Cytokine Single Nucleotide Polymorphisms Research Articles

Cytokine polymorphisms in patients with autoimmune hemolytic anemia.

Autoimmune hemolytic anemia (AIHA) is due to autoantibodies with or without complement activation and involves cellular and cytokine dysregulation. Here, we investigated cytokine single-nucleotide polymorphisms (SNPs) of TNF-α, TGF-β1, IL-10, IL-6, and IFN-γ, along with their serum levels. The former were related to hematological parameters, therapy, and clinical outcome. The study included 123 consecutive patients with primary AIHA [77 warm AIHA and 46 cold agglutinin disease (CAD)], followed up for a median of 49 months. Results show that the allelic frequency of TNF-α -308 G/A polymorphisms was significantly lower in patients versus controls. Moreover, the genotypic frequency of TNF-α -308G/A and TGF-β gene codon 25 G/C genotypes was significantly lower in patients versus controls. Considering cytokine SNP genotypes associated with different gene expression levels, TNF-α high gene expression was significantly more frequent in patients, TGF-β and IL-10 high gene expression was higher in patients with more severe anemia, and TGF-β high gene expression was higher in patients with active disease. Considering treatment, TNF-α and TGF-β high gene expression was more frequent in multitreated patients and particularly in CAD. It may be speculated that this genetic predisposition to a stronger inflammatory response may result in a greater immune dysregulation and in a relapsed/refractory disease. Regarding cytokine serum levels, TNF-α and TGF-β were significantly lower, and IL-10 and IL-6 were significantly higher in patients versus controls, underlying the complex interplay between genetic background and disease features.

The Influence of TNF-α, IL-6, TGF-β1, IFN-γ, IL-10 Polymorphisms on Predisposition to Diabetes Mellitus among Jordanian Patients.

Diabetes mellitus is a long-term disorder with high prevalence globally. It can be classified into two types: Type 1 diabetes and Type 2 diabetes mellitus. Diabetes mellitus is considered a multifactorial disorder in which genetic factors such as cytokines play a major role. Cytokines play a role in immune modulation and are associated with the development of diabetes mellitus. Single nucleotide polymorphisms in cytokines were studied extensively in different populations to determine their association with a predisposition to diabetes mellitus. The aim of this study was to estimate the frequency of single nucleotide polymorphisms in the cytokine genes TNF-α, TGF-β, IL-6, IL-10, and IFN-γ in 102 Jordanian diabetes mellitus patients in comparison to 50 controls and their association to diabetes mellitus susceptibility. Analysis was performed using the highly specific polymerase chain reaction-sequence specific primers methodology. Our findings showed that the IL-10-1082 G/G genotype (P = 0.02) and the TGF-β1 codon 25*G allele (P < 0.01) may be considered risk factors for type 2 diabetes mellitus. In addition, the IFN-γ-874*A allele (P = 0.04) seems to increase the predisposition to type 1 diabetes. Our study showed that the IL-10-1082 G/G genotype and TGF-β1 codon 25*G allele are associated with type 2 diabetes mellitus while the IFN- γ -874*A allele is associated with type 1 diabetes. Our findings may help in the early detection of diabetes mellitus, which would in turn help in undergoing the needed preventative measures to delay the onset of diabetes mellitus.

P1526: AUTOIMMUNE HEMOLYTIC ANEMIAS: RELATIONSHIP BETWEEN SINGLE NUCLEOTIDE POLYMORPHISMS OF CYTOKINE GENES AND CLINICAL/HEMATOLOGICAL PARAMETERS

