IL-6 Variants Research Articles

AB0471 Efficacy and Tolerability of A Homeopathic Medication Incena in Patients with Rheumatoid Arthritis (Randomized, Double-Blind, Placebo-Controlled Study)

BackgroundSymptomatic therapy of rheumatoid arthritis (RA) such as non-steroidal anti-inflammatory medications (NSAIDs) can be accompanied by serious side effects.Objectivesto assess anti-inflammatory, analgesic, immunomodulatory action and tolerability of Incena as an...

IL10 low‐frequency variants in Behçet's disease patients

To explain the missing heritability after the genome-wide association studies era, sequencing studies allow the identification of low-frequency variants with a stronger effect on disease risk. Common variants in the interleukin 10 gene (IL10) have been consistently associated with Behçet's disease (BD) and the goal of this study is to investigate the role of low-frequency IL10 variants in BD susceptibility. To identify IL10 low-frequency variants, a discovery group of 50 Portuguese BD patients were Sanger-sequenced in a 7.7kb genomic region encompassing the complete IL10 gene, 0.9kb upstream and 2kb downstream, and two conserved regions in the putative promoter. To assess if the novel variants are BD- and/or Portuguese-specific, they were assayed in an additional group of BD patients (26 Portuguese and 964 Iranian) and controls (104 Portuguese and 823 Iranian). Rare IL10 coding variants were not detected in BD patients, but we identified 28 known single nucleotide polymorphisms with minor allele frequencies ranging from 0.010 to 0.390, and five novel non-coding variants in five heterozygous cases. ss836185595, located in the IL10 3' untranslated region, was also detected in one Iranian control individual and therefore is not specific to BD. The remaining novel IL10 variants (ss836185596 and ss836185602 in intron 3, ss836185598 and ss836185604 in the putative promoter region) were not found in the replication dataset. This study highlights the importance of screening the whole gene and regulatory regions when searching for novel variants associated with complex diseases, and the need to develop bioinformatics tools to predict the functional impact of non-coding variants and statistical tests which incorporate these predictions.

IL10 Single Nucleotide Polymorphisms are Related to Upregulation of Constitutive IL‐10 Production and Susceptibility to Helicobacter pylori Infection

Helicobacter pylori infection is a strong risk factor for gastric cancer, likely due to the extensive inflammation in the stomach mucosa caused by these bacteria. Many studies have reported an association between IL10 polymorphisms, the risk of gastric cancer, and IL-10 production. The aim of the study was to evaluate the association between IL10 genetic variants, Helicobacter pylori infection, and IL-10 production by peripheral blood leukocytes in children. We genotyped a total of 12 single nucleotide polymorphisms in IL10 in 1259 children aged 4-11years living in a poor urban area in Salvador, Brazil, using TaqMan probe based, 5' nuclease assay minor groove binder chemistry. Association tests were performed by logistic regression for Helicobacter pylori infection and linear regression for IL-10 spontaneous production (whole-blood cultures) including sex, age, and principal components for informative ancestry markers as covariates, using PLINK. Our results shown that IL10 single nucleotide polymorphisms rs1800896 (OR=1.63; 95% CI=1.11-2.39), rs3024491 (OR=1.71; 95% CI=1.14-2.57), rs1878672 (OR=1.79; 95% CI=1.19-2.68), and rs3024496 (OR=1.48; 95% CI=1.05-2.08) were positively associated with Helicobacter pylori infection. Eight single nucleotide polymorphisms were associated with spontaneous production of IL-10 in culture, of which three (rs1800896 and rs1878672, p=.04; rs3024491, p=.01) were strongly associated with infection by Helicobacter pylori. Our results indicate that IL10 variants rs1800896, rs3024491, rs1878672, and rs3024496 are more consistently associated with the presence of anti-H.pylori IgG by inducing increased production of IL-10. Further studies are underway to elucidate the role of additional genetic variants and to investigate their impact on the occurrence of gastric cancer.

