Role Of Cytokine Gene Polymorphisms Research Articles

IL-35 polymorphisms and cognitive decline did not show any association in patients with coronary heart disease over a 2-year period

Prior evidence suggested that inflammation and inflammatory cytokines polymorphisms might be essential in the development of coronary heart disease (CHD) and cognitive decline. The following study investigated the associations between interleukin-35 (IL-35) polymorphisms and cognitive decline in CHD patients over a 2-year period.CHD patients were enrolled between January 2015 and January 2016. Cognitive function, including memory, orientation, verbal and attention were assessed using Telephone Interview for Cognitive Status-Modified (TICS-m) during a 2-year follow-up. Genotypes of the single nucleotide polymorphisms (SNPs), including rs2243115, rs568408, rs582054, rs583911, rs428253, rs4740 and rs393581 of IL-35 were examined by MassArray (Sequenom). The differences of TICS-m score between 2-year interval were used to estimate the cognitive decline; linear regression model was used to analyze the association between IL-35 polymorphisms and cognitive decline in CHD patients after a 2-year follow-up.The mean age of study individuals was 60.58 (±7.86) years old. There were 255 (68.5%) males and 117 (31.5%) female patients. The TICS-m scores, including overall cognition score, verbal attention and memory scores gradually decreased over a 2 year follow up period (P < .001, respectively), whereas there was no difference in orientation function score between the 1-year and 2-year follow-up (P = .448). Furthermore, after adjusting for age, sex, history of hypertension(HT) and Diabetes mellitus(DM), smoking, education, Therapy regimen (PCI, CABG, medication) left ventricular ejection fraction (LVEF), and the severity of coronary artery stenosis (Gensini score), no association was found between IL-35 rs2243115, rs568408, rs582054, rs583911, rs428253, rs4740 genotypes and cognitive decline in CHD patients over a 2-year period.Our data reveled that IL-35 polymorphisms was not associated with cognitive decline in CHD patients over a 2-year period. Yet, further studies are needed to confirm the role of cytokine gene polymorphisms in cognitive decline among CHD patients.

Полиморфизм генов цитокинов как фактор предрасположености к развитию хронического гнойного среднего отита

