Genetic Polymorphisms In Cytokine Genes Research Articles

Role of interleukin 1β and interleukin 10 variants on ocular toxoplasmosis in Brazilian individuals

IntroductionOcular toxoplasmosis (OT) is an intraocular inflammation caused by Toxoplasma gondii infection that affects the retina and choroid, giving rise to posterior uveitis. Genetic polymorphisms in cytokine genes may exert influence in the expression of these molecules and play a significant role in inflammatory responses and susceptibility to OT. The aim of this study was to evaluate the role of polymorphisms rs16944 (–511 C > T) of the interleukin (IL) 1β gene and rs1800896 (–1082 G > A) of the IL10 gene on OT in Brazilian individuals with a serologic diagnosis of T. gondii and after conducting fundoscopic exams.MethodsParticipants with a positive serology were classified into two distinct groups according to the presence (G1; n = 110) or absence (G2; n = 104) of OT. The control group (G3) consisted of individuals without the infection (n = 108).ResultsIt was observed that the C/C genotype of the IL1β gene polymorphism was a protective factor for OT (p = 0.02, OR = 0.28, 95% CI 0.08–0.78 for G1 vs. G2; p = 0.03; OR = 0.29, 95% CI 0.09–0.82 for G1 vs. G3), according to the recessive inheritance model.ConclusionsThe -511C.T polymorphisms of the IL1β gene seems to play an important role in the pathogenesis of OT in Brazilian individuals.

Association between the 308 G>A variant of the TNF-α gene and risk of colorectal cancer

Genetic polymorphisms of cytokine genes may lead to variations in immunological response and genetic susceptibility to complex diseases that include cancer. Tumor necrosis factor-a (TNF-a) is an inflammatory cytokine that performs a crucial function in the immune reaction and may be involved in the development of colorectal cancer (CRC). There is evidence that genetic variations of the TNF-α gene increase susceptibility to CRC. We aimed to investigate the relationship between the TNF-α 308 G > A polymorphism, located in the TNF-α promoter region, and the risk of CRC. One hundred and eleven patients with CRC and 234 controls were recruited. DNA genotyping was undertaken using a Taqman® based assay. The frequency of the minor allele was approximately 0.2. The TNF-α-308G/A polymorphism was associated with an increased risk of CRC (Allele model (A vs. G), OR = 0.43, 95%CI = 0.26–0.71, p = 0.001; recessive model (AA+AG vs. GG), OR = 2.81, 95%CI = 1.60–4.93, p = 0.003; co-dominant model (AG vs. AA+GG), OR = 2.87, 95%CI = 1.60–5.14, p = 0.0004). Further investigations are required in more diverse populations to determine the value of this polymorphism as a risk stratification biomarker for CRC.

Lack of association of IL-10 (rs1800896) and IL-13 (rs1800925) with non-segmental vitiligo susceptibility in South Indian population.

Vitiligo is an autoimmune depigmentation disorder caused by multiple etiologies. Genetic polymorphisms in cytokine genes influence their expression and augment disease development. Analyzing the influence of genetic polymorphisms will help in better understanding of the complex etiopathogenesis of vitiligo. To study the influence of interleukin IL-10 (rs1800896) and IL-13 (rs1800925) polymorphisms on vitiligo risk in South Indian population. Two hundred and sixty-four vitiligo patients and 264 controls were recruited in this study. Genotyping was done by quantitative PCR and plasma cytokine levels were measured by ELISA. Allele frequencies of IL-10 (rs1800896) and IL-13 (rs1800925) SNPs were observed to be equal in the groups. Mutant allele G of IL-10 (rs1800896) enhanced the familial inheritance of vitiligo (P < 0.0001, OR-25.1, 95% CI-7.64-82.7) and influenced the development of vulgaris type of vitiligo (P = 0.034, OR-1.83, 95% CI-1.07-3.13). Ancestral allele A of IL-10 (rs1800896) conferred protection against development of acrofacial vitiligo (P = 0.04, OR-0.56, 95% CI-0.33-0.95). Circulatory IL-10 levels in vitiligo patients were higher than controls (P < 0.0001). Individuals with genotype GG of IL-10 (rs1800896) had the highest circulatory levels of IL-10 (P < 0.0001). Among the genotypes of IL-13 (rs1800925) variant, none influenced the phenotype of nonsegmental vitiligo such as gender, family history, age of onset and types of vitiligo (P > 0.05). In addition, no difference was noted in the circulatory levels of IL-13 between patients and controls (P = 0.48). Within patients, CC genotype of IL-13 (rs1800925) was observed to enhance the circulatory IL-13 levels (P < 0.0001). Replication group analysis in a larger multicentric cohort in future would validate further understanding of vitiligo susceptibility in South Indian ethnics. IL-10 (rs1800896) and IL-13 (rs1800925) polymorphisms did not confer risk to develop vitiligo in South Indian population.

