Cytokine Genetic Polymorphisms Research Articles

Genetic predictors of the risk of developing complications in the immediate postoperative period following combat trauma

Introduction. Paratraumatic eczema (PTE), being a type of microbial eczema, occurs after surgical interventions, chronic wound healing, accompanied by pronounced inflammatory changes with hyperemia, edema, exudation, soreness and itching. Genetic polymorphisms of cytokines and Toll-like receptors (TLRs) may be pathogenetic factors in the development of PTE, causing the penetration of microorganisms and violation of the protective properties of the skin barrier. Goal. To study the relationship of polymorphisms rs1800629 of the TNFα gene, rs5743708 of the TLR2 gene, rs3775291 of the TLR3 gene, rs4986790 of the TLR4 gene with the development of paratraumatic eczema in combat trauma victims. Material and methods. The study included 162 patients, of whom 82 showed signs of PTE (comparison group), 80 people had no signs of PTE (control group). Genotyping of polymorphisms was carried out using the polymerase chain reaction method with electrophoretic detection using test systems of NPF Litech (Russia). The Statistica 10 program (StatSoft, Inc., USA) was used for statistical data processing. Results. A connection with the development of PTE with variants of genotypes and alleles of polymorphisms was established: rs1800629 of the TNFα gene (χ2=6.9; p=0.033 and χ2=8.12; p=0.005); rs3775291 of the TLR3 gene (χ2=6.9; p=0.039 and χ2=5.74; p=0.018); rs4986790 of the TLR4 gene (χ2=8.17; p=0.018 and χ2=7.85; p=0.005). The increase in the chances of developing PTE was influenced by: genotypes GA (OR=1.64; 95% CI 0.83–3.24) and AA (OR=2.94; 95% CI 0.9–9.67), allele A (OR=2.13; 95% CI 1.26–3.6) rs1800629 TNFα gene; genotypes CT (OR=1.58; 74% CI 0.93–3.24) and TT (OR=1.79; 95% CI 0.67–4.8), allele T (OR=1.76; 95% CI 1.1–2.8) rs3775291 TLR3 gene; genotypes AG (OR=2.58; 95% CI 1.24–5.37) and GG (OR=3.0; 95% CI 0.31–29.47), allele G (OR=2.44; 95% CI 1.29–4.62) rs4986790 of the TLR4 gene. Conclusions. Polymorphisms rs1800629 of the TNFα gene, rs3775291 of the TLR3 gene, rs4986790 of the TLR4 gene are associated with the development of paratraumatic eczema in combat trauma victims

Influence of Cytokine Genetic Polymorphisms in Helicobacter pylori-Associated Gastric Inflammation According to Sex in South Korea.

: The relationship between genetic polymorphisms and gastric inflammation remains unclear. This study aimed to evaluate the impact of genetic polymorphisms on Helicobacter pylori (HP)-associated gastritis according to sex. : Two hundred thirty-two male and 404 female subjects with current HP infection were prospectively enrolled. The genotyping of IL-1B-511 C/T, IL-1RN variable number of tandem repeats, IL-6-572 G/C, IL-8-251 A/T, IL-8-781 C/T, IL-10-1082 G/A, IL-10-592 C/A, TNF-A-308 G/A, and transforming growth factor (TGF)-B-509 C/T, was determined by polymerase chain reaction-restriction fragment length polymorphism. The degree of monocyte or neutrophil infiltration, atrophic gastritis, and intestinal metaplasia was evaluated using the updated Sydney system. : Among the male subjects, moderate/severe atrophic gastritis of the corpus was higher in IL-1B-511 CC carriers than in CT and TT carriers independent of age, alcohol consumption, and HP virulence factors (26.9% vs 10.4%; adjusted hazard ratio [HR], 4.377; 95% confidence interval, 1.387 to 13.814). In females, IL-8-251 AA carriers were independently and significantly associated with moderate/severe atrophic gastritis of the corpus compared with that in AT and TT carriers (21.4% vs 6.0%, adjusted HR=3.799). In males, the IL-8-251 TT genotype was associated with moderate/severe intestinal metaplasia of the corpus compared with the AT and AA genotypes (13.4% vs 5.6%, adjusted HR=3.128), while the IL-10-592 CA and CC genotypes were associated with moderate/severe monocyte infiltration of the antrum compared with AA genotype (83.6% vs 71.8%, adjusted HR=2.227). : Genetic polymorphisms in cytokines play different roles in HP-associated gastritis according to sex.