Background: Autoimmune hemolytic anemia (AIHA) is highly heterogeneous and involves several pathogenic mechanisms including autoantibody production, complement activation, and cytokine dysregulation. Hb levels at baseline and the degree of bone marrow compensation are the main predictors of outcome. The contribution of high, intermediate, and low producer genetic profile cytokine genes may give further insights into the pathogenesis of the disease. Aims: To evaluate the frequency of cytokine single nucleotide polymorphisms (SNPs) in warm (wAIHA) and cold agglutinin disease (CAD) and their relationship with clinical and hematological parameters, including the degree of anemia, treatment refractoriness and number of therapies lines. Methods: We investigated SNPs of five cytokine genes [tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, transforming growth factor (TGF)-beta, interleukin (IL)-6 and IL-10] in 72 Italian warm AIHA patients, using the Cytokine Tray (One Lambda, Canoga Park, CA) according to the manufacturer’s recommendations. Allele and genotype frequency results were compared to those described in the Italian population by Uboldi de Capei et al. (2003) and Poli et al. (2002). Results: One hundred and twenty AIHA patients have been evaluated: median age 63 years (range 17-90), classified as wAIHA (n=75) and CAD (n=45). Demographic and hematological characteristics of patients are described in Figure 1A. Regarding cytokine SNP frequencies (Figure 1B), we observed that the TNF-alpha-308 high producers genotypes (G/G and G/A) were significantly more frequent in AIHA patients (37% vs 16%, p=0.0003 or 37% vs 23%, p=0.01) and in wAIHA (43% vs 16%, p<0.0001 or 43% vs 23%, p=0.0014) compared to controls. No differences were observed in CAD patients versus controls. Likewise, no significant differences between AIHA (including wAIHA and CAD subtypes) and controls were noted regarding other cytokine SNPs. Concerning the clinical severity at presentation, the frequency of TGF-beta (82% vs 58%, p=0.01) and IL-10 (17% vs 5%, p=0.03) high producers was higher in patients with Hb ≤7.5 g/dL (median of all AIHA) versus those with less severe presentation. Similarly, the frequency of high/intermediate IFN-gamma producers was higher within the group with Hb levels ≤7.5 g/dL at onset (75% vs 58%, p=0.03). No characteristic patterns were observed regarding IL-6 and TNF-alpha. Finally, the patterns of TNF-alpha and TGF-beta production were differently distributed considering the number of therapy lines: the first both in all AIHA and in CAD patients (p=0.004 and p=0.01, respectively), the second only in CAD patients (p=0.03). No differences in genotype frequencies of cytokine SNPs were observed regarding the number of relapses. Image:Summary/Conclusion: These preliminary data show that AIHA patients display a more pro-inflammatory cytokine signature at molecular level (TNF-alpha high producer genotype) as compared to the Italian control population. Moreover, cytokine SNPs were also associated with clinical severity at onset, and requirement of multiple treatments.

Single Nucleotide Polymorphisms of Cytokine Genes in Warm Autoimmune Hemolytic Anemias: Relationship with Clinical and Hematological Parameters

Background: Autoimmune hemolytic anemia (AIHA) is due to an increased immune peripheral destruction of red blood cells. The disease is characterized by high heterogeneity regarding anemia severity, treatment requirement and occurrence of complications. It has been shown that Hb levels at baseline, presence of complement activation, and the degree of bone marrow compensation are the main predictors of outcome. Moreover, multi-relapsing cases show bone marrow dysmyelopoiesis, and fibrosis suggesting an immune attack against bone marrow precursors. An interesting area to investigate is the genetic landscape of AIHA, including cytokine gene signature and other molecular mechanisms of refractoriness.Aim: To evaluate the frequency of cytokine single nucleotide polymorphisms (SNPs) in warm AIHA and their correlation with clinical and hematological parameters, including the degree of anemia, treatment refractoriness and number of therapies lines.Methods: We investigated SNPs of five cytokine genes [tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, transforming growth factor (TGF)-beta, interleukin (IL)-6 and IL-10] in 72 Italian warm AIHA patients, using the Cytokine Tray (One Lambda, Canoga Park, CA) according to the manufacturer's recommendations. Allele and genotype frequency results were compared to those described in the Italian population by Uboldi de Capei et al. (2003) and Poli et al. (2002).Results: Seventy-two warm AIHA patients have been evaluated: median age 63 years (range 17-90), classified as per DAT positivity in IgG+ (N=48), IgG+C (N=17), IgA+ (N=1), and DAT negative AIHA (N=6). Demographic and hematological characteristics of patients are described in Figure 1A. Regarding cytokine SNP frequencies, we observed that AIHA patients had a significantly higher prevalence of the TNF-alpha-308 high producers genotypes (G/G and G/A) compared to controls (40.3% vs 16% or 23%, p=0.0003 and p=0.006, respectively). No differences were detected regarding genotype frequencies of the other cytokine SNPs (Figure 1B). By dividing patients according to anemia severity at onset, a more frequent low producer genotype of IFN-gamma (A/A) was observed in patients with Hb levels >7.4 g/dL (median value of patients cohort) compared to the other group (p=0.05). Finally, considering the number of relapses or therapy lines, an increased frequency of TNF-alpha -308 high producers genotypes were found among multi-relapsing (> 3 relapses, 70.5% vs 56%) and multi-treated patients (> 3therapy lines, 52% vs 35%), although not significantly.Conclusions: These preliminary data show that wAIHA patients display a more pro-inflammatory cytokine signature at molecular level as compared to the Italian control population. This is highlighted by an increased prevalence of TNF-alpha high producer genotype that is also associated with multiple relapses and greater treatment requirement. Additionally, cytokine SNPs may be also associated with anemia severity at onset, as observed for IFN-gamma low producer genotype that was more frequent in less severe cases. [Display omitted] DisclosuresFattizzo: Alexion, Amgen, Annexon, Apellis, Grifols, Novartis, Momenta: Consultancy, Speakers Bureau. Bianchi: Agios pharmaceutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Barcellini: Agios: Honoraria, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Alexion Pharmaceuticals: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees.

