. Histopathological assessment of necroinflammatory grade and fibrosis stage were scored using the METAVIR system on a liver biopsy sample before treatment. Serum viral load, aminotransferase activity, and insulin level were measured. Insulin resistance index, body mass index, waist/hip ratio, percentage of body fat and fibrosis progression rate were calculated. Applied dose of interferon and ribavirin, platelet and neutrophil count and hemoglobin level were measured. A sustained virological response (SVR) was significantly associated with IL28B polymorphism (CC vs TT allele: odds ratio (OR), 25; CC vs CT allele: OR, 5.4), inflammation activity (G < 1 vs G > 1: OR, 3.9), fibrosis (F < 1 vs F > 1: OR, 5.9), platelet count (> 200 × 10(9)/L vs < 200 × 10(9)/L: OR, 4.7; OR in patients with genotype CT: 12.8), fatty liver (absence vs presence of steatosis: OR, 4.8), insulin resistance index (< 2.5 vs > 2.5: OR, 3.9), and baseline HCV viral load (< 10(6) IU/mL vs > 10(6) IU/mL: OR, 3.0). There was no association with age, sex, aminotransferases activity, body mass index, waist/hip ratio, or percentage body fat. There was borderline significance (P = 0.064) of increased fibrosis in patients with the TT allele, and no differences in the insulin resistance index between groups of patients with CC, CT and TT alleles (P = 0.12). Spearman's rank correlation coefficient between insulin resistance and stage of fibrosis and body mass index was r = 0.618 and r = 0.605, respectively (P < 0.001). Significant differences were found in the insulin resistance index (P = 0.01) between patients with and without steatosis. Patients with the CT allele and absence of a SVR had a higher incidence of requiring threshold dose reduction of interferon (P = 0.07). IL28B variation is the strongest host factor not related to insulin resistance that determines outcome of antiviral therapy. Baseline platelet count predicts the outcome of antiviral therapy in CT allele patients.