Plasma Cytokine Levels and Cytokine Genetic Polymorphisms in Patients with Metastatic Breast Cancer Receiving High-Dose Chemotherapy

Differences in the baseline levels of serum cytokines or in single-nucleotide polymorphisms (SNPs) in cytokine genes may be useful to predict outcomes for patients being treated for metastatic breast cancer. We have measured the plasma levels and characterized individual SNPs for IL-1RA, IL-1β, IL-2, IL-6 and TNFα in 130 patients with metastatic breast cancer treated with high-dose chemotherapy. Patients were treated with high-dose cyclophosphamide (Group 1, 74 patients) or high-dose paclitaxel-containing regimens (Group 2, 56 patients). A high plasma level of IL-1RA and a SNP in the IL-1RA gene indicated a better prognosis for patients in Group 1 (but not Group 2). However, the level of plasma IL-1RA did not correlate with the SNP genotype. A high plasma level of IL-6 or TNFα indicated a poorer outcome for patients in Group 1 although the SNP genotypes for the IL-6 and TNFα SNPs were not associated with differences in outcome. The plasma levels of IL-1β and IL-2 and the genotype of the IL-1β SNPs did not indicate differences in outcome. Although, individually, plasma levels of cytokine or “risk” SNP genotypes may not indicate outcome, in combination there was an increased trend to predict outcome for patients treated with high-dose cyclophosphamide but not high-dose paclitaxel. These results suggest that the immune cytokines may be useful as prognostic biomarkers in the treatment of patients with metastatic breast cancer treated with different types of chemotherapy.

Relationship between genetic polymorphisms of cytokines and self-reported sleep complaints and habitual caffeine consumption

Pro-inflammatory cytokines are involved in sleep-wake regulation and are associated with caffeine consumption. This is a cross-sectional study in 1023 active French workers investigating associations between self-reported sleep complaints (>3months) and total sleep time (TST) with nine single-nucleotide-polymorphisms (SNPs) including pro-inflammatory cytokines, according to caffeine consumption. Participants were characterized as low, moderate and high (0–50, 51–300, and >300 mg/day) caffeine consumers. After adjusting the odd ratios (OR) for age, gender, and smoking, the risk of sleep complaints was higher in subjects with genetic mutations in tumor necrosis factor alpha (TNF-α, rs 1800629) (ORa [95%CI] = 1.43 [1.07–1.92] for both G/A and A/A aggregate genotypes) or interleukin-1 beta (IL-1β, rs1143627) (ORa = 1.61 [1.08–2.44] for homozygous A/A genotype), and the risk was higher when subjects carry the mutations in TNF-α plus IL-1β regardless of caffeine consumption. When stratified with caffeine consumption, the risk of sleep complaints was higher in TNF-α A allele carriers in high caffeine consumers, and in homozygous A/A genotype of IL-1β in moderate and high consumers. None of the nine SNPs influence TST, with the exception of the mutation on CYP1A2 and only when stratified with caffeine consumption. Our results also indicated more caffeine side-effects when carrying mutation on IL1β. This study showed that polymorphisms in TNF-α and/or IL-1β influenced sleep complaints but did not influence total sleep time. This suggests that management of sleep complaints, which can be addressed by clinical interventions, should consider the influence of the genetic profile of pro-inflammatory cytokines.