Cytokine Genetic Variants and Health-Related Quality of Life in Crohn’s Disease: An Exploratory Study

Crohn's disease (CD) is an inflammatory condition that has deleterious effects on patients' health-related quality of life (HRQoL). Demographic, clinical, and psychosocial factors contribute to variability in HRQoL; however, the influence of genetic variations related to altered inflammatory responses in individuals with CD is unknown. This exploratory study compared HRQoL scores across genotypes of functional genetic polymorphisms in cytokine candidate genes among individuals with CD. This study used data and blood samples collected in a parent study in 39 patients with CD aged 15-30 years. Participant reports of HRQoL were collected using the Shortened Inflammatory Bowel Disease Questionnaire (SIBDQ). Genetic data were collected for 18 functional polymorphisms in eight cytokine candidate genes. SIBDQ scores were compared among genotypes using one-way, between-subjects analysis of variance. SIBDQ scores differed across genotypes as follows: for IL-1R2 rs4141134 scores differed for total SIBDQ (p = .004) and systemic (p = .011), emotion (p = .038), and social domains (p = .025); for IL-10 rs1878672, scores differed for total SIBDQ (p = .031) and social domain (p = .008); for NFKB2 rs1056890, scores differed for social domain (p = .041); for TNF-α rs1800629, scores differed for total SIBDQ (p = .001) and bowel (p = .026), systemic (p = .014), and social domains (p = .045). Findings on differences in SIBDQ scores across functional genetic polymorphisms in cytokine genes suggest potential mechanisms that contribute to variability in HRQoL in adolescents and young adults with CD.

Lack of association between single-nucleotide polymorphisms of pro- and anti-inflammatory cytokines and HTLV-1-associated myelopathy / tropical spastic paraparesis development in patients from Rio de Janeiro, Brazil

BackgroundHTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive neurological and inflammatory disease, associated with HTLV-1 infection. HAM/TSP neurological disease is a consequence of an inflammatory reaction, and adaptive immune responses, through the secretion of anti-inflammatory and pro-inflammatory cytokines, play an important role in the outcome of infection and disease progression. Studies addressing the association between cytokines functional single nucleotide polymorphisms and HAM/TSP development are scarce.MethodsThe genetic polymorphisms of cytokine genes were evaluated in HAM/TSP patients (n = 68) and in asymptomatic HTLV-1 positive carriers (n = 83) from Rio de Janeiro, Brazil, in a case-control study. HTLV-1 infected patients were genotyped for SNPs in five cytokine genes: TNFA-308G/A, IL6-174G/C, IFNG + 874 T/A, TGFB at the codons + 10 T/C and + 25G/C, IL10-592C/A and -819C/T, and -1082A/G and proviral load (PVL) was quantified. Associations between genotypes, haplotypes, clinical outcome and pro viral load were evaluated.ResultsLack of association between the cytokine polymorphisms and disease outcome was observed. The genotypes TNFA-308GG, IL6-174GG/GC, IL10-592AA and -819CC and TGFb1 high producers phenotypes were correlated with higher PVL in HAM/TSP patients versus asymptomatic carriers.ConclusionsWe did not observe association between cytokine polymorphisms and risk for HAM/TSP development in Brazilian HTLV-1 infected individuals, regardless of differences in PVL between HAM/TSP versus asymptomatic carriers in specific cytokine polymorphisms.

Cytokine Gene Variants as Predictors of Type 2 Diabetes Mellitus.