В последние десятилетия распространенность хронического гнойного среднего отита (ХГСО) заметно выросла. Значительная роль при воспалении, в том числе в патогенезе ХГСО, отводится клеточным медиаторам - цитокинам. Доказана роль полиморфизма генов цитокинов в развитии заболеваний, ассоциированных с воспалительными процессами. Цель работы - проанализировать взаимосвязь полиморфизма генов IL1В (С3953Т, С511Т, Т31С), IL10 (G1082A, C592A, C819T), IL6 (С174G) и TNFА (G308A) с развитием ХГСО и возрастным фактором начальных его проявлений. Методика. Распределение генотипов аллельных вариантов генов цитокинов (IL-1, IL-6, IL-10 и TNF-α) анализировали у 299 пациентов с ХГСО в зависимости от сроков начала заболевания (в возрасте до 14 лет, от 15 до 30 лет, старше 30 лет). Контрольную группу составили 183 здоровых добровольца с сопоставимым распределением по полу и возрасту. Для определения полиморфных вариантов генов IL1В (-3953, -511, -31), IL10 (-1082, -592, -819), IL6 (-174) и TNFА (-308) применяли метод ПЦР в режиме реального времени. Об ассоциации генотипов с заболеванием судили по величине отношения шансов (Odds Ratio (OR)) и коэффициентов Юла (Q) и контингенции (Фи, Φ). За критический уровень значимости при проверке статистических гипотез принимался p≤0,05. Результаты. Выявлено, что к развитию ХГСО предрасполагают полиморфные варианты генов цитокинов IL1В, IL10 и TNFА. Наиболее значимыми в формировании предрасположенности к развитию заболевания являются генотипы С/С полиморфизмов С3953Т и Т31С гена IL1В, А/А полиморфизма G1082A и Т/Т полиморфизма С819Т гена IL10. Полиморфные варианты генов IL1В (генотип C/C полиморфизмов С3953Т и Т511С) и IL10 (генотип А/A полиморфизма G1082A) сочетаются с дебютом ХГСО в возрасте до 14 лет. Полиморфизм C174G гена IL6 не оказывает предрасполагающего влияния на развитие болезни. Протективный эффект в отношении развития ХГСО связан с носительством гомозиготного генотипа Т/Т полиморфизмов С511Т и Т31С гена IL1В и гомозиготного генотипа G/G полиморфизма G1082A гена IL10. Заключение. К развитию ХГСО предрасполагают полиморфизмы генов про- и противовоспалительных цитокинов, дисбаланс которых обусловливает патологическое течение иммунного ответа и раннюю (в детском возрасте) клиническую манифестацию болезни. In recent decades, prevalence of chronic purulent otitis media has increased markedly. A significant role in inflammation, including the pathogenesis of chronic purulent otitis media, is assigned to the cellular mediators, cytokines. The predisposing role of cytokine gene polymorphism in development of inflammatory-associated diseases has been proven. Aim. To analyze the relationship of IL1B (C3953T, C511T, T31C), IL10 (G1082A, C592A, C819T), IL6 (C174G), and TNFA (G308A) gene polymorphisms with development of chronic purulent otitis media and the age of its primary manifestation. Methods. Distribution of genotypes of allelic variants in cytokine (IL-1, IL-6, IL-10 and TNF-α) genes was analyzed in 299 patients (129 men and 170 women aged 38.0 ± 4.3) based on the age of disease onset (with chronic purulent otitis media diagnosed at age of 14, from 15 to 30, and older than 30). The control group consisted of 183 sex- and age matched healthy volunteers. Genomic DNA was isolated from whole blood leukocytes. Real-time PCR was used for determination of polymorphic variants in IL1B (-3953, -511, -31), IL10 (-1082, -592, -819), IL6 (-174), and TNFA (-308) genes. The association of genotypes with the disease was evaluated by the odds ratio (OR) and the values of Yule (Q) and contingent (Phi, Φ) coefficients. The critical significance level for the statistical hypotheses tests was taken as &lt;0.05. Results. IL1B, IL10, and TNFA cytokine gene polymorphisms predisposed to development of chronic purulent otitis media. The genotypes C/C of C3953T and T31C polymorphisms in the IL1B gene, A/A of G1082A polymorphism, and T/T of C819T polymorphism in the IL10 gene are the most significant ones in the predisposition to disease development. Polymorphic variants of IL1B (C/C genotype of C3953T and T511C polymorphisms) and IL10 (A/A genotype of G1082A polymorphism) genes are associated with the onset of chronic purulent otitis media at age of 14. The C174G polymorphism in the IL6 gene does not predispose to the disease. Protection from the development of chronic purulent otitis media is associated with carriage of the T/T homozygous genotype of C511T and T31C polymorphisms in the IL1B gene and the G/G homozygous genotype of G1082A polymorphism in the IL10 gene. Conclusion. Polymorphisms of pro- and anti-inflammatory cytokine genes predispose to the development of chronic purulent otitis media. An imbalance of these cytokines results in a pathological course of immune response and early (children) clinical manifestation of the disease.

IL-8-251T&gt;A (rs4073) Polymorphism Is Associated with Prognosis in Gastric Cancer Patients

Inflammation is a key process in gastric carcinogenesis. Cytokines are mediators of inflammation and are involved in metastasis and tumorigenicity. We previously assessed the role of cytokine gene polymorphisms in gastric cancer risk in Chile. In the present study, we aimed to analyze whether these polymorphisms are associated with overall survival (OS) in gastric cancer (GC) patients. A total of 153 individuals with GC diagnosis were followed-up for at least 2 years. Hazard ratios (HR) were estimated from Cox regression models using SNPs as predictor variables. The following SNPs were genotyped for study using a TaqMan assay: rs16944 (IL1B -511C>T); rs4073 (IL8 -251 T>A); rs2275913 (IL-17 -197G>A); rs1800872 (IL10 -592 C>A); rs1800896 (IL10 -1082A>G); rs28372698 (IL32). Interleukin-8 rs4073 (IL-8 -251T>A) showed association with OS under the dominant model (TA + AA) only when adjusted by clinicopathological variables (HR=1.64, 95%CI=1.05-2.55, p=0.030, q-value=0.18), but not with the univariate model (HR=1.51, 95%CI=0.98-2.31, p=0.062, q-value=0.37). No significant differences were observed after adjusting for population stratification (PC1 and PC2 from Principal Component Analysis using genotypes from Infinium Global Screening Array). After stratification by clinicopathological variables, the association with shorter overall survival was higher among patients with diffuse-type tumors (HR=2.24, 95%CI=1.16-4.45) and patients with tumor size >5 cm (HR=1.79, 95%CI=1.08-2.97). These results suggest a role of IL-8 rs4073 in cancer prognosis. Its use as a prognostic marker of GC survival warrants further investigation.

A Role of Cytokine Gene Polymorphisms in Cognitive Functioning.