Effect of tumor necrosis factor alpha (TNF-α) -308 and -1031 gene polymorphisms on periodontitis among Saudi subjects

ObjectivesPeriodontitis is an infectious disorder that leads to irreversible loss of the surrounding attachment and bone destruction. Genetic polymorphism of cytokines has been suggested to play a role in periodontitis. This case-control study aimed to investigate the relationship between periodontitis and two single nucleotide polymorphisms (SNPs): rs1800629 (-308 G/A) and rs1799964 (-1031 T/C), in the TNF-α gene promoter area. Materials and methodsPeripheral blood was used to prepare genomic DNA from 60 subjects with stage II to stage III periodontitis, as along with 65 control subjects. Polymerase chain reaction and restriction endonuclease digestion were used to genotype TNF-α SNPs. ResultsThe distribution of both genotypes and alleles of TNF-α (-308 G/A) polymorphism did not vary between periodontitis subjects and the controls (P > 0.05). However, the CT genotype and C allele of the TNF-α (-1031 T/C) polymorphism were observed more frequently in the periodontitis subjects than in the controls, while the TT genotype and the T allele were more predominant in the control subjects than in the periodontitis patients (OR: 3.149; 95% CI: 1.494–6.639; P = 0.002 and OR: 2.933; 95% CI: 1.413–6.090; P = 0.003, sequentially). ConclusionThe TNF-α (-308 G/A) polymorphism potentially has no correlation with periodontitis susceptibility, whereas the TNF-α (-1031) CT genotype and C allele might be related to periodontitis among Saudi subjects.

Interleukin10 rs1800896 and interleukin1B rs16944 polymorphisms and the risk of cervical cancer.

The purpose of this study was to evaluate the relationships between interleukin10 (IL10) (rs1800896) and interleukin1B (IL1B) (rs16944) genetic polymorphisms and the risk for cervical cancer in acohort of women from Croatia. Acase-control study of 81patients with cervical cancer and 80age-matched healthy controls was performed. We collected peripheral blood samples, extracted deoxiribonucleic acid (DNA), and analyzed two single-nucleotide polymorphisms (SNPs) rs1800896 and rs16944 using TaqMan assays (Fa. Thermo Fisher Scientific, Waltham, MA, USA) and real-time polymerase chain reaction (PCR). We investigated apossible association between two cytokine genetic polymorphisms and the occurrence of cervical cancer. Our results showed no significant difference in the frequency of IL10 (rs1800896) and IL1B (rs16944) genotypes between the patients and the controls (χ2 test, P < 0.05). In this study, no association was found between IL10 rs1800896 and IL1B rs16944 polymorphisms and cervical cancer development.

Immunological findings in patients with migraine and other primary headaches: a narrative review.

Experimental findings suggest an involvement of neuroinflammatory mechanisms in the pathophysiology of migraine. Specifically, preclinical models of migraine have emphasized the role of neuroinflammation following the activation of the trigeminal pathway at several peripheral and central sites including dural vessels, the trigeminal ganglion, and the trigeminal nucleus caudalis. The evidence of an induction of inflammatory events in migraine pathophysiological mechanisms has prompted researchers to investigate the human leukocyte antigen (HLA) phenotypes as well as cytokine genetic polymorphisms in order to verify their potential relationship with migraine risk and severity. Furthermore, the role of neuroinflammation in migraine seems to be supported by evidence of an increase in pro-inflammatory cytokines, both ictally and interictally, together with the prevalence of Th1 lymphocytes and a reduction in regulatory lymphocyte subsets in peripheral blood of migraineurs. Cytokine profiles of cluster headache (CH) patients and those of tension-type headache patients further suggest an immunological dysregulation in the pathophysiology of these primary headaches, although evidence is weaker than for migraine. The present review summarizes available findings to date from genetic and biomarker studies that have explored the role of inflammation in primary headaches.

Cytokine (IL-10, IL-6, TNF-α and TGF-β1) Gene Polymorphisms in Chronic Hepatitis C Virus Infection among Malay Male Drug Abusers.

Cytokines play an important role in modulating inflammation during viral infection, including hepatitis C virus (HCV) infection. Genetic polymorphisms of cytokines can alter the immune response against this infection. The objective of this study was to investigate the possible association between chronic hepatitis C virus infection susceptibility and cytokine gene polymorphism for interleukin-10 (IL-10) rs1800896 and rs1800871, interleukin 6 (IL-6) rs1800795, TNF-α rs1800629, and TGF-β1 rs1800471 in Malay male drug abusers. The study was conducted on 76 HCV-positive (HP) male drug abusers and 40 controls (HCV-negative male drug abusers). We found that there were significant differences in the frequencies of genotype for IL-10 rs1800871 (p = 0.0386) and at the allelic level for IL-10 rs1800896 A versus G allele (p = 0.0142) between the HP group and the control group. However, there were no significant differences in gene polymorphism in interleukin 6 rs1800795, TNF-α rs1800629 and TGF-β1 rs1800471. These findings suggest significant associations between gene polymorphism for IL-10 rs1800871, IL-10 rs1800896 (at the allelic level) and susceptibility to HCV infection among Malay male drug abusers.