Association of cytokine gene polymorphisms with chronic hepatitis C virus genotype 1b infection in Chinese Han population: An observational study.

Cytokines are extensively involved in the process of hepatitis C virus (HCV) infection and take a crucial part in host immune regulation. We aimed to explore the potential correlation of cytokine single nucleotide polymorphisms (SNPs) with HCV susceptibility and response rate of interferon (IFN)-based antiviral therapy in Chinese Han population.A case–control genetic association study was conducted between 198 patients with chronic HCV genotype 1b infection and 142 healthy controls. Genetic polymorphisms of TNF-α (rs1800629), TGF-β (rs1800469), IL-10 (rs1800896, rs1800871, and rs1800872), IL-6 (rs1800795, rs1800796), IFN-γ (rs2430561), and IL-28B (rs12979860, rs12980275, and rs8099917) were analyzed by MassARRAY SNP technology. Patients were treated with IFNα-2b or pegylated-IFNα-2a plus ribavirin for 48 weeks. Sustained virological response (SVR) was assessed 6 months after the completion of the treatment.The IL-28B rs12979860-CC (odds ratio [OR] = 4.35, 95% confidence interval [CI]: 1.69–11.21, P = .001), rs12980275-AA (OR = 3.41, 95% CI: 1.08–10.76, P = .028), and rs8099917-TT (OR = 3.86, 95% CI: 1.49–10.12, P = .004) were significantly associated with SVR, and IL-10 rs1800871-TT (OR = .50, 95% CI: 0.25–1.00, P = .049) and rs1800872-AA (OR = .50, 95% CI: 0.25–1.00, P = .049) were also significant for SVR. No association was found between the cytokine SNPs and HCV susceptibility. Additionally, multivariate analysis showed that low baseline viral load (OR = 3.63, 95% CI: 1.01–13.02, P = .048), pegylated-IFN (OR = 9.68, 95% CI: 1.14–82.13, P = .037) and rs12979860-CC (OR = 6.08, 95% CI: 2.00–18.46, P = .001) were independent factors for SVR.IL-28 and IL-10 gene polymorphisms played an important role in predicting host response to IFN-based antiviral therapy in HCV genotype 1b infection.

Helicobacter pylori and cytokine gene variants as predictors of premalignant gastric lesions.