Genetic variants and risk of cervical cancer: epidemiological evidence, meta‐analysis and research review

More than 200 articles have been published in the past 20years on associations between genetic variants and risk of cervical cancer but the results have generally been inconsistent. To provide a synopsis of the current understanding of the genetic architecture of the risk of cervical cancer by conducting a systematic review and meta-analysis. We conducted a systematic literature search by a two-stage strategy using PubMed and other databases on or before 31 March 2012. Cross-sectional, case-control or cohort studies about the relationship between genetic variants and cervical cancer were included. Study outcomes were presented as odds ratios (ORs) with a 95%confidence interval.We did the meta-analysis for genetic variants which had at least three data sources and for which the significant associations were assessed using the Venice criteria. A total of 5605 publications were screened, of which 286 were eligible. Meta-analysis was conducted for 58 variants in 25 genes or loci. Fourteen variants in 11 genes or loci could increase the risk of cervical cancer and five variants in three genes or loci could decrease the risk. The epidemiological evidence of the association was graded as strong for four variants in CTLA4 and HLA DQB1, moderate for five variants in IL-1B, IL-10, XRCC3 and HLA DQA1, and weak for 10 variants. Many genetic variants were associated with the risk of cervical cancer as supported by the epidemiological evidence in this meta-analysis.

Cytokine Gene Considerations in Giant Cell Arteritis: IL10 Promoter Polymorphisms and a Review of the Literature

Polymorphisms of cytokine genes have been investigated as susceptibility markers of giant cell arteritis (GCA). Here, we have reviewed the evidence to date and especially addressed the functional consequences of IL10 (-592C/A and -1082A/G) gene polymorphisms and their association with susceptibility to and disease phenotype in GCA. A total number of 71 patients with GCA and 124 age-matched controls were genotyped using allele-specific primers and restriction fragment length polymorphism analysis. As previous studies in GCA showed inconsistent results, a meta-analysis of the existing studies was also conducted by using both fixed and random-effects models. The levels of circulating IL10 and the production of IL10 by peripheral blood mononuclear cells after in vitro stimulation were studied by Cytometric Bead Array. Data showed no significant differences in genotype or allele frequency distribution between patients and controls. The clinical characteristics and prognosis of these patients were also unrelated to the presence of these polymorphisms. However, the meta-analysis found a significant association of IL10 -592C/A polymorphism with susceptibility to GCA (odds ratio 2.205 (95% confidence interval 1.074-4.524); p = 0.031). In both patients and age-matched controls, no differences in circulating IL10 levels or IL10 production were observed depending on the genotypes of the IL10 gene. In conclusion, although our cohort results do not support the impact of IL10 variants in susceptibility or clinical phenotype of GCA patients, the meta-analysis revealed a significant association of -592C/A polymorphism with susceptibility to GCA. In this population, no functional association was found between IL10 gene variants and IL10 production.

Maternal Genetic Variants of IL4/IL13 Pathway Genes on IgE With "Western or Eastern Environments/Lifestyles".

PurposeWe investigated maternal genetic effects of four IL-4/IL-13 pathway genes as well as their interactions with the "Western or Eastern lifestyles/environments" on IgE in Karelian children.MethodsThis study included 609 children and their mothers. Total IgE levels in children and mothers were measured and 10 single nucleotide polymorphisms (SNPs) in IL-4, IL-4Ra, IL-13, and STAT6 were genotyped in mothers and their children.ResultsThe maternal G allele of IL-13 130 (rs20541) was significantly (P=0.001) associated with decreased IgE in children in the Karelian population (Pooling Finnish and Russian children), as well as in Finnish (P=0.030) and Russian children (P=0.018). The IgE levels were significantly (P=0.001) higher in Russian children whose mothers were homozygous for the G allele of the IL-4Ra 50 (rs1805010) SNP than that in Russian children of mothers who were AG heterozygotes or AA homozygotes. After accounting for children's genotypes, we observed interactive effects on children's IgE for maternal IL-13 130 genotypes (P=0.014) and maternal IL-4Ra 50 genotypes (P=0.0003) with "Western or Eastern" lifestyles/environments. With the adjustment for multiple comparisons using a false discovery rate (FDR) of 0.05, the interactive effect of the maternal IL-4Ra50 SNP was significant.ConclusionMaternal genetic variants in IL-4/IL-13 pathway genes, such as IL-13 130 and IL-4Ra50, influenced IgE levels in school children that were independent of the children's genetic effects. These effects differ in "Western or Eastern" environments.