Association of genetic polymorphism of cytokines and antioxidant enzymes with the development of asbestosis

Introduction. Various industries widely use chrysotile asbestos, which determines the relevance of research aimed at the prevention of asbestos-related diseases. It is promising to assess the role of specific genes, which products are potentially involved in the development and regulation of certain links in the pathogenesis of asbestosis, forming a genetic predisposition to the disease. The study aims to analyze the presence of associations of genetic polymorphism of cytokines and antioxidant enzymes with asbestosis development. Materials and methods. Groups were formed for examination among employees of OJSC "Uralasbest" with an established diagnosis of asbestosis and without lung diseases. For each person included in the study, dust exposure doses were calculated considering the percentage of time spent at the workplace during the shift for the entire work time. Genotyping of single nucleotide polymorphisms of cytokines IL1b (rs16944), IL4 (rs2243250), IL6 (rs1800795), TNFα (rs1800629) and antioxidant enzymes SOD2 (rs4880), GSTP1 (rs1610011), CAT (rs1001179) was carried out. Results. The authors revealed the associations of polymorphic variants A511G IL1b gene (OR=2.457, 95% CI=1.232-4.899) and C47T SOD2 gene (OR=1.705, 95% CI=1.055-2.756) with the development of asbestosis. There was an increase in the T allele IL4 gene (C589T) frequency in persons with asbestosis at lower values of dust exposure doses (OR=2.185, 95% CI=1.057-4.514). The study showed the associations of polymorphism C589T IL4 gene and C174G IL6 gene with more severe asbestosis, polymorphism A313G GSTP1 gene with pleural lesions in asbestosis. Conclusion. Polymorphic variants of the genes of cytokines and antioxidant enzymes, the protein products directly involved in the pathogenetic mechanisms of the formation of asbestosis, contribute to forming a genetic predisposition to the development and severe course of asbestosis. Using the identified genetic markers to identify risk groups for the development and intense period of asbestos-related pathology will optimize treatment and preventive measures, considering the organism's characteristics.

Genetic polymorphisms of cytokines in asthma and allergic rhinitis

Genetic polymorphisms of cytokines in asthma and allergic rhinitis

Lack of Association between Cytokine Genetic Polymorphisms in Takayasu's Arteritis in Mexican Patients.

Aim: To investigate the relation between polymorphisms in the interleukin 10 (IL)-10, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β and interferon (IFN)-γ genes and Takayasu’s arteritis in the Mexican population. Methods: A case-control study was performed to investigate the associations of IL-10, TNF-α, TGF-β and IFN-γ polymorphisms in a sample of 52 Takayasu’s arteritis patients, diagnosed according to the criteria of the American College of Rheumatology and EULAR PRINTO criteria when the patients were under 18 years of age; 60 clinically healthy unrelated Mexican individuals by the 5′ exonuclease TaqMan polymerase chain reaction. Polymorphic haplotypes were constructed after linkage disequilibrium analysis. Results: Significant differences were not found in the distribution for genotype and allele frequencies of the polymorphisms studied between healthy controls and Takayasu´s arteritis patients. Likewise, significant associations were not detected in the haplotype analysis with the different genes studied. Conclusions: These findings suggest that the polymorphisms in IL-10, TNF-α, TGF-β and IFN-γ might not contribute to the susceptibility of Takayasu´s arteritis in the Mexican population.

TNF-α (-308) Gene Polymorphism and Type 2 Diabetes Mellitus in Ethiopian Diabetes Patients.