The changes in cognitive functions that occur with aging and in various pathological conditions are a subject of growing interest. Experimental and clinical data justify the hypothesis about the influence the immune system exerts on cognitive processes. The balance between pro-inflammatory and anti-inflammatory cytokines has been established as a necessary factor for normal cognitive functioning. Cytokine production is under strong genetic control and various single nucleotide polymorphisms (SNPs) in cytokine genes have been described. As cytokine SNPs have been demonstrated to affect the gene expression or the functional activity of the immune protein this logically led to the suggestion about the role of these polymorphisms in cognitive functioning. Studies exploring the association between different genetic variants of cytokine gene polymorphisms and cognitive abilities in healthy subjects and in demented patients show divergent results. The review of relevant literature suggests that SNPs implement their effect on cognition in large interactions with each other, as well as with many other factors, some of which still remain to be identified. This article summarizes the contemporary knowledge about the correlations between SNPs in cytokine genes and cognitive status in humans. Further research is needed to determine the precise role and the molecular mechanisms of action of the SNPs in cognitive processes.

The impact of cytokine gene polymorphisms on the outcome of HLA matched sibling hematopoietic stem cell transplantation

Graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic stem cell transplantation (HSCT); cytokines are recognized as important mediators in its pathogenesis. In this study we investigated the role of cytokine gene polymorphisms on HSCT outcome. A total of 106 patient and 98 donors were genotyped by polymerase chain reaction sequence specific primers (PCR-SSP) based assay for tumor necrosis factor-α−308 (TNFα -308), interleukin (IL)-6-174, IL-10-1082, −819, −592, Interferon-γ+874 (IFN-γ+874), and transforming growth factor-β1 (TGF-β1) codon10 and 25 polymorphisms. Except one in each category, all patients and donors were TNFα -308 high producers and the majority were IL-6-174 high producers (93.3% and 90.8% respectively); a pattern that would alleviate any potential biological impact. Patient's IFN-γ+874 showed significant association with the development of chronic GVHD. Patients with IFN-γ +874 high producer showed an 8 folds likelihood to develop chronic GVHD as compared to those with IFN-γ+874 low producer predicted phenotype (95% CI: 1.59-40.2, p = 0.01). Patient's TGFβ1-codon 10 and 25 high/intermediate producers showed a lower incidence of acute GVHD though it did not achieve statistical significance (p = 0.065) on account of the low frequency of this genotype in our patients and donors (11.4 and 8.2% respectively). Other factors contributing to risk of GVHD included older age for both acute and chronic (p = 0.01 and 0.02 respectively) with age 24 as the best discriminating cutoff; CD34+ cell dose for chronic GVHD (p = 0.045) with a dose of 8 × 106/kg as the best discriminating cutoff; and conditioning regimen with Flu/Bu associated with the lowest incidence of acute GVHD (p = 0.003) and no impact on chronic GVHD. In conclusion the current study further indicates a potential role of some cytokine gene polymorphisms in the development of GVHD. The relative distribution of high and low producer genotypes in different ethnic groups contributes to their biological impact in different populations.

The role of cytokine gene polymorphism in the development of acute myocardial infarction

The continuous growth of cardiovascular diseases is one of the important challenges facing the modern medicine. They are the primary cause of death both in developed countries and inUkrainein particular. The aim of the study is to perform analysis of modern literary sources related to the role of cytokine gene polymorphism in the development of acute myocardial infarction. The basis for the search for candidate genes was study of individual characteristics and identifying genetic polymorphisms that increase the risk of triggering mechanisms of atherosclerotic lesions of the coronary vessels and the consequent acute myocardial infarction development. Cytokine genes feature a very high level of polymorphisms. The obtained results of the study are quite contradictory, in addition there is no consensus on their application. One of these candidate genes is the gene encoding interleukin-6 production. This is one of the proinflammatory cytokines, elevated levels of which are associated with the development and course of coronary heart disease, as well as with the processes of the atherosclerotic plaque destabilization. Polymorphic marker in interleukin-6 (-174-G/C) gene promoter is associated with IL-6 gene expression level and the level of Interleukin-6 inplasma, and can affect the course of ischemic heart disease. The tumor necrosis factor-α is a multifunctional proinflammatory cytokine which is produced mainly by monocytes and macrophages. Concentration of tumor necrosis factor-α in blood plasma is constantly increased in patients after acute myocardial infarction with an increased risk of recurrent coronary events. These data support the hypothesis that stable patients are at risk of constant inflammatory instability. Increased production of tumor necrosis factor-α is considered an important cause of destabilization of atherosclerotic plaques. The gene cluster of tumor necrosis factor-α is within the region of class III genes of highly polymorphic major histocompatibility complex, located on human chromosome 6 at the position 6p21.1–21.3. Another candidate gene encodes interleukin-10, being an anti-inflammatory cytokine is an inhibitor of inflammation located on chromosome 1 at the position 1q31–q32. The research identified a number of IL-10 gene polymorphisms at positions -592, -627, -1082. Conclusions. Analysis of the above literature allows us to make a conclusion that: first, the concentration of cytokines depends on the genetic characteristics of an individual; secondly, cytokine gene polymorphism may be of importance in regard to the course of coronary heart disease.