Polymorphism of the cytokine genes (H4, ИМ) and peculiarities of immune response depending on the control over atopic bronchial asthma in children

Background. The aim of this study was to investigate the main indices of humoral and cellular immunity, the levels of cytokines (IL-2, IL-4, IL-10, TNFa) and polymorphism of promoter regions of cytokine genes (IL4 and IL10) in children with atopic bronchial asthma (ABA) with different levels of disease control. Methods. We have analyzed 110 children with ABA - controlled (CABA, n=59) and uncontrolled (UABA, n=51) and healthy children (control group, n=52). Parameters of cellular immunity were determined by fluorescence microscopy using monoclonal antibodies to surface receptors. Parameters of humoral immunity and cytokine levels in the samples of serum were measured by ELISA. Genotyping of single-nucleotide polymorphisms in the IL4 (С-590Т) and IL10 (С597А) genes was performed by PCR. Results. The level of TNFa and the relative amount of CD8+ cells was increased, while the counts of CD3+ cells and the relative amount of CD4+ cells was decreased in UABA as compared to CABA. In CABA, lower concentration of the IL-10 in serum associated with the IL10 A-597 allele was observed. The IL4 T-590 allele tends to be associated with non-controlled ABA. Conclusion. The level of TNFa, and the CD3+, CD4+ and CD8+ cell counts were identified as markers of uncontrolled course of ABA in children. Polymorphic variants of IL4 and IL10 genes can be considered as candidate markers of uncontrolled ABA.

PW03-011 – New Behçet's loci and gene-gene interactions

We previously identified disease-associated common variants in IL10 and IL23R, as well as HLA-B*51, in a Behcet’s disease (BD) genome-wide association study (GWAS) performed with 311,459 SNPs in 1,215 cases and 1,278 controls from Turkey, but the disease-associated variants in these genes do not fully account for the estimated genetic contribution to disease risk.

Preferential Binding to Elk-1 by SLE-Associated IL10 Risk Allele Upregulates IL10 Expression

Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.

Impact of genetic variants of IL-6, IL6R, LRP5, ESR1 and SP7 genes on bone mineral density in postmenopausal Mexican-Mestizo women with obesity

BackgroundSince obesity and osteoporosis present a high genetic predisposition and polymorphisms of IL-6, IL6R, LRP5, ESR1 and SP7 may influence the risk of both diseases, the aim of this study was to analyze the possible association of polymorphisms in these genes, as well as their haplotypes, with BMD variations in postmenopausal Mexican-Mestizo women with grade 2 or grade 3 obesity. MethodsOne hundred eighty unrelated postmenopausal women with grade 2 or grade 3 obesity were included. BMD was measured in total hip and lumbar spine by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Rs1800795 of IL-6, rs2228145 of IL6R, rs3736228 of LRP5, rs9340799 (XbaI) and rs2234693 (PvuII), of ESR1, rs10876432 and rs2016266, of SP7 (and their haplotypes), were studied by real-time PCR allelic discrimination. Deviations from Hardy–Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r2, and haplotype analysis was conducted. ResultsUsing WHO criteria, 54.5% had grade 2 obesity, and 45.5% had grade 3 obesity. Regarding DXA results, 11.1% women had osteoporosis, 41.7% had osteopenia, and 47.2% had normal BMD. Genotype and haplotype analysis showed no significant differences with BMD variations at the lumbar spine, total hip or femoral neck. ConclusionsWe did not find a significant association between the polymorphisms analyzed or their haplotypes and BMD variations in postmenopausal women with obesity. The higher BMD observed in women with obesity could be the result of an adaptive response to the higher loading of the skeleton.