BackgroundType 2 diabetes mellitus (T2DM) is a metabolic disorder resulting from insulin insufficiency or function. Predisposing factors for T2DM are mainly genetic and environmental. Genetic polymorphism of cytokines like tumor necrosis factor-alpha (TNF-α) is suggestive of interference with insulin-sensitive glucose uptake and induces insulin resistance that ultimately could lead to T2DM. In this study, we assessed the effect of TNF-α (−308) G/A gene polymorphism and its association with the development of T2DM in an Ethiopian population.MethodsAn institutional-based cross-sectional study was conducted on study subjects with T2DM and non-diabetic healthy controls. DNA was extracted and genotyping was carried out by using amplification refractory mutation system polymerase chain reaction. A genetic-polymorphism on TNF-α (−308) G/A with T2DM was evaluated by logistic regression and Student’s t-test. A P-value <0.05 was considered as statistically significant.ResultsIn the present study, we observed a significant association between T2DM and TNF-α (−308) gene polymorphism’s GG genotype [χ2 test P = 0.005, OR (95% CI) =2.667 (1.309–5.45d8)]. In contrast, no statistically significant differences were observed in the frequencies of genotypes AA and AG (χ2 test P=0.132 and 0.067, respectively). Moreover, T2DM individuals had higher concentrations of lipid profiles for those carrying the TNF-α (−308) GG genotype as compared to the control group.ConclusionTNF-α (−308) genetic polymorphism may be implicated in the genetic susceptibility for, as well as the development of T2DM and lipid metabolism in the Ethiopian population. Therefore, a large-scale study and early screening of TNF-α (−308) genetic polymorphism may help in early management and control of diabetes and related outcomes.

Cytokine Gene Polymorphisms Are Associated with Disease Response to Blinatumomab in Patients with B-Cell Acute Lymphoblastic Leukemia

Blinatumomab (BT), a CD19/CD3 bispecific T-cell engager (BiTE) antibody recently approved for treatment of relapsed/refractory acute lymphoblastic leukemia (r/r ALL), has resulted in a 40-50% complete response (CR)/CR with incomplete count recovery (CRi) rate and frequent cytokine release syndrome (CRS) events. While extent of disease burden has been identified as a key predictor of disease response, there have been no studies to date evaluating the impact of single nucleotide polymorphisms (SNPs) in cytokine genes on disease response or CRS after treatment with BT. Here, we evaluated the possible association between cytokine SNPs, disease response, and/or CRS in r/r ALL patients with receiving BT.A total of 82 patients (consecutive case-series) received BT between 2012 and 2017 at City of Hope. Of these, 68 patients had archived DNA samples available for study and analysis. Genotyping was done using Illumina's Omni 5-4 bead array, which interrogates more than 4.2 million SNPs. Array processing was done following manufacturer's recommendations and arrays were scanned by Illumina's iScan instrument. Beeline software and Genome Studio (Illumina) were used for analysis of scanned images and to generate the genotyping calls and quality control reports, respectively. Our analysis focused on the following cytokine genes of interest (known to be associated with autoimmune diseases/graft-versus-host disease): IL-1B, IL-2, IL-6, IL-7R, IL-10, IL-11, IL-12, IL-17A, IL-23R, TNF-α, TGF-β, and IFN-γ. Two modes of inheritance (dominant and recessive) were considered whenever appropriate. Univariate analyses of SNPs, response and CRS were performed using Fisher's exact test. P values were not adjusted for multiple hypothesis testing due to the exploratory nature of the analyses.In our cohort, median age of patients at BT treatment was 34 years old (range: 7-85), with 32 females (39%) and 50 males (61%). Patients' race/ethnicity included 49 Hispanic (60%), 20 non-Hispanic Caucasians (24%), 9 Asians (11%), and 3 African Americans (3%). All patients had primary refractory (n=16) or relapsed disease status (1st relapse: n=38, 2nd or subsequent relapse: n=27) with median lines of prior therapy of 2 (range: 0-5). Cytogenetic abnormalities included Ph+ALL in 11 patients, while 50 patients had other cytogenetic abnormalities and 15 had normal cytogenetics. Bone marrow blasts of >50% at BT treatment was detected in 45 patients, and 22 patients had a history of or active extra-medullary involvement. After BT treatment, 37 patients (45%) achieved CR/CRi with a median duration of 9.5 months (range: 1-37), 54 patients (66%) experienced CRS (grade 1: n=35, grade 2: n=14, and grade 3: n=5), and 9 patients developed neurotoxicity. Lastly, the peak C-reactive protein level (median/range) was 17 mg/L (range: 1-392).By univariate analysis, disease response (CR/CRi) to BT was significantly associated with the following cytokine SNPs: IL2 rs2069762 [48.3% (T/T-G/T: n=60) Vs. 0% (G/G; n=7), p=0.016], IL17A rs3819024 [30.8% (A/A; n=39) Vs. 58.6% (A/G-G/G; n=29), p=0.027], and IL17A rs4711998 [54.5% (A/A: n=33) Vs. 29.4% (A/G-G/G: n=34), p=0.049]. (Table 1) These three cytokine SNPs and two additional SNPs with p-values between 0.05 and 0.1 (IL7R rs1494555, IL17A rs8193036) were evaluated by multivariable analysis, adjusted for >50% bone marrow blasts, which was associated with lower rate of CR/CRi (33% vs. 63% with <50%, p=0.02). By multivariable analysis, IL17A rs3819024 remained significant while IL17A rs4711998 was at borderline significance (p=0.06). (IL2 rs2069762 could not be tested due to no CR/CRi occurrence). None of the cytokine SNPs analyzed were associated with CRS (0 vs. any grade, or grades 0-1 vs. 2-3).In conclusion, to our knowledge this is the first study to demonstrate a possible association between treatment response to BT and cytokine genetic polymorphisms. Our hypothesis-generating data suggest a potential role of IL17 and IL2 in BT response and justify a larger confirmatory study, which may lead to personalized BT immunotherapy for B-ALL. [Display omitted] DisclosuresStein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