Diabetes is the third widespread after heart disease and cancer. We have investigated genetic polymorphisms in cytokine genes viz. IL-4, IL-1Ra, IL-1β, IL-18, IL-6, TNF-α, IL-10 and ADIPOQ. The aim of study was to investigate the haplotypes, gene-gene interactions and their role in determining individual susceptibility to T2DM of family members with diabetic history. Haplotype analysis of 2 SNPs each in IL-6 and adiponectin genes showing Pairwise Linkage disequilibrium (LD) was done by SHEsis software. Logistic regression was used to study various combinations of gene-gene interactions. The TCGT* set of allele combination appeared to increase the disease risk upto 2 times while TATG* upto 51.4 times when four SNPs are taken together viz. IL-1β-511 C/T, IL-18-607 A/C, ADIPOQ1 +45 G/T and ADIPOQ2 +10211 T/G. Interaction of SNPs in eight genes showed one highly significant combination of alleles, TCGAGCTT* which increased the risk of T2DM upto 7.4 times while CAGAGCGT* allele combination increased the risk upto 4 times. During pedigree analysis in six families with four SNPs, it was interesting to note that susceptible 'AC' genotype of IL-18-607 A/C was frequent in diabetic individuals in almost all families. Moreover, when checked for the presence of risk haplotypes it was observed that TCGT* and TATG* sets of allele combinations were present in most of the diabetic individuals. Individuals with certain abnormal biochemical parameters but not yet diagnosed for T2DM carried the risk genotype or haplotype. This suggested that individuals carrying risk genotypes/haplotypes might be susceptible to T2DM and develop the disease in the future.

Genetic Polymorphisms in Cytokine Genes in Colombian Patients with Ocular Toxoplasmosis.

Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii, which has the capacity to infect all warm-blooded animals worldwide. Toxoplasmosis is a major cause of visual defects in the Colombian population; however, the association between genetic polymorphisms in cytokine genes and susceptibility to ocular toxoplasmosis has not been studied in this population. This work evaluates the associations between polymorphisms in genes coding for the cytokines tumor necrosis factor alpha (TNF-α) (rs1799964, rs1800629, rs1799724, rs1800630, and rs361525), interleukin 1β (IL-1β) (rs16944, rs1143634, and rs1143627), IL-1α (rs1800587), gamma interferon (IFN-γ) (rs2430561), and IL-10 (rs1800896 and rs1800871) and the presence of ocular toxoplasmosis (OT) in a sample of a Colombian population (61 patients with OT and 116 healthy controls). Genotyping was performed with the "dideoxynucleotide (ddNTP) primer extension" technique. Functional-effect predictions of single nucleotide polymorphisms (SNPs) were done by using FuncPred. A polymorphism in the IL-10 gene promoter (-1082G/A) was significantly more prevalent in OT patients than in controls (P = 1.93e-08; odds ratio [OR] = 5.27e+03; 95% confidence interval [CI] = 3.18 to 8.739; Bonferroni correction [BONF] = 3.48e-07). In contrast, haplotype "AG" of the IL-10 gene promoter polymorphisms (rs1800896 and rs1800871) was present at a lower frequency in OT patients (P = 7e-04; OR = 0.10; 95% CI = 0.03 to 0.35). The +874A/T polymorphism of IFN-γ was associated with OT (P = 3.37e-05; OR = 4.2; 95% CI = 2.478 to 7.12; BONF = 6.07e-04). Haplotype "GAG" of the IL-1β gene promoter polymorphisms (rs1143634, rs1143627, and rs16944) appeared to be significantly associated with OT (P = 0.0494). The IL-10, IFN-γ, and IL-1β polymorphisms influence the development of OT in the Colombian population.

A role of the immune system in the pathogenesis of schizophrenia

The review addresses immunological aspects of schizophrenia, a multifactor disease caused by genetic factors, innate disorders of the central nervous system (CNS), including the consequences of perinatal hypoxia and infections, and adverse environmental influences. Neuroinflammation as a part of the pathophysiology of schizophrenia is characterized by the higher transcription of CNS inflammatory mediators, excessive activation of microglia, inhibition of glutamatergic receptors that leads to the decrease in the number of cortical synapses and neuronal apoptosis. The authors discuss a role of genetic polymorphisms of cytokine genes, complement system components etc. The literature data on the changes in systemic immune response and imbalance in Th1/Th2 adaptive immune responses are analyzed as well. Some papers showed higher levels of proinflammatory mediators in CSF and blood of patients with schizophrenia that indicated the involvement of blood brain barrier (BBB) dysfunction. The authors present the recent data on BBB dysfunction in schizophrenia and its role in the pathogenesis of the disease, autoimmunity in patients comparing it with immune activation and genetic predisposition. An important and arguable issues about a role of parasite and viral infections in the pathogenesis of schizophrenia, initiation of immune responses and direct impacts on the brain, an influence of antipsychotic treatment on immunity are discussed. In author's opinion, conflicting results of genetic and immunological studies of schizophrenia may be explained by different methodological approaches to selection of patients and healthy controls and the differences in schizophrenia classification.