Molecular genetic analysis of polymorphisms pertaining to the susceptibility to chronic asthma in Egyptian patients

BackgroundAsthma is a multifactorial inflammatory disorder that might result from the interaction of multiple genes and environmental factors. Several studies of genetic epidemiology have reported the association of cytokine genes with asthma among various populations. However, the results are inconsistent and inconclusive. ObjectiveTo determine the association of cytokine gene polymorphisms with asthma susceptibility in adult Egyptian cases. SubjectsThe study included, 50 adult Egyptian asthmatic cases with a mean age of 53.62±14.61years in addition to 98 healthy individuals as control. For all participants, DNA was isolated from peripheral blood samples and analyzed for TNF-α-308 G>A, IL-10-1082 G>A, IL-6-174 G>C and IL-1Ra VNTR polymorphisms. ResultsThe comparison between the cases and controls has showed significantly higher frequency of the genotypic polymorphisms: IL-10-1082 AG+GG (dominant mode) (76.1% vs. 91.8%, p=0.01, OR=0.3, 95% CI (0.1–0.7), TNF-α-308 GA+AA (dominant mode) (72.0% vs. 93.9%, p=0.001, OR=0.17, 95% CI=0.06–0.47) and IL-1RA VNTR heterozygous genotype A1A2 (90.0% vs. 58.8%, p=0.0003). Otherwise, compared to controls, cases showed statistically non-significant frequency of genotypes corresponding to IL-6-174 CC+GC vs. GG (dominant mode) (92.0% vs. 94.9%, p=0.5, OR=0.6). ConclusionsThe IL-10, TNF-α and IL-1Ra allelic variants showed a potent association with chronic asthma among Egyptian cases that might be used as markers with a potential impact on prophylactic and or therapeutic measures for asthma control. Whereas the IL-6-174 allelic variants showed no association with chronic asthma among Egyptian cases.

AB0019 A genetic association between juvenile idiopathic arthritis and the il10 polymorphism

BackgroundJuvenile idiopathic arthritis (JIA) is a generic term for arthritis that has an onset before the age of 16 and persists for more than 6 weeks. JIA is probably a...

IL10 and TNF variants and risk of non-Hodgkin lymphoma among three Asian populations

Genetic variation in immune-related genes, such as IL10 and TNF, have been associated with the development of non-Hodgkin lymphoma (NHL) in Caucasian populations. To test the hypothesis that IL10 and TNF polymorphisms may be associated with NHL risk in Asian populations, we genotyped 20 single nucleotide polymorphisms (SNPs) within the IL10 and TNF/LTA loci in three independent case-control studies (2635 cases and 4234 controls). IL10 rs1800871, rs1800872, and rs1800896 were genotyped in all three studies, while 5 of the remaining SNPs were genotyped in two studies, and 12 in a single study. IL10 rs1800896 was associated with B cell lymphoma [per-allele odds ratio (OR)=1.25, 95% confidence interval (CI)1.08-1.45; p trend=0.003], specifically diffuse large B cell lymphoma (DLBCL) (per-allele OR=1.29, 95% CI1.08-1.53; p trend=0.004), as well as T cell lymphoma (per-allele OR=1.44, 95% CI1.13-1.82; p trend=0.003). TNF rs1800629, which was genotyped in only two of our studies, was also associated with B cell lymphoma (per-allele OR=0.77, 95% CI0.64-0.91; p trend=0.003), specifically DLBCL (per-allele OR=0.69, 95% CI0.55-0.86; p trend=0.001). Our findings suggest that genetic variation in IL10 and TNF may also play a role in lymphomagenesis in Asian populations.