Genetic influence of cytokine polymorphisms on the clinical outcome of Japanese gastrointestinal cancer patients in palliative care.

Gastrointestinal cancer is one of the most common causes of mortality globally. The present study examined the influence of cytokine genetic polymorphisms [interleukin (IL)-1B C-31T, IL-1RN VNTR, IL-6 C-634G, IL-8 T-251A, IL-10 T-819C and IL-10 A-1082G] on clinical outcomes in patients with gastrointestinal cancer in palliative care. A total of 59 patients with gastrointestinal cancer who were admitted to Iga City General Hospital were analyzed. Genotyping was conducted using a polymerase chain reaction with confronting two-pair primers. Patients with at least one IL-1RN 2 allele demonstrated a significantly better survival (P=0.0275) while those with IL-6-634 G/G demonstrated a worse survival (P=0.0024). Multivariate analyses using the Cox proportional hazard model revealed that those with at least one IL-1RN 2 allele, IL-6-634 G/G or IL-10-1082 A/G had a significantly elevated adjusted hazard ratio of 9.20 (P=0.014), 41.01 (P=0.001) or 6.49 (P=0.046), respectively, compared with those with each homozygous wild-type polymorphism. In addition, the evaluation of weight loss by genotype revealed the potential influence of IL-10 T-819C genotype (P=0.072). IL-1RN, IL-6 and IL-10 polymorphisms were associated with the survival of patients with gastrointestinal cancer, suggesting the clinical feasibility of genetic testing in patients with gastrointestinal cancer in palliative care.

Genetic Polymorphism of Cytokines as a Predictor of Phenotypic Development of Chronic Pain Syndrome in Cancer Patients

Genetic Polymorphism of Cytokines as a Predictor of Phenotypic Development of Chronic Pain Syndrome in Cancer Patients

Impact of cytokine genetic polymorphisms on the risk of renal parenchymal infection in children