Gastric cancer remains the third leading cause of mortality from cancer worldwide and carries a poor prognosis, due largely to late diagnosis. The importance of the interaction between Helicobacter pylori (H. pylori) infection, the main risk factor, and host-related genetic factors has been studied intensively in recent years. The genetic predisposition for non-hereditary gastric cancer is difficult to assess, as neither the real prevalence of premalignant gastric lesions in various populations nor the environmental risk factors for cancer progression are clearly defined. For non-cardiac intestinal-type cancer, identifying the factors that modulate the progression from inflammation toward cancer is crucial in order to develop preventive strategies. The role of cytokines and their gene variants has been questioned in regard to non-self-limiting H. pylori gastritis and its evolution to gastric atrophy and intestinal metaplasia; the literature now includes various and non-conclusive results on this topic. The influence of the majority of cytokine single nucleotide polymorphisms has been investigated for gastric cancer but not for preneoplastic gastric lesions. Among the investigated gene variants onlyIL10T-819C, IL-8-251, IL-18RAP917997, IL-22 rs1179251, IL1-B-511, IL1-B-3954, IL4R-398 and IL1RN were identified as predictors for premalignant gastric lesions risk. One of the most important limiting factors is the inhomogeneity of the studies (e.g., the lack of data on concomitant H. pylori infection, methods used to assess preneoplastic lesions, and source population). Testing the modifying effect of H. pylori infection upon the relationship between cytokine gene variants and premalignant gastric lesions, or even testing the interaction between H. pylori and cytokine gene variants in multivariable models adjusted for potential covariates, could increase generalizability of results.

Understanding the Relation Between Early-Life Adversity and Depression Symptoms: The Moderating Role of Sex and an Interleukin-1β Gene Variant.

Pro-inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), are thought to play a fundamental role in the pathogenesis of depression within a subset of individuals. However, the involvement of IL-1β has not been as consistently linked to depression, possibly owing to difficulties in detecting this cytokine in blood samples or that changes in circulating levels might only be apparent in a subgroup of patients who have experienced early-life adversity. From this perspective, the association between early-life adversity and depressive illness might depend on genetic variants regulating IL-1β activity. Considering the inflammatory-depression link, and that women are twice as likely to experience depression compared to men, the current study (N = 475 university students) examined the moderating role of three independent cytokine single nucleotide polymorphisms (SNPs; IL-1β rs16944, IL-6 rs1800795 SNP, TNF-α rs1800629) in the relationship between early-life adversity and depressive symptoms, and whether these relations differed between males and females. The relation between childhood adversity and depressive symptoms was moderated by the IL-1β SNP, and further varied according to sex. Specifically, among females, higher childhood maltreatment was accompanied by elevated depressive symptoms irrespective of the IL-1β SNP, but among males, this relationship was particularly pronounced for those carrying the GG genotype of the IL-1β SNP. These findings suggest that, in the context of early life adversity, genetic variations of IL-1β functioning are related to depressive symptomatology and this may vary among males and females. The present study also, more broadly, highlights the importance of considering the confluence of experiential factors (e.g., early life adversity) and personal characteristics (e.g., sex and genetics) in understanding depressive disorders, an approach increasingly recognized in developing personalized treatment approaches to this illness.

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.

IFNG +874 A/T is associated with acute lymphoblastic leukemia in Mexican Mestizos

Acute lymphoblastic leukemia (ALL), the most common type of cancer in children worldwide, has one of the highest incidence rates in Mexico. It is a multifactorial disease and different cytokine single nucleotide polymorphisms (SNP), have been associated with ALL expression. Few studies have been published analyzing IFNG +874 T/A and IL2 −330 G/T in this type of leukemia. These SNPs are involved in high or low expression, and are central to cellular immunity, influencing greatly tumor growth. The purpose of this work was to explore the association of IFNG +874 A/T (rs2430561) and IL2 −330 G/T (rs2069762) SNPs with ALL susceptibility and/or protection in 488 Mexican Mestizos patients, as compared to 950 Mexican Mestizo healthy controls. The results demonstrated that IFNG +874 T allele (pc = 0.00004, OR = 0.673) and the TT genotype (pc = 0.00015, OR = 0.349), protect against ALL expression with no specific gender association; however, the TT homozygote genotype (vs. TA+AA) seems more protective in males (pc = 0.00683). IL2 −330 G/T does not contribute to the development of ALL. In healthy Mexicans, the most common genotypes for IL2 and IFNG, are the low cytokine producers, suggesting that the genetic background in this ethnic group, may be partly responsible for the high incidence of ALL. These results show for the first time in Mexicans, the relevant role that IFNG SNP has in the genetic etiology of ALL. Thus, a large group of patients belonging to different ethnicities will be very helpful to study in order to demonstrate if these SNPs contribute to the genetic etiology of ALL, as shown here in Mexican Mestizos.

