IL-10 Genotypes Research Articles

Association between polymorphisms in the interleukin-10 gene and risk of abdominal aortic aneurysm

In this case-control study, we attempted to investigate the role of three common single nucleotide polymorphisms (SNPs; -1082G/A rs1800896, -819T/C rs1800871, and -592A/C rs1800872) in the IL-10 gene in the development of abdominal aortic aneurysm in a Chinese population. Three hundred and eighty-one patients with abdominal aortic aneurysm and age- and gender-matched healthy controls (N = 381) were collected between March 2012 and March 2014. The IL-10 -1082G/A, -819T/C, and -592A/C polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Logistic regression analyses revealed that the AA genotype of IL-10 -1082G/A was associated with an increased risk of abdominal aortic aneurysm compared to the GG genotype in a codominant model [odds ratio (OR) = 1.64, 95% confidence interval (CI) = 1.04-2.60]. Moreover, the GA+AA genotype was correlated with an elevated risk of abdominal aortic aneurysm compared to the GG genotype in a dominant model (OR = 1.34, 95%CI = 1.01-1.79). In conclusion, the results of our study suggested that the A allele of IL-10 -1082G/A is significantly associated with the development of abdominal aortic aneurysm compared to the wide-type genotype.

Analysis of IFN-γ (+874 A/T) and IL-10 (-1082 G/A) genes polymorphisms with risk of schizophrenia.

Schizophrenia is a sophisticated mental disability which has affected nearly1.1% of people all over the world. According to recent researches, the key proteins triggered in the immune system are cytokines which might also be taking part in the pathogenesis of schizophrenia. The aim of this study was to evaluate the relationship between the -1082G/A and +874T/A polymorphisms of IL-10 and IFN-γ genes, respectively, in patients with schizophrenia. Materials and Methods: Total of 94 schizophrenic patients and 97 individuals as control samples were enrolled in this study. All samples were genotyped by amplification mutation refractory system-polymerase chain reaction (ARMS PCR) for candidate SNPs in IFN-γ and IL-10 genes. Results: No significant association was found among various genotypes of IFN-γ and IL-10 in selected SNPs with risk of schizophrenia, As well as there was no significant variation in allelic frequency of IFN-γ and IL-10 genes with the risk of disease. Conclusion: These data suggest that the -1082G/A of IL-10 and +874T/A IFNγ genes are not involved in the development of schizophrenia risk. To validate of this data, suggesting more studies in diverse populations with larger sample size.

Cytokines Polymorphisms and Relationship with Cytokine Expression in Sickle Cell Disease

Sickle cell disease (SCD) is a chronic inflammatory condition, even in steady state, as indicated by elevated levels of inflammatory cytokines and increased Th17 responses, compared with healthy controls. These inflammatory pathways may be directly regulated by genetic polymorphisms and could be associated to different outcomes of the disease. High levels of a number of different circulating cytokines were found in SCD patients in several studies, and changes in the cytokine balance in SCD patients are an important risk factor for the occurrence of clinical events. Moreover, inter-patient variations in cytokine levels could be attributed to gene polymorphisms. To investigate cytokine polymorphisms and their association with cytokines expression we evaluated the IL4 intron3 VNTR (genotypes 1.1, 1.2, 2.2, 2.3), IL4T590C/T, IL6174G/C and TNFA308A/G polymorphisms and their correlation with TGFB, IL-4, IL-6 and IL-10 expression in steady-state SCD patients.Methods. Fourth-nine patients (24 male and 25 female; 39.8 ± 9.59 years) with SCD and 28 (22 male and 6 female; 35.5 ± 10.2 years) healthy blood donors were evaluated. The polymorphisms were performed by PCR-RFLP analysis described as [individuals (genotype frequencies)] and the expression of TGFB, IL-4, IL-6 and IL-10 by q-PCR expressed as [median (max-min)].Results. A higher frequency of 1.2, 2.2 and 2.3 genotypes was found in SCD patients compared with normal controls [34(0.69) vs 12 (0.44), P=0.03]; higher expression of IL-4 was found in the ones carrying the 1.1 genotype [0.31 (2.53-0.01) vs 0.05 (0.95-0.0), P=0.047] and although no differences were found in the IL4T590C/T, IL6174G/C and TNFA308A/G polymorphism frequencies, a significantly greater expression of TGFB, IL6 and IL10 was observed in the patients cohort compared to normal individuals [1.55 (9.02-0.0) vs 0.97 (5.46-0.0), P=0.019]; [0.18 (45.45-0.0) vs 0.0 (8.14-0.0), P=0.03] and [0.98 (22.84-0.0) vs 0.0 (9.95-0.0), P<0.001, respectively]. All the genotype frequencies are consistent with Hardy-Weinberg equilibrium.Conclusion: A unique distribution of IL-4 genotypes was observed in our cohort of patients and controls, probably related to the miscellaneous ethnic background of our population. The highest prevalence of the IL4intron3 polymorphism in sickle cell patients suggests a less secretory phenotype associated with increased expression of inflammatory cytokines. IL-4 plays an important role in tissue adhesion and inflammation, including induction of adhesion molecules on vascular endothelial cells and could be responsible for a more “inflammatory” phenotype. Despite the small number of patients enrolled, our study brings insights and new data regarding the deregulation in immune system affecting SCD patients and this information must be investigated in larger cohorts, and may help to better characterize individual variations in immune responses and new markers for disease morbidity. DisclosuresNo relevant conflicts of interest to declare.