Association of TNFα-308, IFNγ+874, and IL10-1082 gene polymorphisms and the risk of non-small cell lung cancer in the population of the South Indian state of Telangana.

Cytokine-mediated inflammation is important in the pathogenesis of non-small cell lung cancer (NSCLC). Genetic polymorphisms in cytokine genes and their association with lung cancer in the Indian population have not been reported. For the first time, we analyzed genetic polymorphisms of TNFα -308, IFNγ +874, and IL10 -1082 genes in 246 NSCLC patients and 250 healthy controls in the South Indian population from Telangana using ARMS PCR. IFNγ+874 A/T and IL10-1082 G/G gene polymorphisms were found to be significantly associated with NSCLC with 1.56- and 1.68-fold disease risk, respectively. There was no association between the risk of NSCLC and TNFα-308 polymorphism. Gene polymorphisms stratified according to smoking revealed that IFNγ+874 A/T polymorphisms in smokers increased the disease risk by 2.91 fold. IL10-1082 G/G polymorphisms showed 2-fold increased risk among patients who were smokers when compared to the controls. However, there was no association between TNFα-308, IFNγ+874, and IL10-1082 gene polymorphism and the stage of the NSCLC patients. The overall risk associated with the combination of these polymorphisms indicated that the TNFα-308 G/A+IFNγ+874 A/T+IL10-1082 G/G genotype increased the risk by 1.5 fold. The results of our study indicate an association between cytokine gene polymorphisms and the risk of NSCLC in an Indian population.

Influence of genetic polymorphisms of cytokine genes in the outcome of HLA-matched allogeneic stem cell transplantation in a South East Asian population

Non-HLA gene polymorphisms have been shown to be associated with the risk of graft-versus-host disease (GVHD) and outcome of allogeneic haematopoietic stem cell transplantation (AHSCT). This study aims to investigate the role of IL6, TNFα, IL10, IL2 and IL12 gene polymorphisms in the outcome of AHSCT in a South East Asian population. A total of 67 patients and 59 donors who underwent HLA-identical matched sibling AHSCT were available for analysis. There was no significant association between the different cytokine genotypes of patients with the incidence and severity of acute GVHD. Patients with IL2 166∗T allele and patients who received donor stem cells who had IL2 166∗G allele appeared to have reduced incidence of cGVHD. Patients who received donor stem cells with IL12 1188∗C allele are found to be associated with better disease free survival. These results suggest a possible role of IL2 and IL12 gene polymorphisms in the outcome of AHSCT in a South East Asian population.

Lack of association between genetic polymorphisms in cytokine genes and tumor recurrence in patients with hepatocellular carcinoma undergoing transplantation

Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains one of the most common causes of poor long-term survival. However, the host genetic factors affecting increased risk of tumor recurrence after transplantation have not been thoroughly elucidated. The present study was designed to investigate the association of cytokine gene polymorphisms with the risk of tumor recurrence in LT patients for HCC. Eleven single-nucleotide polymorphisms within the promoter regions of 7 cytokine genes, i.e., the IL-1 family (IL-1alpha and IL-1beta), IL-6, IL-8, IL-10, TNF-alpha, and TGF-beta1, were genotyped in 93 HCC patients treated with LT using DNA sequencing. The association between these polymorphisms and the risk of tumor recurrence was evaluated while controlling confounding clinical variables. The genotype frequency of IL-10 -1082 A/G in patients with and without recurrence of HCC was AA 83.3%, GA 16.7% and AA 97.6%, GA 2.4%, respectively. The association between IL-10 -1082 GA and recurrence was significant (P=0.033). No other single-nucleotide polymorphism in the cytokine gene was found to be associated with recurrence. Kaplan-Meier survival curves showed that the homozygous AA patients had a significantly longer mean recurrence-free survival than heterozygous GA patients (23.5 vs 5.7 months, P=0.001). However, multivariate analysis failed to reveal that the GA genotype of IL-10 -1082 A/G was an independent indicator of recurrence. This study suggests the lack of association of selected cytokine gene polymorphisms with HCC recurrence after LT in the Han Chinese population. The finding does not exclude the idea that other cytokine polymorphisms could act as candidate biomarkers of disease prognosis.