Association of cytokine gene polymorphisms with osteoarthritis susceptibility.

Osteoarthritis (OA) is a multifactorial disease characterized by low-grade inflammatory processes that are mediated initially by the cells and factors of the innate immune system. In addition to their key role in inflammation, cytokines contribute to the pathogenesis of OA through angiogenesis and chemotaxis. The purpose of the present case-control study was to investigate a possible association of four cytokine single nucleotide polymorphisms (SNPs), IL-4R -3223C>T (rs2057768), IL-8 -251T>A (rs4073), IL-10 -1082A>G (rs1800896) and TNF -A-308G>A (rs1800629) with OA susceptibility. Genomic DNA was isolated from blood samples collected from 305 Romanian subjects (90 patients with OA and 215 controls) and the genotyping of the SNPs was performed by TaqMan allelic discrimination polymerase chain reaction using predesigned assays. Our data indicated a significant association for IL-4R rs2057768 C>T SNP. The subjects that carried the CT genotype were at a higher risk for OA (OR 2.03, 95% CI: 1.21-3.42, P=0.007) compared with those that had the CC genotype. Furthermore, the carriers of the T allele were at a 1.9 fold higher risk for OA (OR 1.92; 95% CI, 1.17-3.17; P=0.009) in a dominant model. The association remained significant only for knee OA in the subgroups analysis. No correlations were observed between the other remaining SNPs and OA. The results suggested that the IL-4R rs2057768 SNP could contribute to OA susceptibility in the Romanian population, providing novel evidence for the involvement of IL-4/IL-4R pair in the pathogenesis of OA.

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.

No association of IL2, IL4, IL6, TNF, and IFNG gene polymorphisms was found with Taenia solium human infection or neurocysticercosis severity in a family-based study

Neurocysticercosis (NC) is caused by the establishment of the metacestode stage of Taenia solium in the human central nervous system. A great heterogeneity in the susceptibility to the infection and to the disease has been reported. While the factors involved in this heterogeneity are not completely understood, clearly different immune-inflammatory profiles have been associated to each condition. This study evaluated the association of cytokine single nucleotide polymorphisms (SNPs) with susceptibility to infection and disease severity in NC patients.Blood samples from 92 NC cases and their parents (trios) were genotyped for SNPs in five cytokines relevant for the immune response: IL4 (−589C/T), IL6 (−174C/G), IFNG (+874T/A), TNF (−238G/A), and IL2 (−330G/T). Specific DNA fragments were amplified by the polymerase chain reaction, using the 5′-nuclease Taqman assay on a 7500 platform, allowing the detection of the polymorphism genotypes.No association between the polymorphisms evaluated neither with susceptibility to infection nor with disease severity was found, although previous studies reported variations in the levels of these cytokines among different NC clinical pictures. These results, nevertheless, add new elements to our understanding of the complex pathogenic mechanisms involved in susceptibility to infection by T. solium cysticerci and the severity of the ensuing disease.

Association between cytokine genes polymorphisms and type 1 diabetes: a case-control study on Saudi population

ABSTRACT Background: Association studies of genes encoding cytokines that play an important role in inflammatory response represent one approach to finding type 1 diabetes (T1D) disease genes. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) within cytokine genes with T1D in a cohort of Saudi subjects. Methods: A total of 300 well-characterized type 1 diabetic patients and 300 T1D-free control subjects were enrolled in this investigation. Cytokine SNPs were genotyped by using Polymerase chain reaction (PCR) with sequence-specific primers. Results: Our data revealed that IFN-γ +874T allele carriers [odds ratio (OR) = 1.87, p < 0.001] and TT homozygotes (OR = 1.28, p < 0.001) were significantly more susceptible to developing T1D than the A allele carriers. In addition, TNF-α −308A allele carriers (OR = 1.73, p < 0.001) and AA homozygotes (OR = 1.74, p < 0.001) were also overrepresented among the diabetics than G allele carriers. IL-4 −590C/T TT homozygotes (OR = 2.23, p < 0.001) were significantly more susceptible to develop T1D than CC genotypes, whereas CT heterozygotes were not significantly associated (OR = 1.43, p = 0.78) with T1D. Furthermore, IL-4 T allele was statistically associated with T1D patients compared to control group (OR = 2.24, p < 0.001). Similarly, IL-1β −511C/T TT homozygotes (OR = 1.85, p = 0.012) and the T allele (OR = 1.85, p < 0.001) were significantly more susceptible to T1D than CC genotypes, whereas TC heterozygotes (OR = 1.04, p = 0.86) were not significantly associated with T1D. Conclusion: Our data concluded that IFN-γ +874T allele, TNF-α −308A allele, IL-1β −511T allele, and IL-4 −590T allele could be considered risk factors for T1D development in Saudi subjects.