P-179 Assessment of Allelic and Genotypic Distribution of IL-6 and IL-10 Cytokine Genes in Ulcerative Colitis

Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD) and is often confused with Irritable bowel Syndrome (IBS). Ulcerative colitis is treated as an autoimmune disease. A number of cytokines have been implicated in chronic inflammatory lesions of UC. It has been reported that inflammatory cytokines play important role in the development of the disease. The production of Il 10 presents important interindividual variations regulated by gene polymorphism within the promoter region. Studies have found that the inflamed mucosa from patients with UC revealed the increased expression and link between polymorphism of pro inflammatory cytokine IL 6. The aim of present study is to evaluate the role of cytokines IL-6 (174G/C) and IL-10 (1082G/A, -819C/T, -592C/A) gene polymorphism in UC and IBS patients. In this study we enrolled 56 patients of IBS, 36 patients of UC and 16 healthy controls (HC). Blood samples were obtained after informed consent for DNA isolation. PCR for IL 10 (-1082G/A, -819C/T, -592C/A) followed by restriction digestion using enzyme Mnl1, RsaI and MaeIII was done. For IL-6 (174G/C) PCR was done using ARMS PCR. Standard protocol has been followed for PCR and RFLP. The PCR products obtained were analysed on 2% agarose gel. Genotypic study of IL-10-1082G/A IBS, UC patients and HC showed dominance of AA genotype having 57.1%, 61.1% and 62% respectively. AG genotype was found 28.6% in IBS, 22.2% in UC and 12.5% in HC and GG genotype was found to be least in all the 3 groups having 14.3% in IBS, 16.7 in UC and 25% in HC. For IL-10-819 genotype maximum number of 50% of healthy controls followed by 39% of IBS showed CC genotype whereas 57% of UC patients had CT genotype. In genotype IL-10-592C/A majority of IBS (64.3%) followed by UC patients (44%) and HC (25%) showed AA genotype. Whereas IL-6 (174G/C) genotype was found to be 72.2% in UC and 69.64% in IBS patients and 75% in HC were GG genotype. Distribution of allelic frequency for IL10 (1082A/G), allele A was higher 71.43%, 75.0% and 68.75 in IBS, UC and HC respectively. In IL10 (819C/T) allele C was found to be higher in IBS (58.03%) and HC (62.5%) while T allele was higher in 61.12% in UC. In IL 10 (592C/A) allele A was higher in IBS (74.1%) and UC (63.88%) while allele C was higher in HC (56.25%). Whereas in IL 6 (174G/C) allele G was higher in all the study group having 83.33% in UC, 82.14% in IBS and 85.93% in HC. Results indicate AA genotype (low producer) of anti inflammatory cytokines IL-10 in patients with UC and IBS and A allele of IL 10 (592) showed significantly higher association. For IL-6 we found that the IBS and UC patients showed almost equal genotypic distribution and higher G allele frequency.

GENETICS OF INTERLEUKIN 6 AND SELENOPROTEIN S THAT HAVE A ROLE IN INFLAMMATION AND CORONARY ARTERY DISEASE

Coronary artery disease (CAD) is inflammatory and caused by genetic/environmental factors. Interleukin (IL) 6 is a pro-inflammatory cytokine implicated in CAD. Selenoprotein S (SelS) has recently been implicated in inflammation...