CYTOKINE GENE POLYMORPHISMS AS PREDICTORS OF CHRONIC PAIN SYNDROME IN ONCOLOGY

The literature review on the role of cytokine gene polymorphisms in the development of chronic pain in cancer patients was presented using MedLine, PubMed, NEB elibrary.ru, WileyOnlineLibrary, WebofScience, OxfordUniversityPress and SAGEPremier databases for years 1995 to 2016. The role of inter-individual differences based on cytokine gene polymorphisms and their receptors for personalized anesthetic and accompanying treatment in oncology was shown.

The role of cytokine gene polymorphism in the formation of arterial hypertension associated with metabolic syndrome

We investigated the association of polymorphisms of genes tumor necrosis factors and their receptors (-308G/A TNFa, +250A/G Lta, +36 A/G TNFR1, +1663 A/G TNFR2) with the predisposition to the development of essential hypertension (EH) and the features of its clinical course in patients with metabolic syndrome. It has been demonstrated that the molecular genetic marker +36G TNFR1 (OR=1,25) is involved in the formation EH in individuals with metabolic syndrome. The risk of stage III EH in patients with metabolic syndrome is enhanced by genetic variants -308GA TNFa (OR=2,72), -308A TNFa (OR=2,72), +250G Lta (OR=1,80), and combinations thereof -308A TNFa with +1663G TNFR2 (OR=3,85), +250G Lta with +36G TNFR1 (OR=3,85), +250G Lta with +1663G TNFR2 (OR=3,85) while protective properties are inherent in -308GG TNFa (OR=0,32), +250AA Lta (OR=0,45), -308G TNFa (OR=0,37), +250A Lta (OR=0,56) and a combination of genetic markers -308GG TNFa with +250A Lta (OR=0,31), -308G TNFa with +250AA Lta (OR=0,39), -308G TNFa with +250A Lta (OR=0,31).

Role of cytokine gene polymorphisms in acute and chronic kidney disease following liver transplantation.

Development of renal dysfunction, including acute kidney injury (AKI) and chronic kidney disease (CKD), after liver transplantation (LT) remains a critical issue adversely affecting patient survival in both the short and long term. Previous reports have suggested that inflammatory and antiinflammatory cytokines and their functionally relevant gene polymorphisms may play critical roles in the development of AKI and CKD. However, the involvement of these cytokines and their gene polymorphisms in renal deterioration following LT remains unclear. We examined 62 recipients who underwent LT at Nagoya University between 2004 and 2009 and who had survived for at least 1year. The following gene polymorphisms in recipients were analyzed: tumor necrosis factor-A (TNFA) T-1031C, interleukin-2 (IL2) T-330G, IL10 C-819T, IL13 C-1111T, transforming growth factor-B (TGFB) T29C, and IL4 T-33C. Thirteen patients (21%) developed AKI within 4weeks after LT. Of the investigated gene polymorphisms, the IL4 -33 T/T genotype was significantly associated with higher incidence of AKI compared with the other two genotypes [hazard ratio (HR)=5.48, 95% confidence interval (CI) 1.18-25.52, p=0.03]. On the other hand, 16 patients (26%) had developed CKD at median follow-up of 9.2years after LT. We showed the lack of association between investigated gene polymorphisms in recipients and CKD development. The IL4 -33 T/T genotype might be a risk factor for AKI in LT, and this might contribute to earlier withdrawal of immunosuppressive agents to minimize renal toxicity. In contrast, none of the investigated cytokine gene polymorphisms were associated with CKD.

Hepatitis-related hepatocellular carcinoma: Insights into cytokine gene polymorphisms.