Cytokine single-nucleotide polymorphisms and risk of non-small-cell lung cancer.

Lung cancer, particularly the non-small-cell lung cancer (NSCLC) subtype, is the leading cause of cancer-related death worldwide. Several functional polymorphisms in inflammatory cytokine genes, such as IL1B, IL6, IL12A, IL13 and IL16, have been associated with the risk of NSCLC. The aim of this study was to evaluate the association between ILs gene polymorphisms and the risk of developing NSCLC. A retrospective case-control study was carried out, including 174 NSCLC cases and 298 controls of Spanish origin. IL1B (rs1143634), IL1B (rs12621220), IL1B (rs1143623), IL1B (rs16944), IL1B (rs1143627), IL12A (rs662959), IL13 (rs1881457), IL6 (rs1800795) and IL16 (rs7170924) gene polymorphisms were analysed by TaqMan. The genotypic logistic regression model adjusted by smoking status showed that the IL1B rs1143634-TT genotype was associated with a lower risk of NSCLC (P=0.04312; odds ratio=0.226; 95% confidence interval=0.044-0.840). No other gene polymorphisms showed an association with NSCLC in any of the models tested. In conclusion, IL1B rs1143634 was significantly associated with a higher risk of NSCLC. No influence of IL1B rs12621220, rs1143623, rs16944, rs1143627, IL12A rs662959, IL13 rs1881457 and IL16 rs7170924 on the risk of developing NSCLC was found in our study.

Association of TNF-alpha (−308 A/G) and IFN-gamma (+874 A/T) gene polymorphisms in response to spontaneous and treatment induced viral clearance in HCV infected multitransfused thalassemic patients

BackgroundMultitransfused thalassemic individuals are at high risk of developing transfusion transmitted Hepatitis C virus (HCV) infection. The aim of the study was to correlate the effects of host cytokine single nucleotide polymorphisms of TNF-α (-308 A/G) and IFN-γ (+874 A/T) in spontaneous or IFN induced treatment response in the HCV infected thalassemic individuals. MethodsA total of 427 HCV sero-reactive thalassemic individuals were processed for HCV viral genomic diversity and host gene polymorphisms analysis of TNF-α (-308 A/G) and IFN-γ (+874 A/T). ResultsOut of 427 HCV sero-reactive individuals, 69.09% were found to be HCV RNA positive with genotype 3 as the predominant infecting strain (94.29%). Study highlighted that, A allele was significantly associated with (p < .05) spontaneous clearance of HCV infection and G allele was correlated with viral persistence at TNF-α (−308) gene polymorphism. Whereas in case of IFN-γ (+874) SNPs, A allele was significantly responsible (p < .05) for spontaneous clearance than T allele. Our study also indicated that in relapsed cases, IFN-γ (+874) T allele is more responsible than A allele. Though no significant correlation was found at both TNF-α (−308) and IFN-γ (+874) gene polymorphism among SVR and relapsed thalassemic patients. ConclusionA allele at both TNF-α (−308) and IFN-γ (+874) were strongly associated with spontaneous clearance among this population. But in case of SVR and relapsed cases no significant association was found. This cytokine gene polymorphisms pattern will help clinicians to take an informed decision about therapeutic management of HCV infected thalassemic individuals.