Pro- and anti-inflammatory cytokine gene single-nucleotide polymorphisms in inflammatory bowel disease.

Anti-inflammatory cytokines have an important role in disease, tumour and transplant processes. Alterations in the regulation of several cytokines have been implicated in a variety of inflammatory disorders, including IBD (inflammatory bowel disease) [Crohn's disease (CD) and ulcerative colitis (UC)]. Cytokine polymorphisms are also known to affect the level of gene expression. Thus, the aim of this study was to determine the relationship between cytokine polymorphisms and the IBD pathologies in a Spanish population. Polymorphisms analysis was performed using PCR-SSOP using a microbeads luminex assay. The following polymorphisms were determined: TNFα [-238G/A (rs361525) and -308G/A (rs1800629)], IFNγ [+874A/T (rs62559044)], TGFβ [+869C/T (rs1982073) and +915G/C (rs1800471)], IL10 [-1082A/A (rs1800896), -592A/C (rs1800872), -819C/T (rs1800871)], IL6 [-174C/G (rs1800795)], IL12p40 [3'UTR -1188A/C (rs3212227)], IL1α [-889C/T (rs1800587)], IL1β [-511C/T (rs1143634) and +3962C/T (rs1143633)], IL1R [Pst-1 1970C/T] and IL1RA [Mspa-1 11100C/T]. No statistical differences in TNFα, IFNγ, TGFβ, IL10, IL6, IL1α, IL1β, IL1R and IL1Ra genotypes and allele distributions between the IBD groups and healthy controls were found. However, we observed significant differences in the 3'UTR -1188A/C polymorphism of IL12p40. So -1188A allele was increased in patients with UC and the -1188C allele (high IL12p40 production) was increased in patients with CD with respect to controls. These data are in concordance with the fact that CD has been shown to be associated with a Th1 T-cell-mediated inflammation model and high IL12/IFNγ production at histological affected sites. These data suggest that cytokine polymorphisms in TNFα, IFNγ, TGFβ, IL10, IL6 and IL1α, IL1β, IL1R and IL1Ra cytokine gene do not seem to be relevant in IBD susceptibility and IL12p40 3'UTR -1188A/C polymorphism seems to be associated with a differential IBD development.

Role of cytokine gene (interferon-γ, transforming growth factor-β1, tumor necrosis factor-α, interleukin-6, and interleukin-10) polymorphisms in the risk of oral precancerous lesions in Taiwanese

Oral squamous cell carcinoma can be preceded by some benign oral lesions with malignant potential, including leukoplakia, erythroplakia, oral lichen planus, and oral submucous fibrosis. There are different degrees of inflammatory cells infiltration in histopathology. Inflammatory cytokines may play a pathogenic role in the development of oral precancerous lesions (OPCLs). Genetic polymorphisms of cytokine-encoding genes are known to predispose to malignant disease. We hypothesized that the risk of OPCLs might be associated with cytokine gene polymorphisms of interferon (IFN)-γ, transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10. In the present study, 42 OPCL patients and 128 controls were analyzed for eight polymorphisms in five different cytokine genes [IFN-γ (+874 T/A), TGF-β1 (codons 10 T/C and 25 G/C), TNF-α (−308 G/A), IL-6 (−174 G/C), and IL-10 (−1082 A/G, –819 T/C, and −592 A/C)]. Cytokine genotyping was determined by the polymerase chain reaction sequence-specific primer technique using commercial primers. Allele and genotype data were analyzed for significance of differences between cases and controls using the Chi-square (χ2) test. Two-sided p < 0.05 were considered to be statistically significant. A series of multivariate logistic regression models, adjusted for age, sex, betel quid chewing, alcohol consumption, and smoking, was constructed in order to access the contribution of homozygous or heterozygous variant genotypes of polymorphisms. The TNF-α (−308) polymorphism was significantly associated with OPCLs. There were significant differences in the distribution of AA, GA, and GG genotypes between OPCL patients and controls (p = 0.0004). Patients with the AA or GA genotype had a 3.63-fold increased risk of OPCLs. The TGF-β1 (codon 10 and 25) polymorphism was also significantly associated with OPCLs (p < 0.001). The IL-6 polymorphism was significantly associated with OPCLs. There are significant differences in the distribution of CC, GC, and GG genotypes between OPCL patients and controls (p < 0.001). Patients with the CC or GC genotype had a 35- or 20.59-fold increased risk of OPCLs. There were no significant differences in the distribution of IL-10 and IFN-γ genotypes between different groups of control individuals and OPCL patients. The IL-6, TGF-β1, and TNF-α gene polymorphisms may have a significant association with the development of OPCLs.