POLYMORPHISMS OF CYTOKINE GENES ASSOCIATED WITH OCULAR TOXOPLASMOSIS.

POLYMORPHISMS OF CYTOKINE GENES ASSOCIATED WITH OCULAR TOXOPLASMOSIS.

Polymorphisms in immune function genes and non-Hodgkin lymphoma survival

Cytokines play a critical role in regulating the immune system. In the tumor microenvironment, they influence survival, proliferation, differentiation, and movement of both tumor and stromal cells, and regulate tumor interactions with the extracellular matrix. Given these biologic properties, there is reason to hypothesize that cytokine activity influences the pathogenesis of non-Hodgkin lymphoma (NHL). We investigated the effect of genetic variation in cytokine genes on NHL prognosis and survival by evaluating genetic variation in individual SNPs as well as the combined effect of multiple deleterious genotypes. Survival information from 496 female incident NHL cases diagnosed during 1996-2000 in Connecticut were abstracted from Connecticut Tumor Registry in 2008. Survival analyses were conducted by comparing Kaplan-Meier curves and hazard ratios (HR) were computed using Cox proportional hazard models adjusting for demographic and tumor characteristics for genes that were suggested by previous studies to be associated with NHL survival. We found that the variant IL6 genotype is significantly associated (HR = 0.42; 95%CI: 0.23-0.77) with a decreased risk of death, as well as relapse and secondary cancer occurrence, among those with NHL. We also found that risk of death, relapse, and secondary cancers varied by specific SNPs for the follicular, DLBCL, and CLL/SLL histologic types. We identified combinations of polymorphisms whose combined deleterious effect significantly alter overall NHL survival and disease-free survival. Our study provides evidence that the identification of genetic polymorphisms in cytokine genes may help improve the prediction of NHL survival and prognosis.

Prediction of atopic dermatitis in 2‐yr‐old children by cord blood IgE, genetic polymorphisms in cytokine genes, and maternal mentality during pregnancy

Atopic dermatitis (AD) is the most common skin disease in childhood and the first step of atopic march. This study aimed to investigate whether AD in children could be better predicted by biologic markers (cord blood IgE [cbIgE], LT-αNcoI alleles, and FcεRI-β E237G genotypes) and maternal mentality during pregnancy, taking into account gender, socio-demographic factors, and parental atopy. From 2001 to 2005, 1264 mother-infant pairs were recruited to participate in a birth cohort study. Prenatal questionnaire was used to collect family history, maternal gestational conditions and mentality, and environmental exposures. Cord blood was collected and assayed for genotypes and IgE levels. Phone interviews at 6 months and 2 yrs of age were conducted to inquire children's health status, including AD occurrence. In addition to the known risk factors such as gender, maternal education, and parental atopy, biomarkers and maternal mentality during pregnancy were screened by logistic regression as candidate predictors of AD. Area-under-curve (AUC) statistic from receiver-operating characteristic (ROC) curve analysis was used to compare two predicting models with and without biomarkers and maternal mentality. A total of 730 pairs completed the prenatal questionnaire and phone interview and were included in final analysis. The prevalence of ever having physician-diagnosed AD by 2-yr-olds was 5.9%. Elevated cbIgE levels (≥0.5 kU/l), LT-αNcoI alleles, FcεRI-β E237G genotype, and maternal psychologic stress during pregnancy were significantly associated with AD. Comparison with AUCs of the classic model (including gender, maternal education, and parental atopy), the model adding cbIgE levels, genotypes in cytokine genes, and maternal stress (model 2) showed higher ability to discriminate between children with and without AD (AUC statistics: 0.63 [95% CI = 0.60-0.67] vs. 0.73 [95% CI = 0.70-0.76], respectively; model comparison, p = 0.027). We conclude that elevated cbIgE, LT-α and FcεRI-β genotypes, and maternal stress during pregnancy were associated with ever having physician-diagnosed AD in 2-yr-old children and increased the predictive ability for AD after taking into account gender, maternal education, and parental atopic history.