Influence of polymorphisms in genes encoding immunoregulatory proteins and metabolizing enzymes on susceptibility and outcome in patients with diffuse large B-cell lymphoma treated with rituximab

We analyzed the allelic distribution of 12 candidate polymorphisms in a large retrospective study of 486 patients with diffuse large B-cell lymphoma (DLBCL) treated at Oslo University Hospital with 1056 blood donors serving as controls. Variants in TNFα (rs1800629) (GG vs. AG/AA, p < 0.001) and LTA (rs909253) (AA vs. AG/GG, p = 0.02) and deletions in GSTM1 and GSTT1 (undeleted vs. deleted, p = 0.01 and p = 0.01, respectively) were associated with increased susceptibility of developing DLBCL. IL-10 (rs1800896) variants (GG vs. AG/AA, p = 0.03) were associated with decreased susceptibility. In line with several previous reports, patients carrying the TNFα (rs1800629) A allele treated in the pre-rituximab era had inferior outcome compared to patients carrying the homozygous GG genotype (p = 0.004, n = 33). However, patients receiving at least one dose of rituximab had equal outcome regardless of their TNFα genotype (HR = 0.94, p = 0.79, n = 307). Deletion in GSTM1 was associated with inferior outcome for patients with low International Prognostic Index (IPI) score (p = 0.04). Our findings support the suggestions that polymorphisms in genes encoding immunoregulatory proteins and enzymes that metabolize carcinogens and chemotherapeutic drugs influence DLBCL susceptibility and possibly treatment outcome. The influence of polymorphisms in immunoregulatory genes on outcome in DLBCL should be reevaluated in the rituximab era.

Factors that predict the clinical reactivity and tolerance in children with cow's milk allergy

BackgroundSpecific IgE (sIgE) may be used for the diagnosis of cow's milk allergy (CMA) and as a guide to perform food challenge tests in patients with CMA. The effect of genetic variants on the prognosis of food allergy is largely unknown. ObjectiveTo examine the performance of sIgE analysis and the utility of the genetic variants of CD14, STAT6, IL13, IL10, SPINK5, and TSLP in predicting the clinical course in children with CMA. MethodsSerum sIgE levels of 94 children who underwent open food challenges and 54 children with anaphylaxis due to cow's milk (CM) were retrospectively analyzed between January 2002 and May 2009. The genetic polymorphisms were determined in 72 children. ResultsA total of 148 children were followed up for a median of 3.5 years, and 42 of the 94 challenge results were positive. The probability curves with 95% decision points were 2.8 kU/L for younger than 1 year, 11.1 for younger than 2 years, 11.7 for younger than 4 years, and 13.7 for younger than 6 years. Sixty-six children outgrew CMA during follow-up. Children with initial an CM sIgE level less than 6 kU/L outgrew CMA earlier than children with an initial CM sIgE level of 6 kU/L or higher (P < .001). The age of tolerance development for CM was significantly higher in children with the GG genotype at rs324015 of the STAT6 gene compared with those with the AA+AG genotype (2 years [range, 1.5-3.9 years] vs 1.2 years [range, 1.0-2.2 years]) (P = .02). ConclusionThe decision points of sIgE obtained in different age groups may help to determine the likelihood of clinical reactivity more precisely. The results suggest that sIgE levels and STAT6 gene variants may be important determinants to predict longer persistence of CMA.