IL6 genotype, tumour ER-status, and treatment predicted disease-free survival in a prospective breast cancer cohort.

BackgroundIn breast cancer, high levels of the inflammatory cytokine interleukin-6 (IL-6) have been associated with disease-free survival and treatment resistance. Increased serum levels of IL-6 have been correlated with increased levels of NF-κβ and aromatase expression in adipose tissue. Several IL6 single nucleotide polymorphisms have been associated with breast cancer prognosis, but the impact may differ depending on tumour oestrogen receptor (ER) status. This translational study investigated the association between IL6 genotypes, ER-status, and treatment on the risk of early events among breast cancer patients.MethodsThe study included 634 25- to 99-year-old primary breast cancer patients in Sweden from 2002–2008. Genotyped IL6 single nucleotide polymorphisms rs1800797, rs1800796, rs1800795, and rs2069849 were analysed separately and as diplotypes. Disease-free survival was assessed for 567 patients. Clinical data, patient-, and tumour-characteristics were obtained from questionnaires, patient charts, population registries, and pathology reports.ResultsThe median follow-up time was 5.1 years. IL6 diplotype was not associated with early events for all 567 patients, but AGCC/AGCC diplotype-carriers with ER-negative tumours had an increased risk, (adjusted Hazard Ratio (HR) = 5.91, 95% CI: 1.28–27.42). Any C-carriers (rs1800795) with ER-negative tumours had a higher risk of early events than GG-carriers with ER-negative tumours, (adjusted HR = 3.76, 95% CI: 1.05–13.43), particularly after radiotherapy (adjusted HR = 7.17, 95% CI: 1.16–32.28). Irrespective of ER-status, chemotherapy-treated Any C-carriers had a higher risk of early events than GG-carriers (adjusted HR = 3.42, 95% CI: 1.01–11.54).ConclusionsThe main finding of the present study was that IL6 genotype was strongly associated with early events among patients with ER-negative tumours, particularly among radiotherapy-treated patients, and among chemotherapy-treated patients irrespective of ER-status. The high risk for early events observed in these subgroups of patients suggests that combined information on IL6 genotype, tumour ER-status, and breast cancer treatment may represent a tool for identifying patients who require more personalised treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-759) contains supplementary material, which is available to authorized users.

Gene polymorphisms of IL-10 and MxA in responders and non-responders to interferon therapy in HCV Egyptian patients genotype 4.

Hepatitis C virus (HCV) is a major cause of chronic liver disease, with about 170 million people infected worldwide. The standard regimen for treatment of HCV consists of a combination of pegylated interferon with ribavirin. Failure of interferon-α treatment in patients with chronic HCV infection remains a challenging obstacle. Both viral and host environmental factors have been implicated in reducing responsiveness to IFN-α therapy. Host genetic diversity is also believed to contribute to the different clinical outcomes in HCV infection. The objective of the study was to investigate the association of both IL-10 (-819 and -592) and MxA (-88 and -123) single-nucleotide polymorphisms (SNPs) of the promoter regions, with response to interferon (IFN) therapy in Egyptian patients infected with HCV genotype 4. Polymorphisms of both genes in 85 HCV patients and 100 controls were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The frequency of SNP was compared between sustained responders (n = 52) and non-responders (n = 33), as determined by biochemical and virological response to IFN and ribavirin combined therapy. The frequency of the -819T/T and the -592A/A genotypes of IL-10 was significantly higher among responders compared to non-responders (51.92 vs 39.4 %, P = 0.03; 51.92 vs 42.42 %;P = 0.046 respectively). The G/G genotype at position -88 of the MxA gene was significantly lower in responders than in non-responders (25 vs 75.76 %, P = 0.046), whereas heterozygotes (G/T) were more likely responders (65.38 vs 18.18 %, P = 0). The -123C/A genotype was significantly associated with responders (48.08 vs 30.30 %, P = 0.014). Findings suggest that homozygosity for both -819T/T and -592A/A polymorphisms of IL-10 gene and that heterozygosity for both -88G/T and -123C/A polymorphisms of the MxA gene are important host factors that influence the response to IFN therapy in patients with chronic HCV infection.