Hodgkin disease risk: Role of genetic polymorphisms and gene–gene interactions in inflammation pathway genes

Inflammation is a critical component of cancer development. The clinical and pathological features of Hodgkin disease (HD) reflect an abnormal immunity that results from cytokines secreted by Reed-Sternberg cells and the surrounding tumor. Numerous studies have reported the association between genetic polymorphisms in cytokine genes and the susceptibility to different hematologic cancers. However, the effects of such SNPs on modulating HD risk have not yet been investigated. We hypothesized that gene-gene interactions between candidate genes in the anti- and pro-inflammatory pathways carrying suspicious polymorphisms may contribute to susceptibility to HD. To test this hypothesis, we conducted a study on 200 HD cases and 220 controls to assess associations between HD risk and 38 functional SNPs in inflammatory genes. We evaluated potential gene-gene interactions using a multi-analytic strategy combining logistic regression, multi-factor dimensionality reduction, and classification and regression tree (CART) approaches. We observed that, in combination, allelic variants in the COX2, IL18, ILR4, and IL10 genes modify the risk for developing HD. Moreover, the cumulative genetic risk score (CGRS) revealed a significant trend where the risk for developing HD increases as the number of adverse alleles in the cytokine genes increase. These findings support the notion that epigenetic-interactions between these cytokines may influence pathogenesis of HD modulating the proliferation of regulatory T cells. In this way, the innate and adaptative immune responses may be altered and defy their usual functions in the host anti-tumor response. Our study is the first to report the association between polymorphisms in inflammation genes and HD susceptibility risk.

Functional genetic polymorphisms in interleukin-12B gene in association with systemic lupus erythematosus

Genetic polymorphisms in cytokine genes, which influence gene expression, may have an important impact on SLE susceptibility and severity. The aim of this study was to examine the possible influence of two functional polymorphisms in cis-regulatory regions of IL12B gene in the susceptibility and clinical symptoms of SLE in Bulgarian patients. Female SLE patients (n = 141) and 124 healthy women were included in the study. Genotyping for the IL12B A/C polymorphism in 3'UTR was performed by restriction fragment length polymorphisms PCR assay and for the IL12Bpro polymorphism by allele-specific PCR. Genotype-22 of IL12Bpro polymorphism was overrepresented among women with SLE (28 vs. 17%; OR = 1.875; 95% CI: 1.037 ÷ 3.390; P = 0.037). Respectively, a higher frequency of allele-2 was found in patients than in controls (51% vs. 40%; OR = 1.566; 95% CI: 1.110 ÷ 2.210; P = 0.011). Also, we found significantly elevated frequency of genotype-22 of IL12Bpro polymorphism among SLE patients who were simultaneously carrier of genotype-AA of SNP in 3'UTR. Women with both homozygous genotypes, genotype-AA of SNP in 3'UTR and genotype-22 of IL12Bpro polymorphism, had a 2.1-fold significantly elevated risk for SLE development. The carrying of genotype-11 of IL12Bpro polymorphism was positively associated with hematological and neuropsychiatric manifestations of SLE. We have provided evidence that the IL12Bpro polymorphism was associated with SLE development among Bulgarian women. Although a strong individual effect of SNP in 3'UTR of IL12B was not detected, we found that genotype-22 of IL12Bpro was predominantly combined with genotype-AA of SNP in 3'UTR among SLE patients and this combination elevates the risk of SLE.

Association between genetic polymorphisms in cytokine genes and recurrent miscarriage – a meta-analysis

A meta-analysis of association studies was performed to assess whether the reported genetic polymorphisms in cytokine genes are risk factors for recurrent miscarriage (RM). The electronic PubMed database was searched for case–control studies on immunity-related genes in RM. Investigations of a single polymorphism/gene involvement in RM reported more than five times were selected. Aggregating data from seven case-control studies on −308/tumour necrosis factor-α polymorphism, the odds ratio (OR) for RM was 1.1 (0.87–1.39) if the polymorphism was considered under a dominant genetic model. In six studies on −1082/interleukin-10 (IL-10) polymorphism, the OR under a dominant model was 0.76 (0.58–0.99), and under a recessive model the OR was 0.90 (0.71–1.15). In five case–control studies on −174/IL-6 polymorphism, the OR for RM under a recessive model was 1.29 (0.69–2.40). The results show a statistically significant association with RM for the −1082/IL-10 genotype.