Analysis of TNF-β, IL-10, and IL-1 Cluster Gene Polymorphisms and Clinical Risk Factors on Acute Renal Graft Rejection

Introduction: There is growing evidence of the genetic association between certain cytokine and acute renal graft rejection. We sought to investigate the role of recipients’ TNF-β, IL-10, IL-1β and IL-1 receptor antagonist (ra) gene polymorphism as well as other variables such as PRA levels and HLA mismatches in acute renal graft rejection. Methods: TNF-β (+252A/G), IL-10(-592A/C), IL-1β (-511C/T) and IL-1ra (86bp VNTR) gene polymorphisms were determined in 157 renal allograft recipients with and without acute rejection using PCR. TNF-β, IL-10, IL-1β and IL-1ra genotypic variants were investigated for correlation with acute rejection within the first year after renal transplantation. Results: Patients with increased panel-reactive antibody (PRA) levels were predisposed to acute renal graft rejection (P=0.001). After adjusting for all variables of P 10% remained significant risk factor in a multivariate logistic regression analysis (OR=5.897, 95% confidence intervals=1.884-18.456, P=0.002). No significant difference was found between recipients with and without acute rejection regarding TNF β, IL-10, IL-1β and IL-1ra gene polymorphisms. Conclusion: Increased PRA levels have more significant impacts than cytokine gene polymorphisms on the likelihood of developing acute renal graft rejection. We should take necessary pre-transplant and/or post-transplant measures such as plasma exchange or immune adsorption to lower the PRA levels. To identify the actual role of both PRA levels and gene polymorphisms in acute renal graft rejection additional studies with larger sample sizes will be necessary.

Lack of association of IL-6 (−174 G > C) and TNF-α (−238 G > A) variants with paranoid schizophrenia in Indian Bengalee population

Schizophrenia is a chronic debilitating neuropsychiatric disorder with complex etiopathology. Growing evidence suggests a significant role of chronic low grade inflammation in the pathophysiology of schizophrenia. Multiple immunological, genetic polymorphism and gene expression studies have established crucial roles of certain pro-inflammatory cytokines in the immune-mediated risk of schizophrenia. Although genetic studies suggest some variants within the pro-inflammatory IL-1β, IL-6, and TNF-α genes conferring risk to schizophrenia, the results however have been contradictory in various populations. In the present investigation, promoter SNPs of IL-6 (−174 G>C) and TNF-α (−238 G>A) genes have been studied to evaluate whether these variants contribute to schizophrenia susceptibility in Indian Bengalee population. Genotyping of the above SNPs was done in 100 well characterized and confirmed cases of paranoid schizophrenia and equal number of healthy donors belonging to the same ethnic group by using ABI 3730 Genetic Analyzer. No significant differences in genotype as well as allele frequencies were observed for IL-6 and TNF-α variants between the patient and control groups.

CD14 and IL6 polymorphisms are associated with a pro-atherogenic profile in young adults with acute myocardial infarction

This study investigated the relationship of polymorphisms in genes encoding CD14, IL-6 and TLR4 with metabolic, inflammatory and endothelial markers in young adults with acute myocardial infarction (AMI). Glucose, lipids, nitrate and inflammatory markers, flow mediated vasodilatation (FMV) and flow mediated by nitrate (FMN) were evaluated in 102 AMI and 108 non-AMI (control group) young individuals (<45years). CD14 -260C>T (rs2569190), IL6 -174G>C (rs1800795) and TLR4 c.896A>G (rs4986790) and TLR4 c.1196C>T (rs4986791) polymorphisms were analyzed by PCR-RFLP. Minor allele frequencies of CD14, IL6 and TLR4 polymorphisms were similar between AMI and control groups (p>0.05). In AMI group, individuals carrying IL6 -174CC genotype had higher serum triglycerides, VLDL cholesterol and glucose compared to the IL6 -174GG/GC genotype carriers (p<0.05). Multiple logistic analysis showed that IL6 -174CC genotype carriers had increased risk for hyperglycemia (>5.77mmol/l) [OR: 6.75, 95% CI: 1.80-24.40, p=0.004] and hypertriglyceridemia (>2.68mmol/l) [OR: 3.00, 95% CI: 1.00-9.00, p=0.043]. Moreover, CD14 -260TT genotype was associated with reduced serum HDL cholesterol [OR: 3.10, 95% CI: 1.00-9.01, p=0.044] and apolipoprotein AI [OR: 3.20, 95% CI: 1.00-9.70, p=0.038] in AMI group. Relationship between CD14 and IL6 variants and altered inflammatory and endothelial (nitrate, FMV and FMN) markers was not found in both AMI and control groups. The IL6 -174G>C and CD14 -260C>T polymorphisms are likely to be associated with a pro-atherogenic profile but not with increased inflammatory markers and endothelial dysfunction in young AMI patients.