PP272-SUN: Risk Factors Associated With Underfeeding in Critically Ill Children

status. All the 283 hospitalized children divided into two groups, as mentioned, underwent IL-6 190 C/T gene polymorphism testing, measurement of some anthropometric parameters (MUAC-mid-upper arm circumference and TSTtricipital skinfold thickness), and biochemical evaluation (protein, albumin). Results: It was found that CT heterozygotes were more frequent in the malnutrition group for the IL-6 190 gene (p = 0.003). In our group of children with malnutrition, BMI, MUAC, TST and low serum albumin levels correlated with CT genotype of IL-6 190 gene, whereas the TT genotype of these gene was a protective factor for malnutrition (p = 0.0001). Conclusion: IL-6 190 TT genotype seem to have a protective function for malnutrition; further studies are needed to clarify the role of these polymorphisms in child malnutrition. This work was supported by Internal Research Grants (Project No. 19/11.12.2013) from the University of Medicine and Pharmacy Tirgu Mures, Romania.

MOLECULAR GENETIC ANALYSIS OF INTERLEUKIN 4 GENE POLYMORPHISM AMONG TELEUTIANS, SHORIANS, AND CAUCASIANS IN KEMEROVO REGION

An interleukin 4 polymorphism has been studied in Teleutians, Shorians, and Caucasoids living in the Kemerovo Region. The groups of Teleutians and Caucasoids are characterised with even or close-to-even distribution of the IL-4 alleles. The most widespread genotype in populations of Teleutians and Caucasoids was the 2R/3R heterozygosity, and 3R/3R proved to be the mostly rare. These data are indicative for mixing processes among Teleutians in the Kemerovo Region and Siberian Caucasoids. The major IL-4 genotype in Shorian population was 3R/3R, and the heterozygotic genotype 2R/3R took the second position.

IL-6(-572/-597) polymorphism and expression in HBV disease chronicity in an Indian population.

This study evaluated the association among IL-6(-572) and IL-6(-597) genotypes, haplotypes, mRNA, and protein levels with hepatitis B virus (HBV)-Hepatocellular carcinoma (HCC) risk in India. For this, 403 participants (153 controls, 61 inactive HBV-carriers, 65 chronic-active HBV patients, 63 HBV-cirrhotics, and 61 HBV-HCC participants) were enrolled in the study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), ELISA, and RT-PCR methods were used for assessing polymorphism, protein, and the mRNA levels, respectively, of IL-6. The study revealed that the IL-6(-572) GC genotype shared a positive association with hepatitis among controls, and a negative association with cirrhosis and consequent HCC development among carriers. However, the CC genotype shared a significant negative association with cirrhosis among controls and carriers. The IL-6(-597G>A), GA genotype acted as a potential protective factor for hepatitis, cirrhosis, and subsequent HCC development among carriers. The GA and CG haplotypes acted as a vital risk factor for HCC among controls and carriers. On the contrary, the CA haplotype was found to be a potential protective factor for HCC among carriers. Besides, the IL-6 levels significantly increased with cirrhosis development, as compared to carriers and hepatitis subjects. These preliminary findings indicate a potential role of IL-6(-572/-597) genotypes in HBV disease pathogenesis in an Indian population.

Use of floss/interdental brushes is associated with lower risk for new cardiovascular events among patients with coronary heart disease.