Correlation of IL-6 and IL-10 production following bone marrow transplantation with donor cytokine gene polymorphisms

Several candidate gene studies have demonstrated that genetic polymorphisms in cytokine genes contribute to variations in the levels of cytokines produced and this variation may influence the occurrence and severity of complications after stem cell transplantation (HSCT). In this work we compared the serum concentrations of TNF-α, IFN-γ, IL-6, IL-10, and TGF-β1 in 13 recipients following HSCT with the TNF-308, IFNG+874, IL6-174, IL10-1082,-819,-592, and TGFB1+869,+915 polymorphisms. Serum cytokine levels were assessed using commercial ELISA kits for TNF-α, IFN-γ, IL-6, IL-10, and TGF-β1 (BioSource®, Nivelles, Belgium, Europe). Donor/recipient genotypes for these cytokine polymorphisms were analyzed by polymerase chain reaction-sequence-specific primer (PCR-SSP) with the Cytokine Genotyping Primers Kit (One Lambda , Canoga Park, CA, USA). We found correlation between the levels of IL-6 and IL-10 concentrations following HSCT and the IL6-174 and IL10-1082,-819,-592 polymorphisms, but not for other cytokines investigated in this study. Those with genotypes associated with low production of IL-6 and IL-10 produced lower levels of these cytokines than those with genotypes associated with high or intermediate production of these cytokines (P < 0.05).

Cytokine gene polymorphisms in Chinese patients with psoriasis

Previous studies have shown that cytokine gene polymorphisms may confer susceptibility to psoriasis. To determine whether genetic polymorphisms of the cytokine genes might influence the development of psoriasis in Chinese patients in Taiwan. DNA samples were obtained from 170 patients with psoriasis vulgaris (PV), 102 patients with psoriatic arthritis (PsA) and 210 control subjects. Using direct sequencing and microsatellite genotyping, we examined 28 polymorphisms in 11 cytokine genes including the interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist, IL-4, IL-8, IL-10, IL-12B, IL-13, tumour necrosis factor (TNF)-alpha, TNF-beta and interferon-gamma genes. Genotypes of HLA-Cw*0602, killer cell immunoglobulin-like receptor (KIR) genes and major histocompatibility complex class I chain-related gene A (MICA) were also determined in patients with PsA. The patients with PV were more likely to carry the +4496G allele of the IL-12B gene (59.4% vs. 49.3%, P = 0.0067, P(c) = 0.033). However, no significantly different allelic and genotypic distributions of the other analysed genes including IL-1beta, TNF-alpha, TNF-beta, KIR genes and MICA were found between the PV/PsA patients and controls. Moreover, no association was observed with disease onset, gender, peripheral arthritis or joint erosion. With regards to HLA-Cw*0602, its allele frequency was significantly increased in patients with early-onset PV (25.3% vs. 4.8%, P < 10(-7)), but not in patients with PsA. The IL-12B gene polymorphism conferred a risk for PV in our Chinese population, although the effect was more minor than that of HLA-Cw*0602. Cw*0602, KIR2DS1/S2 and MICA-A9 were unlikely to be risk alleles in our patients with PsA. The other analysed genetic polymorphisms of cytokine genes do not appear to be associated with susceptibility to PV and PsA in Chinese patients in Taiwan.

Lack of association between genetic polymorphisms in cytokine genes and disease expression in patients with hereditary non-polyposis colorectal cancer

Objective. Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in DNA mismatch repair (MMR) genes and is characterized by familial aggregations of early-onset epithelial cancers. Inflammatory cells produce an attractive environment for tumour growth since reactive oxygen and nitrogen species generated by inflammatory cytokine induction can cause damage to DNA and proteins. In this study the objective was to investigate single nucleotide polymorphisms (SNPs) in cytokine genes to assess their impact on disease expression in individuals diagnosed with HNPCC. Material and methods. DNA samples from 220 participants diagnosed with HNPCC were genotyped for SNPs in IL-6, IL-1β, TNF-α, IFN-γ, IL-10, IL-4 and IL-1RN. The association between the polymorphisms and disease characteristics, i.e. affected or unaffected with colorectal cancer (CRC) and age of diagnosis of CRC, was tested with the Pearson χ2 test and by Kaplan-Meier survival analysis. Results. There was no significant difference between CRC patients and unaffected MMR gene mutation carriers for any of the SNPs studied and the Kaplan-Meier survival analysis showed no significant difference between age of diagnosis of CRC and genotype. Conclusions. The SNPs selected for this study do not appear to modify disease expression in HNPCC. Given the complexity of the inflammatory response, the limited number of SNPs studied does not rule out the notion that other cytokine polymorphisms could act as disease modifiers of disease expression in HNPCC.