Hepatocellular carcinoma (HCC) is a primary liver cancer, which is one of the most prevalent cancers among humans. Many factors are involved in the liver carcinogenesis as lifestyle and environmental factors. Hepatitis virus infections are now recognized as the chief etiology of HCC; however, the precise mechanism is still enigmatic till now. The inflammation triggered by the cytokine-mediated immune response, was reported to be the closest factor of HCC development. Cytokines are immunoregulatory proteins produced by immune cells, functioning as orchestrators of the immune response. Genes of cytokines and their receptors are known to be polymorphic, which give rise to variations in their genes. These variations have a great impact on the expression levels of the secreted cytokines. Therefore, cytokine gene polymorphisms are involved in the molecular mechanisms of several diseases. This piece of work aims to shed much light on the role of cytokine gene polymorphisms as genetic host factor in hepatitis related HCC.

Role of cytokine gene polymorphisms on prognosis in hepatocellular carcinoma after radical surgery resection.

This study aimed to determine whether SNPs of cytokine genes influence survival of hepatocellular carcinoma (HCC) patients after radical surgery resection. We evaluated 14 SNPs of eight cytokine genes in 263 patients treated with radical surgery resection of HCC. Categorical variables were compared by the χ(2) test and Fisher's exact test. The Kaplan-Meier methods with log-rank test and Cox regression models were used to compare survival of resected HCC patients according to the genotype. Among the 14 studied SNPs of cytokine genes, only the TNF-α-863 (CA+CC) genotypes were revealed to be significant independent predictors of prolonged overall survival (OS) after HCC radical surgery resection (HR: 0.586, 95% CI: 0.355-0.968), considering for other clinical factors in a Cox proportional hazard model. Meanwhile, no significant association was found between the 14 SNPs and relapse-free survival (RFS) of resected HCC patients. In addition, combination analysis with the Th1 cytokine (IFN-γ, IL-2, IL-12B, TGF-β1) or Th2 cytokine (IL-6, IL-10) genetic polymorphisms by the Kaplan-Meier method and Cox multivariate analysis did not reveal any significant association between OS and RFS of resected HCC patients.

Immunoregulatory cytokines gene polymorphisms in Egyptian patients affected with acquired aplastic anemia

The immune system is thought to play an important role in aplastic anemia (AA) in light of recent findings of hematologic reconstitution after immunosuppressive therapy. T cell activation, apoptosis, and the cytokines interferon- and TNF-α are suspected to play a role in the suppression of growth of progenitor cells and induced apoptosis in CD34 target cells, TGFβ is a multifunctional peptide, usually produced in latent form and requiring activation to produce a biological response. Also, TGF-β1 has been described as an important negative regulator of haemopoiesis. Over production of IL-6 is described in AA but is of unknown pathophysiological significance. To investigate the role of cytokine gene polymorphisms (IL-6/-174, TNF-α/-308, IFN-γ/+874, and TGFβ1/-509) in patients with acquired AA to assess if genotypes associated with higher or lower production were more prevalent than in established control population and to study the possible association of these genotypes with the disease severity. Fifty AA patients were included in this study. Polymerase chain reaction-amplification refractory mutation system (PCR-ARMS) technique was used to detect INF-γ single nucleotide polymorphism -874A/T, and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to assess IL-6-174 C/G, TNF-α-308G/A, and TGFb1-509C/T gene polymorphisms. Genotypes associated with high production of TNF-α, TGF-β and IFN-γ, and IL-6 were more frequent in patients than in control; no association was found between the presence of hypersecretory genotypes and the disease severity.

Cytokine Gene Polymorphisms and Viral Hepatitis Infections in Kidney Transplant Recipients

Objectives: To examine the prevalence and role of cytokine gene polymorphism in susceptibility to viral hepatitis infections among kidney transplant recipients. Methods: The genetic polymorphisms of interleukin 6 ( IL-6 ) G-174C, transforming growth factor beta ( TGF-β ) T+869C, interleukin 4 ( IL-4 ) C-590T, and interferon gamma ( IFN-γ ) T+874A cytokines from 100 kidney transplant recipients were evaluated by amplification refractory mutation system–polymerase chain reaction (ARMS-PCR) and polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) methods. Results: The IFN-γ +874 TT genotype ( P =.02) significantly correlated with hepatitis C virus (HCV) infection in kidney transplant recipients. The IL-6 +174 GG genotype ( P =.01) was significantly associated with acute rejection in kidney transplant recipients without HCV infection. A significant relationship to the IFN-γ +874 AA genotype ( P =.04) was observed in kidney transplant recipients who did not experience transplant rejection and who are not infected with HBV. Also, a significant relationship was detected between the IL-6 and174 GC genotypes ( P =.03) with nonacute rejection in kidney transplant recipients. Conclusion: We confirm a significant association between the cytokine genetic polymorphisms discussed herein. This information could be helpful toward better prediction of acute kidney rejection with or without viral hepatitis infections. * HBV : hepatitis B virus HCV : hepatitis C virus; SNPs : single nucleotide polymorphisms; IFN -γ : interferon gamma; TGF -β : transforming growth factor beta; IL-6 : interleukin 6; IL-4 : interleukin 4; HBsAg : hepatitis B surface antigen; Th1 : T helper 1; Th2 : T helper 2; OKT3 : ortho kung T3; PCR-RFLP : polymerase chain reaction–restriction fragment length polymorphism; RT : reverse transcriptase; ORs : odds ratios; CIs : confidence intervals; ARMS : amplification refractory mutation system