Periodontitis has been found to be associated with coronary heart disease (CHD) and stroke. However, only little is known about whether periodontitis and associated confounders are associated with new cardiovascular events among patients with CHD. A total of 942 inpatients with CHD were examined regarding periodontitis, oral care habits, bacteria in the subgingival biofilm and the expression of interleukin-(IL)-6 c. (coding DNA)-174 genotypes (rs 1800793) to determine whether these confounders are associated with new cardiovascular events within a 1-year follow-up period. Adjusted hazard ratios (HR) with respect of age, gender, smoking, body mass index, use of aids for interdental hygiene, plaque index, occurrence of severe periodontitis and further internal diseases such as diabetes, hypertension, dyslipoproteinemia, number of missing teeth, serological parameters and IL-6 genotypes were generated with Cox regression. In all, 941 cardiovascular patients completed the 1-year follow up and 7.3% of the patients achieved the primary endpoint (myocardial infarction: 2.1%, stroke/transient ischemic attack: 1.8%, cardiovascular deaths: 3.4%). Patients who reported practicing interdental cleaning were younger, less likely to be male or to have severe periodontitis, had a reduced tobacco exposure, had fewer missing teeth, less indices for plaque and bleeding on probing and a significant decreased adjusted risk for new cardiovascular events (HR=0.2, CI 0.06-0.6, p=0.01) than those patients with CHD who did not report practicing interdental cleaning. We did not obtain significant increased HR for patients with severe periodontitis (HR=1.2, CI 0.7-2.1, p=0.53), carriers of the IL-6 genotypes GC or CC (HR=1.4, CI 0.8-2.5, p=0.24) and did not find a significant association between the number of detected various oral species and the incidence of the combined endpoint (HR=0.9, CI 0.8-1.01, p=0.07). These findings suggest that flossing and brushing of interdental spaces might reduce the risk for new cardiovascular events among patients with CHD. The hypothesis that interdental cleaning per se reduces the risk of new cardiovascular events should be examined in an interventional study.

Polymorphisms in IL-6, IL-10, TNF-α, IFN-γ and TGF-β1 Genes and Susceptibility to Acute Otitis Media in Early Infancy

Genetic susceptibility has a major role in the pathogenesis of acute otitis media (AOM). In the present study, we investigated the variability of 5 cytokine genotypes as related to susceptibility and outcome of AOM in early infancy. Single nucleotide polymorphisms in IL-6 (-174 G→C), IL-10 (-592 C→A, -819 C→T and -1082 G→A), TNF-α (-308 G→A), IFN-γ (+874 A→T) and TGF-β1 (codon 10 C→T; codon 25 G→C) genes were investigated and related to clinical course and outcome in 96 infants younger than 9 months with AOM. Compared with wild genotypes, IL-10 (-592, -819 and -1082) and TGF-β1 (codon 10) genotypes carrying the alternative allele were related to more AOM episodes (P < 0.0001, P < 0.0001, P < 0.0001 and P = 0.002, respectively) and the need for tympanostomy tubes. Furthermore, IL-10 (-1082) and TGF-β1 (codon 10) genotypes carrying the alternative allele were related to later onset of first AOM episode than wild-type genotypes (P = 0.007 and P = 0.039, respectively). No relationship was found about AOM complications. Our findings suggest that IL-10 and TGF-β1 genotypes are related to the age of AOM onset, multiple AOM episodes and insertion of tympanostomy tubes, pointing to the involvement of anti-inflammatory cytokines in AOM during infancy.

Polymorphisms of inflammation-related genes and colorectal cancer risk: a population-based case-control study in China.

The previous studies found that chronic inflammation related to an increased risk of colorectal cancer (CRC). This study aims to explore the associations of polymorphisms in inflammation-related genes (IL10, IL10RA, IL6R, TNFRSF1A, TNFRSF1B, LTA and IL4) and their interactions with the risk of colorectal cancer among Chinese population. A population-based case-control study including 299 cases and 296 controls was conducted from January 2001 to December 2009. Multivariate unconditional logistic regression was used to analyse the association of nine SNPs in inflammation-related genes with the risk of CRC, colon cancer and rectal cancer, respectively. Generalized multifactor dimensionality reduction (GMDR) was implemented to explore the gene-gene interactions among all SNPs on CRC. A decreased risk of colorectal cancer in subjects with rs1800872 AC genotype of IL10 (OR = 0.643, 95%CI = 0.453, 0.912) or AC/CC genotype (OR = 0.636, 95%CI = 0.457, 0.885) was observed, compared with those with AA genotype. Meanwhile, similar associations were observed between rs1800872 and rectal cancer. Additionally, in rs1061624 of TNFRSF1B gene, AG genotype (OR=0.566; 95% CI= 0.362, 0.885) and AG/GG genotype (OR=0.638; 95% CI=0.420, 0.971) were significantly associated with a decreased risk of rectal cancer, respectively. Our findings indicated that mutants in IL10 and TNFRSF1B genes may change the CRC risk. However, there is no interaction between inflammation-related genes on CRC risk.

The role of IL-6 572 C/G, 190 C/T, and 174 G/C gene polymorphisms in children's obesity.