P.7.a.003 - No association of D310 and D514 repeat polymorphisms of mitochondrial D-loop region with attention deficit hyperactivity disorder

Neurocysticercosis (NC) is caused by the establishment of the metacestode stage of Taenia solium in the human central nervous system. A great heterogeneity in the susceptibility to the infection and to the disease has been reported. While the factors involved in this heterogeneity are not completely understood, clearly different immune-inflammatory profiles have been associated to each condition. This study evaluated the association of cytokine single nucleotide polymorphisms (SNPs) with susceptibility to infection and disease severity in NC patients.Blood samples from 92 NC cases and their parents (trios) were genotyped for SNPs in five cytokines relevant for the immune response: IL4 (−589C/T), IL6 (−174C/G), IFNG (+874T/A), TNF (−238G/A), and IL2 (−330G/T). Specific DNA fragments were amplified by the polymerase chain reaction, using the 5′-nuclease Taqman assay on a 7500 platform, allowing the detection of the polymorphism genotypes.No association between the polymorphisms evaluated neither with susceptibility to infection nor with disease severity was found, although previous studies reported variations in the levels of these cytokines among different NC clinical pictures. These results, nevertheless, add new elements to our understanding of the complex pathogenic mechanisms involved in susceptibility to infection by T. solium cysticerci and the severity of the ensuing disease.

Association of IL-10 gene polymorphisms and susceptibility to Juvenile Idiopathic Arthritis in Egyptian children and adolescents: a case-control study

BackgroundJuvenile Idiopathic Arthritis (JIA) is the most common chronic arthritis in children worldwide. Among anti-inflammatory cytokines, interleukin-10 (IL-10) is a key immunosuppressive cytokine involved in the pathogenesis of JIA. To date, only a few studies concerned the association of interleukin-10 gene polymorphisms with JIA. In this study, we aimed to investigate 3 cytokine single-nucleotide polymorphisms situated at positions -1082(G/A), −819(C/T), and −592(C/A) in the promoter region of the IL-10 gene to determine whether this polymorphism could be a marker of susceptibility to JIA in Egyptian children and adolescents. We also measured the serum level of IL-10 to assess its relation to such polymorphism.MethodsThis was a case-control study included 100 patients diagnosed with JIA, and matched with age, gender, ethnicity 100 healthy control subjects.Interleukin-10 −1082(G/A), −819(C/T), and −592(C/A) polymorphisms were genotyped by amplification refractory mutation system- polymerase chain reaction (ARMS)-PCR methodology, while the serum IL10 levels were measured by ELISA method.ResultsCompared to the controls subjects, the frequency of IL-10- AA genotype and A allele at the –1082 position were overrepresented in patients with JIA (OR = 2.7; 95% CI: 1.1–6.4 for the AA genotype; P <0.05 and OR: 1.5; 95% CI: 1.03–2.3 for the A allele; P <0.05 respectively). On the other hand, no significant differences were found between the 2 groups in the genotype or allele frequencies for the –819 and –592 positions. Of note, we found a significant positive association between the IL-10 (-1082) AA genotype and susceptibility to polyarticular JIA (OR: 4.3; 95% CI: 1.5–12.7; P <0.01). We observed that patients with the IL-10 (-1082) AA genotype had significantly lower serum IL-10 levels (2.3 ± 0.9 pg/ml) compared to those with AG genotype (7.6 ± 1.5 pg/ml) and GG genotype (9.5 ± 1.2 pg/ml); P < 0.01, respectively.ConclusionWe demonstrate for the first time, to the best of our knowledge, that the presence of an A allele or AA gene variant at the –1082 position of the promoter region of the interleukin-10 gene may constitute risk factors for developing JIA in Egyptian children and adolescents. Moreover, we observed a significant positive association between the IL10 –1082 AA gene variant and susceptibility to polyarticular JIA.

Interleukin-4 cytokine single nucleotide polymorphisms in kawasaki disease: a case-control study and a review of knowledge.