A study on the association of TNF-α-308, IL-6-174, IL-10-1082 and IL-1RaVNTR gene polymorphisms with rheumatic heart disease in Pakistani patients

Inflammation is an important contributor to the pathogenesis of rheumatic heart disease (RHD), a disorder of heart valves caused by a combination of immune, genetic and environmental factors. Cytokines are important mediators of inflammatory and immune responses. The aim of this study was to investigate the role of cytokine gene polymorphisms and their potential usefulness as biomarkers in RHD patients from Pakistan. We screened 150 RHD patients and 204 ethnically matched controls for tumor necrosis factor (TNF)-α-308G/A, interleukin (IL)-10−1082 G/A, interleukin (IL)-6-174 G/C and a variable number of tandem repeats (VNTRs) polymorphism of the IL-1Ra gene using polymerase chain reaction. The results showed that TNF-α-308 A and IL-6-174 G alleles were associated with susceptibility to RHD (p=0.000; OR=2.81; CI=1.5–5.14 and p=0.025; OR=1.50; CI=1.04–2.16 respectively). The TNF-α-308 AA and GA genotypes were associated with susceptibility to RHD (p=0.012; OR=9.94; CI; 1.21–217.3 and p=0.046; OR=1.97; CI=0.98–3.97 respectively) while the GG genotype seemed to confer resistance (p=0.003; OR=0.39; CI=0.20–0.76). The GG genotype for IL-6-174 was significantly associated with predisposition to RHD (p=0.015; OR=2.6; CI=1.17–5.85). The A1 (four repeats) and A2 (two repeats) alleles at the IL-1Ra VNTR polymorphism were associated with resistance and susceptibility to RHD respectively. However, this polymorphism deviated from Hardy–Weinberg equilibrium in both patients and controls in our population. TNF-α-308 and IL-6-174 polymorphisms may be useful markers for the identification of individuals susceptible to RHD in Pakistan. These individuals could be provided aggressive prophylactic intervention to prevent the morbidity and mortality associated with RHD.

Cytokine Gene Polymorphisms and Severe Acute Graft-Versus-Host Disease (grade ≥II) After Allogeneic Hematopoietic Stem Cell Transplantation From HLA Identical Siblings