The aim of this study was to establish the correlations between the polymorphisms of the genes interleukin (IL)-6 572, 190, and 174 in obese children. We assessed 222 hospitalized children divided into two groups: group I (control) included 110 patients with normal nutritional status, and group II consisted of 102 obesity patients. The two groups underwent IL-6 572 C/G, 190 C/T, and 174 G/C polymorphism testing, measurement of anthropometric parameters (mid-upper arm circumference and tricipital skinfold thickness), and paraclinical evaluation (protein, albumin, leptin, adiponectin, and vascular endothelial growth factor (VEGF)). We observed that phenotype CC was more frequent in obese children for IL-6 572 (p = 0.0001), whereas CG heterozygotes were more frequent in the obese group for the IL-6 190 gene (62.7 %; p = 0.0001). Leptin was dependent on IL-6 572 and IL-6 174 gene polymorphisms and albumin, whereas adiponectin was dependent on the IL-6 174 gene polymorphism. Body mass index (BMI), mid-upper arm circumference (MUAC), and tricipital skinfold thickness (TST) serum albumin levels correlated with C allele carriers of the IL-6 572 and IL-6 190 genes in children with obesity, whereas the CC genotype of IL-6 174 was a protective factor for obesity. Obesity is most frequently associated in children with IL-6 174 C allele carriers and with IL-6 190 C allele carriers.

Interleukin-10 Gene Polymorphisms in Recurrent Aphthous Stomatitis

Recurrent aphthous stomatitis (RAS) is a common oral inflammatory disease with unknown etiology in which the immune system seems to have a role in oral tolerance. Interleukin (IL)-10 is a cytokine synthesis inhibitory factor. Single nucleotide polymorphisms (SNPs) of IL10 gene could alter this cytokine production. The aim of this study was to investigate frequencies of IL10 alleles and genotypes in a group of individuals with RAS. Genomic DNA of 60 Iranian patients with RAS were typed for IL10 gene (C/A −1082, C/T −819, and C/A −592), using PCR-SSP method. Frequency of each allele and genotype was compared to control group.A significantly higher frequencies of the T allele at position −819 (p = 0.006) and the A allele at position of −592 (p < 0.001) were found in the patients with RAS group, when compared to the controls. IL10 GA genotype at position −1082 (p = 0.007), CA genotype at position −592 (p = 0.001), and CT genotype at position −819 (p = 0.001) were significantly higher in the RAS patients. The results of this study suggest that certain SNPs of IL10 gene have association with predisposition of individuals to RAS. However, further multicenter studies should be conducted to confirm the results of this study.

Association of Cytokine Gene Polymorphisms in Patients with Tuberculosis and Their Household Contacts

Cytokine gene polymorphisms are known to be associated with functional differences in cytokine regulation and may affect host susceptibility to tuberculosis (TB). Contacts are important group in developing tuberculosis infection and are 10-60 times more likely to develop TB than general population. The present study was carried out in patients with TB (N=176), their household contacts (HHC; N=155) from Free Chest TB Clinic PPM DOTS (1TU) covering 500,000 population at Mahavir Hospital and Research Centre, Hyderabad, and healthy controls (HC; N=170) also included. The association of single-nucleotide polymorphisms (SNPs) in the promoter region of TNF-α (-308G/A), IL-2 (-330T/G), IL-4 (-589C/T) and in exon region of TGF-β1 (+869T/C) genes was assessed by ARMS & PCR-RFLP using specific primers in the above-mentioned subjects. The differences in allelic or genotypic frequencies of TNF-α (-308G/A) between patients, their HHC and HC were not statistically significant (P>0.05). IL-2 (-330T/G) TG genotype was significantly different between patients, HHC compared to HC (P<0.002, OR-1.997, 95%CI-1.260-3.168, P<0.03, OR-1.602, 955CI-1.003-2.561).IL-4 (-589C/T) CC genotype was significantly different between patients and HC (P<0.03, OR-1.791, 95%CI-1.009-3.189) as well as between HHC and HC at P<0.0001, OR-2.56, 95%CI-1.448-4.545. In addition, the TGF-β 1 (+869T/C) TC genotype was significantly associated with susceptibility to tuberculosis in patients when compared against HC(P<0.0001, OR-3.416, 95%CI-2.063-5.670) and HHC (P<0.0001, OR-2.357, 95%CI-1.439-3.868), respectively.MDR analysis indicated that TT genotype of TGF-β1 with TT and CT genotypes of IL-4 showed high risk with GA, TT genotypes of TNF-α, IL-2, respectively. Our results suggest that IL-2 (-330T/G), IL-4 (-589 C/T) and TGF-β1 (+869T/C) gene polymorphisms may be associated with TB susceptibility.