Host genetic risk factors for community-acquired pneumonia

This study was conducted to establish the contribution of genetic host factors in the susceptibility to community acquired pneumonia (CAP) in the Russian population. Patients with CAP (n=334), volunteers without a previous history of CAP, constantly exposed to infectious agents, control A group (n=141) and a second control group B consisted of healthy persons (n=314) were included in the study. All subjects were genotyped for 13 polymorphic variants in the genes of xenobiotics detoxification CYP1A1 (rs2606345, rs4646903, and rs1048943), GSTM1 (Ins/del), GSTT1 (Ins/del), ABCB1 rs1045642); immune and inflammation response IL-6 (rs1800795), TNF-a (rs1800629), MBL2 (rs7096206), CCR5 (rs333), NOS3 (rs1799983), angiotensin-converting enzyme ACE (rs4340), and occlusive vascular disease/hyperhomocysteinemia MTHFR (rs1801133). Seven polymorphic variants in genes CYP1A1, GSTM1, ABCB1, NOS3, IL6, CCR5 and ACE were associated with CAP. For two genes CYP1A1 and GSTM1 associations remained significant after correction for multiple comparisons. Multiple analysis by the number of all risk genotypes showed a highly significant association with CAP (P=2.4×10−7, OR=3.03, 95% CI 1.98–4.64) with the threshold for three risk genotypes. Using the ROC-analysis, the AUC value for multi-locus model was estimated as 68.38.

Association of the IL-10 Gene Family Locus on Chromosome 1 with Juvenile Idiopathic Arthritis (JIA)

BackgroundThe cytokine IL-10 and its family members have been implicated in autoimmune diseases and we have previously reported that genetic variants in IL-10 were associated with a rare group of diseases called juvenile idiopathic arthritis (JIA). The aim of this study was to fine map genetic variants within the IL-10 cytokine family cluster on chromosome 1 using linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (tSNPs) approach with imputation and conditional analysis to test for disease associations.Methodology/Principal FindingsFifty-three tSNPs were tested for association between Caucasian paediatric cohorts [219 systemic JIA (sJIA), 187 persistent oligoarticular JIA (pOJIA), and 139 extended OJIA (eOJIA) patients], and controls (Wellcome Trust control cohort, WTCCC2). Significant association with sJIA was detected at rs1400986 in the promoter of IL-20 (odds ratio 1.53; 95% CI 1.21–1.93; p = 0.0004), but in no other subtypes. Imputation analysis identified additional associated SNPs for pOJIA at IL-20 and IL-24, including a rare, functional, missense variant at IL-24 with a p = 0.0002. Penalised logistic regression analysis with HyperLasso and conditional analysis identified several further associations with JIA subtypes. In particular, haplotype analysis refined the sJIA association, with a joint effect at rs1400986 and rs4129024 in intron 1 of MAPKAPK2 (p = 3.2E−5). For pOJIA, a 3-SNP haplotype including rs1878672 in intron 3 of IL-10 showed evidence for association (p = 0.0018). In eOJIA, rs10863962 (3′UTR of FCAMR) and rs12409577 (intron of IL-19) haplotype showed some evidence of association (p = 0.0003).ConclusionsThis study supports previous association of IL-20 with sJIA. Haplotype analyses provided stronger association signals than single point analyses, while a penalised logistic regression approach also suggested multiple independent association signals. Replication studies are required to confirm or refute these findings. The results indicate that combined effects with unknown/rare variants remain to be characterised in JIA, and represent a possible example of synthetic association in this region.