Kawasaki disease (KD) is a systemic vasculitis of medium-sized arteries. High levels of interleukin 4 (IL-4) and the dominance of Th2 cytokines seem to be a key feature in the acute phase of KD. In this study, the role of IL-4 and IL-4R gene polymorphisms were investigated in Iranian children with KD. Fifty-five patients with KD and 140 healthy subjects as a control group were enrolled in this study. Single nucleotide polymorphisms (SNPs) of IL-4 gene at positions -1098 (rs2243248), -590 (rs2243250) and -33 (rs2070874), as well as IL-4RA gene at position +1902 (rs180275) were assessed in patients and the control group. The C allele and CC genotype of IL-4 gene at position -590 and at position -33 had positive associations and the CT genotype at -590 was negatively associated with KD (odds ratio (95% CI)=0.04 [0.01-0.09]). The haplotype TCC was more frequent among the patients, while the haplotypes TTT and TTC had a negative association with KD. IL-4 polymorphisms might be associated with KD in an Iranian population.

Polymorphisms in cytokine genes influence cognitive and functional performance in a population aged 75 years and above.

To investigate the frequency of the cytokine single nucleotide polymorphisms (SNPs) tumor necrosis factor (TNF)-α -308G > A, tumor growth factor (TGF)-β1 codon +10C > T, TGF-β1 codon +25G > C, interleukin (IL)-10 -1082A > G, IL-10 -819C > T, IL-10 -592C > A, IL-6 -174G > C, and IFN-γ +874T > A in a sample of healthy and cognitively impaired elderlies and to verify the probable association between these SNPs and cognitive and functional performance of subjects aged 75 years and above. 259 Brazilian subjects were included, comprising 81 with cognitive impairment no dementia (CIND) and 54 demented seniors (together made up the cognitively impaired group, CI) and 124 age-matched and gender-matched cognitively healthy controls (CHS). The genotyping was performed by multiplex polymerase chain reaction. The cognitive performance was evaluated by Mini-Mental State Examination Brief Cognitive Screening Battery. The functional performance was accessed by Functional Activities Questionnaire. The CClower genotype of TGF-β1 codon +25G > C was frequent in both patient groups. The TThigher genotype of INF-γ +874T > A was less frequent in the dementia group. IL-10 haplotypes of lower expression were more frequent among CIND and demented patients. In CI, individuals with genetic variants that produce higher expression of TGF-β1, INF-γ, and IL-10 showed better normalized cognitive performance. Additionally, the Alower allele of INF-γ +874T > A was related to worse functional performance in CI, while the Alower allele of TNF-α -308G > A was associated with better cognitive and functional scores in the CIND group. Our findings suggest a potential role for certain cytokine SNPs in the development of CIND and dementia, which may influence the functional and cognitive performance of these patients. Copyright © 2016 John Wiley & Sons, Ltd.

Pro-inflammatory cytokine single nucleotide polymorphisms in Kawasaki disease.

Kawasaki disease (KD) is a systemic vasculitis of children associated with cardiovascular sequelae. Proinflammatory cytokines play a major role in KD pathogenesis. However, their role is both influenced and modified by regulatory T-cells. IL-1 gene cluster, IL-6 and TNF-α polymorphisms have shown significant associations with some vasculitides. Herein we investigated their role in KD. Fifty-five patients with KD who were randomly selected from referrals to the main pediatric hospital were enrolled in this case-control study. Single nucleotide polymorphisms (SNPs) of the following genes were assessed in patients and 140 healthy subjects as control group: IL-1α at -889 (rs1800587), IL-1β at -511 (rs16944), IL-1β at +3962 (rs1143634), IL-1R at Pst-I 1970 (rs2234650), IL-1RN/A at Mspa-I 11100 (rs315952), TNF-α at -308 (rs1800629), TNF-α at -238, IL-6 at -174 (rs1800795) and IL-6 at +565. Twenty-one percent of the control group had A allele at TNF-α -238 while only 8% of KD patients had A allele at this position (P = 0.003, OR [95%CI] = 0.32 [0.14-0.71]). Consistently, TNF-α genotype GG at -238 had significant association with KD (OR [95% CI] = 4.31 [1.79-10.73]). Most controls carried the CG genotype at IL-6 -174 (n = 93 [66.9%]) while GG genotype was the most common genotype (n = 27 [49%]) among patients. Carriers of the GG haplotype at TNF-α (-308, -238) were significantly more prevalent among the KD group. No association was found between IL-1 gene cluster, allelic or haplotypic variants and KD. TNF-α GG genotype at -238 and GG haplotype at positions -308 and -238 were associated with KD in an Iranian population.