Pro-Inflammatory Interleukin-1 Genotypes Potentiate the Risk of Coronary Artery Disease and Cardiovascular Events Mediated by Oxidized Phospholipids and Lipoprotein(a)

The aim of this study was to assess the influence of pro-inflammatory interleukin (IL)-1 genotype status on the risk for coronary artery disease (CAD), defined as >50% diameter stenosis, and cardiovascular events mediated by oxidized phospholipids (OxPLs) and lipoprotein (Lp) (a). OxPLs are pro-inflammatory, circulate on Lp(a), and mediate CAD. Genetic variations in the IL-1 region are associated with increased inflammatory mediators. IL-1 genotypes, OxPL on apolipoprotein B-100 (OxPL/apoB), and Lp(a) levels were measured in 499 patients undergoing coronary angiography. The composite genotype termed IL-1(+) was defined by 3 single-nucleotide polymorphisms in the IL-1 gene cluster associated with higher levels of pro-inflammatory cytokines. All other IL-1 genotypes were termed IL-1(-). Among IL-1(+) patients, the highest quartile of OxPL/apoB was significantly associated with a higher risk for CAD compared with the lowest quartile (odds ratio [OR]: 2.84; p = 0.001). This effect was accentuated in patients age ≤60 years (OR: 7.03; p < 0.001). In IL-1(-) patients, OxPL/apoB levels showed no association with CAD. The interaction was significant for OxPL/apoB (OR: 1.99; p = 0.004) and Lp(a) (OR: 1.96; p < 0.001) in the IL-1(+) group versus the IL-1(-) group in patients age ≤60 years but not in those age >60 years. In IL-1(+) patients age ≤60 years, after adjustment for established risk factors, high-sensitivity C-reactive protein, and Lp(a), OxPL/apoB remained an independent predictor of CAD. IL-1(+) patients above the median OxPL/apoB presented to the cardiac catheterization laboratory a mean of 3.9 years earlier (p = 0.002) and had worse 4-year event-free survival (death, myocardial infarction, stroke, and need for revascularization) compared with other groups (p = 0.006). Our study suggests that IL-1 genotype status can stratify population risk for CAD and cardiovascular events mediated by OxPL. These data suggest a clinically relevant biological link between pro-inflammatory IL-1 genotype, oxidation of phospholipids, Lp(a), and genetic predisposition to CAD and cardiovascular events.

Very Early Onset Inflammatory Bowel Disease Associated with Aberrant Trafficking of IL-10R1 and Cure by T Cell Replete Haploidentical Bone Marrow Transplantation

Loss-of-function mutations in IL10 and IL10R cause very early onset inflammatory bowel disease (VEO-IBD). Here, we investigated the molecular pathomechanism of a novel intronic IL10RA mutation and describe a new therapeutic approach of T cell replete haploidentical hematopoietic stem cell transplantation (HSCT). Clinical data were collected by chart review. Genotypes of IL10 and IL10R genes were determined by Sanger sequencing. Expression and function of mutated IL-10R1 were assessed by quantitative PCR, Western blot analysis, enzyme-linked immunosorbent assays, confocal microscopy, and flow cytometry. We identified a novel homozygous point mutation in intron 3 of the IL10RA (c.368-10C > G) in three related children with VEO-IBD. Bioinformatical analysis predicted an additional 3' splice site created by the mutation. Quantitative PCR analysis showed normal mRNA expression of mutated IL10RA. Sequencing of the patient's cDNA revealed an insertion of the last nine nucleotides of intron 3 as a result of aberrant splicing. Structure-based modeling suggested misfolding of mutated IL-10R1. Western blot analysis demonstrated a different N-linked glycosylation pattern of mutated protein. Immunofluorescence and FACS analysis revealed impaired expression of mutated IL-10R1 at the plasma membrane. In the absence of HLA-identical donors, T cell replete haploidentical HSCT was successfully performed in two patients. Our findings expand the spectrum of IL10R mutations in VEO-IBD and emphasize the need for genetic diagnosis of mutations in conserved non-coding sequences of candidate genes. Transplantation of haploidentical stem cells represents a curative therapy in IL-10R-deficient patients, but may be complicated by non-engraftment.