AbstractAbstract 4180Graft-versus-host disease (GvHD) is one of the most important complications after allogeneic hematopoietic stem cell transplantation (HSCT) and influences morbidity and mortality, even when the donor is a human leucocyte antigen (HLA)-matched sibling. Polymorphisms at genes coding for several proinflammatorycytokines and for their related receptors or receptor inhibitors are involved in this complication.To assess the role of cytokine gene polymorphisms on acute GvHD (aGVHD), we analysed 189 pairs of donor and recipients transplanted from HLA identical sibling for malignant hematological diseases between 2000 and 2007, using a non T depleted graft after a myeloablativeor a reduced intensity conditioning regimen. Material and methods:The median age of the recipients at transplantation was 43.4 years (1–68). Two third of the patients received bone marrow before myelo-ablative conditioning regimen and the median delay between diagnosis and transplantation was 9 months (1–76).Five different polymorphisms from 3 cytokine genes were analyzed: IL-10 –592C/A, -819C/T and -1082G/A, IL-1b -511A/G and TGFb1 –509C/T.All the pairs were studied for each gene polymorphism using the Taqman technology as previously described (Malkki2007). Each kit contains several primers pairs for amplification and two allele-specific probes, each of them conjugated with a different fluorescent marker. After amplification, analysis was driven on a Roche LC480 platform. The interpretation of the final results was performed using allelic discrimination specific software.In our study, the frequencies of the TGFb1, IL1b, and IL-10 genotypes in recipients and donors were almost equal, and were consistent with previously reported results for the Caucasoid population and with the NCBI SNP databases. Results:Univariate analysis found a significant negative impact of donor genotypes carrying IL1b A allele (p=0,02) or IL10–592 A allele (p=0,03) on aGvHD.We did not find any effect associated with IL10–819 and -1082 polymorphisms, but as previously described (Lin 2003), the presence of IL10 A-T-A haplotype in the donor, significantly increased the risk of aGVHD (p=0.043). We performed a multivariate analysis on aGVHD incidence taking into account TGFb1–509, IL-10–592 and IL1bpolymorphisms, together with other known risk factors.A higher incidence of aGVHD was found in pairs where donor has an IL1b A allele (HR 4,16 - p=0,0031) and increased when the donor is A/A (HR>15 – p=0,0091). For IL10–592, the impact of the A allele was found different when carried by the donor (higher risk of aGVHD, HR 3,52 – p=0,00083) or the recipient (lower risk of aGVHD, HR 0,48 – p=0,024), but this effect seems only significant in pairs where donor did not carry any A allele (rec AC × don CC – HR 0.2 – p=0.05). Donor with TGFb1–509 T allele was found to have a significant lower risk of aGVHD (HR 0,42 – p=0,02). (table 1).The role of the cytokine cascade in the physiopathology of GVHD is well established. Our study documents the possible role of IL-1b, TGFb1and IL10 gene polymorphisms in this setting.A proven association of cytokine gene polymorphisms with acute GVHD would enable the clinician to modify the therapeutic strategy and enhance the outcomes.Table 1CytokineAllele recHRpAllele donHRpRecx donReferenceHRpIL1bA2.130.036AG × AGGG × GG4.160.0031GG × AGGG × GG4.350.028AA × AAGG × GG>150.0091TGFbT0.420.02CC × CTCC × CC0.250.012CT × CTCC × CC0.140.0013IL10-592A0.480.024A3.520.00083AC × ACCC × CC2.460.038CC × ACCC × CC4.930.013ACx CCCC × CC0.20.05 Disclosures:Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Predictive Role of Cytokine Gene Polymorphisms for the Development of Femoral Head Osteonecrosis

Introduction: Osteonecrosis (ON) is a multifactorial disease that leads to hip destruction. Lately, much focus has been at femoral head preservation with nonsurgical methods. In this study we examined the polymorphisms of IL-1α, IL-1R, IL-1RA, IL-4Rα, IL-1β, IL-12,γIFN, TGF-β, TNF-a, IL-2, IL-4, IL-6 and IL-10 genes for evaluation of their contribution in ON.Material and methods: DNA was extracted from 112 ON patients and 438 healthy donors. Analysis of the polymorphisms was completed using the PCR-SSP method. Statistical analysis was performed using theχ2test to compare the genotype and allelic frequency distribution.Results: The CT and GA genotypes of the IL-1α(-889) and TNF-a (-238) genes were found higher in the patients (51.8% and 10.8%, respectively) compared to the healthy donors (39.7% and 2.1%, respectively). In TGF-βcodon 25, the G to C polymorphism in the homozygous state was found in 1.8% of the patients and the C allele frequency was 8.9%, whereas the G allele frequency was 91.1%. Also, at the IL-10 (-1082) gene the GG genotype was 16.2% in the controls whereas in the patients was 7.2%.Conclusions: Based on the above, we showed that certain genotypes of the IL-1α, TGF-β, IL-10 and TNF-a genes could be related in the pathogenesis of a complicated disease, such as osteonecrosis. The presence of one of the above mentioned polymorphisms or the simultaneous carriage of more than one may further increase the risk for osteonecrosis, especially in those at high risk, such as patients receiving corticosteroids.

Evaluation of a role of cytokine gene polymorphisms in development of bronchial asthma in the Republic of Bashkortostan

Summary. Asthma is one of the most common, severe and debilitating multifactorial diseases resulting from complex interaction between genes and environ mental factors. The aim of the present work was to analyze the association between cytokine gene polymorphisms and development of asthma in population of the Republic of Bashkortostan. A total of 638 patients with asthma and 366 healthy individuals were recruited in our investigation. In summary, the study of cytokine gene polymorphisms and genegene interaction suggested an important role of TNFA, IL4, CCL11 and IL13 genepolymorphisms in the development of asthma in Bashkortostan population.

Predictive role of cytokine gene polymorphisms for the development of femoral head osteonecrosis.