Acute pyelonephritis is associated with renal scarring in up to 30% of patients. Renal scarring may cause significant long-term morbidity. The pathogenesis of acute pyelonephritis remains unclear, although it involves interaction among uroepithelium, the immune system cells, and the locally produced cytokines. That some UTI-prone children develop acute pyelonephritis, and eventually renal parenchymal scarring, suggests a genetic role. Interleukin-6, interleukin-8, chemokine receptor-1 (CXCR1), and tumor necrosis factor-alpha (TNFα), the key regulators of the host immune responses, are proteins whose secretion is controlled by genes. We postulated that functional polymorphic variants of their genes might have a role in APN susceptibility. We sought to investigate a possible association of the common functional polymorphisms in genes encoding IL-6, IL-8, CXCR1, and TNFα with the risk of APN in children. Urine culture was used to diagnose 300 children with UTI, of mean age of 51.31±37.4 months (2-180 months). 99Tc-DMSA scans diagnosed 86 children with APN. Follow-up scans identified new renal scars in 18 children. Six functional single-nucleotide polymorphisms (SNPs) in genes encoding IL-6, IL-8, CXCR1, and TNFα were genotyped in all subjects (IL-6 rs1800795 (-174G/C), IL-6 rs1800796 (-572G/C), IL-8 rs2227306 (781C/T), IL8 rs4073 (-251A/T), CXCR1 rs2234671 (2607G/C), and TNFα rs1800629 (-308G/A)). TT genotype of IL-8 -251A/T polymorphism was significantly higher in APN patients (26.7%) than those with lower UTI (11.7%, p=0.01) and control individuals (12.2%, p=0.002). T allele was significantly more common in APN than in lower UTI (p=0.025) and was significantly more common in APN (46%) than in the controls (p=0.001). Similarly, TT genotype of IL-8 781C/T polymorphism was significantly more common in APN patients (31.4%) than those with lower UTI (17.3%, p=0.003) and the controls (14.3%, p=0.001). T allele was significantly more common in APN (55%) than lower UTI (40%, p=0.005) and controls (37%, p=0.001). However, IL-8 -251A/T and +781C/T SNPs did not qualify as an independent risk for parenchymal infection (OR 1.9, 95% CI 0.68-2.6, p=0.13 and OR 2.3, 95% CI 0.89-3.7, p=0.091, respectively). Lower UTI did not differ from the controls. The frequency of the genotypes and alleles of IL-6, CXCR1, and TNFα SNPs did not differ significantly among the different groups of the study. IL-8 -251A/T and +781C/T SNPs are associated with susceptibility to renal parenchymal infection in children and could be implicated in APN risk. However, none of these variants could clearly and independently predict this risk.

Impact of pharmacogenomics on imatinib toxicity in gastrointestinal stromal tumors.

11043 Background: Imatinib-induced side effects are common, although most of these side effects are mild, some will be severe and lead to disruption of Imatinib treatment in gastrointestinal stromal tumor (GIST). It is necessary to explore a biological predictors to predict and optimal therapeutic strategy. But there were few studied conducted to explore the mechanisms of Imatinib-induced side effects. The present study comprehensively investigated the effects of genetic polymorphisms of cytokines involved in cell proliferation and metabolic enzymes and transporters involved in Imatinib metabolism on these side effects. Methods: A total of 154 GSIT patients treated with Imatinib were enrolled. 22 SNPs (single nucleotide polymorphisms) in KIT/ PDGFRA/ PDGFRB/ SHC1/ FLT1/ MAPK1/ EGFR/ CCL5/ CXCL14were detected using Agena Massarray matrix-assisted laser desorption / ionization-time of flight (MALDI-TOF) platform. Logistic regression analyses were performed to evaluate their effects on Imatinib-induced toxicities. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: Imatinibdose, FLT1 rs9951465, MAPK1 rs13515, PDGFRB rs55712339 and SHC1 rs3766920 were found to be correlated with the incidence of myelosuppression ( P= 0.027, 0.009, 0.002, 0.008, &lt; 0.001, respectively), moreover, FLT1 rs9554314 was correlated with severe myelosuppression (Grade 0,1 vs. 2+, P= 0.009, OR (95%CI) = 3.042 (1.314-7,042)). Meanwhile, EGFR rs10228436 was found to be correlated with the incidence of skin rash ( P= 0.027), moreover, CCL5 rs4796120 and CXCL14 rs7716492 were correlated with severe skin rash (Grade 0,1 vs. 2+), with OR (95%CI) and p value were 8.542 (0.934-78.107), 13.504 (2.308-79.004) and 0.057, 0.020, respectively. Conclusions: This is the first comprehensive report on the biomarkers for Imatinib toxicities. These biomarkers might be able to distinguish patients with mild or more severe forms of Imatinib toxicities, thus enabling the optimization of Imatinib therapy and lead patients benefit from Imatinib treatment in a long-term.

Polymorphisms in cytokine genes as prognostic markers in diffuse large B cell lymphoma patients treated with (R)-CHOP

To investigate whether cytokine genetic polymorphisms influence the outcome of diffuse large B cell lymphoma (DLBCL), we tested 337 consecutive DLBCL treated with CHOP or rituximab-CHOP (R-CHOP) from interleukin 10 (IL10), Bcl-2, and tumor necrosis factor (TNF)-α polymorphisms. Patients who carried the IL10 rs1800871 TT or rs1800872 AA genotype showed higher complete response (CR) and overall response rate (ORR) significantly. A longer progression-free survival (PFS) was observed in patients with IL10 rs1800871 TT (P = 0.017) or rs1800872 AA (P = 0.017) genotype after rituximab-based chemotherapy, and better PFS was also noted with Bcl-2 rs1801018 AA genotype in the CHOP group (P = 0.048). Furthermore, the R-CHOP group patients who carried the IL10 non-CCA haplotype had longer PFS (P = 0.030). Cox proportional hazards analyses demonstrated that the genotype TT of IL10 rs1800871 and AA plus AC of rs1800872 were predictive of longer PFS and event-free survival (EFS) in DLBCL patients treated with R-CHOP. And the Bcl-2 rs2279115 AA plus AC genotypes and rs1801018 GG genotype were risk factors for EFS in DLBCL patients treated with CHOP. In conclusion, the results reminded us those DLBCL patients with IL10 rs1800871 TT, rs1800872 AA, or IL10 non-CCA haplotype are likely to benefit from the therapy of rituximab-based chemotherapy.

Genetic polymorphism of cytokines in patients with keloids

Genetic polymorphism of cytokines in patients with keloids

Evaluation of cytokine genetic polymorphisms in adult patients with common variable immunodeficiency: A single-center study

Common variable immunodeficiency (CVID) is a heterogeneous disease characterized by impaired B-cell differentiation and maturation accompanied with the defective antibody production. Several investigators addressed the possibility that disturbed cytokine production of TNF, IL-6, IFN-γ and IL-10, among a variety of others, may be implicated in CVID. The aim of this study was to test the hypothesis that genetic polymorphisms involving TNF (−308G/A), IFNG (+874 T/A), IL10 (−1082G/A, −819T/C and −592A/C), and IL6 (−174G/C) cytokine genes might contribute to susceptibility to CVID. Thirty five patients with CVID and 250 healthy controls were genotyped for indicated single nucleotide polymorphisms (SNP) in TNF, IL6, IFNG and IL10 using Taqman-based assays. CVID patients had significantly higher frequency of TNF A allele and AA genotype than in healthy subjects (p=0.006; OR=2.27; 95%CI=1.24-4.17 and p=0.038, OR=15.64; 95%CI=1.38-177.20, respectively). In addition, the frequency of GG genotype was significantly higher in healthy controls than in patient group (p=0.019, OR=0.43, 95%CI=0.21-0.89). Genetic analysis of IL6 SNP showed that allele G confers increased risk for CVID (p=0.037, OR=1.78, 95% CI=1.03-3.08) while IFNG allele T was associated with splenomegaly in CVID (p=0.032; OR=2.86; 95% CI=1.08-7.56). We observed no association between genotypes, alleles and haplotypes of IL-10 gene and CVID or its clinical complications. In conclusion, our results indicated association between CVID and cytokine gene polymorphisms −308G/A TNF and −174G/C IL6. In addition, we demonstrated that splenomegaly, one of the most common complications in this disease, is associated with +874T/A IFNG polymorphism. These findings add further support to the notion that cytokines may play significant role in pathogenesis of this primary antibody deficiency. However, further investigation that would involve a larger study group of CVID patients is warranted to confirm our findings.