Introduction: Osteonecrosis (ON) is a multifactorial disease that leads to hip destruction. Lately, much focus has been at femoral head preservation with nonsurgical methods. In this study we examined the polymorphisms of IL-1α, IL-1R, IL-1RA, IL-4Rα, IL-1β, IL-12, γIFN, TGF-β, TNF-a, IL-2, IL-4, IL-6 and IL-10 genes for evaluation of their contribution in ON. Material and methods: DNA was extracted from 112 ON patients and 438 healthy donors. Analysis of the polymorphisms was completed using the PCR-SSP method. Statistical analysis was performed using the χ2 test to compare the genotype and allelic frequency distribution. Results: The CT and GA genotypes of the IL-1α (-889) and TNF-a (-238) genes were found higher in the patients (51.8% and 10.8%, respectively) compared to the healthy donors (39.7% and 2.1%, respectively). In TGF-β codon 25, the G to C polymorphism in the homozygous state was found in 1.8% of the patients and the C allele frequency was 8.9%, whereas the G allele frequency was 91.1%. Also, at the IL-10 (-1082) gene the GG genotype was 16.2% in the controls whereas in the patients was 7.2%. Conclusions: Based on the above, we showed that certain genotypes of the IL-1α, TGF-β, IL-10 and TNF-a genes could be related in the pathogenesis of a complicated disease, such as osteonecrosis. The presence of one of the above mentioned polymorphisms or the simultaneous carriage of more than one may further increase the risk for osteonecrosis, especially in those at high risk, such as patients receiving corticosteroids.

Association Study of Interferon Gamma (IFN-γ) +874T/A Gene Polymorphism in Patients with Paranoid Schizophrenia

Schizophrenia is a multifactorial disease with changes affecting the immune system. Dysregulation of the cytokine network in schizophrenia has been well documented. Such changes may occur due to disturbances in cytokine levels that are linked to polymorphisms of cytokine genes. However, research in the role of cytokine gene polymorphisms in schizophrenia has been surprisingly scanty. The aim of this study was to identify, in a case control study, whether polymorphism of IFN-γ gene is a risk factor for the development of paranoid schizophrenia. To the best of our knowledge, this is the first study that examines the association between the IFN-γ gene polymorphism and psychopathological symptoms in patients with paranoid schizophrenia. Polymorphism of IFN-γ (+874T/A, rs 62559044) in schizophrenic patients (n=179), as well as healthy individuals (n=196), both Polish residents, was genotyped using AS-PCR method. Of note, when analyzing the results, we took into consideration the gender of studied individuals. Surprisingly, a single-nucleotide polymorphism in the first intron of the IFN-γ gene was found to be associated with paranoid schizophrenia in males, but not in females. The presence of allele A at position +874 in the IFN-γ gene correlates with 1.66-fold higher risk of paranoid schizophrenia development in males. Differences in the genotypes may have an important role in determining the level of I gene transcription. Because other polymorphisms have been demonstrated to influence IFN-γ transcription, further analysis is necessary to clarify the role of this gene in the pathogenesis of paranoid schizophrenia.

Impact of cytokine genotype on cardiovascular surrogate markers in hemodialysis patients

Background/aims: Cytokine gene polymorphisms have been implicated as potential genetic risk factors for cardiovascular diseases (CVDs). Atherosclerosis and left ventricular hypertrophy (LVH) are surrogate markers for CVDs in uremic patients. The aim of this study was to assess the role of cytokine gene polymorphisms in carotid intima–media thickness (CIMT) and left ventricular mass index (LVMI) progression in nondiabetic hemodialysis (HD) patients.Methods: About 102 nondiabetic patients on maintenance HD were included in this study. Patients were followed up for 2 years. Genetic polymorphisms of TNF-alpha (−308 G/A, −238A/G) and IL-10 (−1082 A/G, −819 C/T, −592 A/C) were determined by polymerase chain reaction. Biochemical parameters and inflammatory markers and ambulatory blood pressure (BP) measurements were determined during the study period. CIMT and LVMI were also determined at baseline and after the first and second year. Results: Cardiovascular risk factors did not differ between TNF-alpha −308 high-/low-producer genotype groups. However, CIMT and LVMI progression were detected at higher levels in patients with high-producer genotypes (AA+AG) than in patients with the low-producer genotype (GG) during the study period. The TNF-alpha −308 G/A polymorphism was closely associated with C-reactive protein (CRP), a marker of systemic inflammation in the study population. Analysis also showed that the combination of high production of TNF-alpha and low production of IL-10 was associated with higher average IMT and LVMI progression and elevated average CRP levels compared with a combination of low production of TNF-alpha and high production of IL-10. Conclusion: Polymorphisms in inflammatory genes may represent an additional factor affecting inflammation and CVD progression in nondiabetic HD patients.