Interleukin-6 Genotypes Research Articles

Effects of IL6 C-634G polymorphism on tooth loss and their interaction with smoking habits.

To examine the association between an IL6 (Interleukin-6) polymorphism (C-634G or rs1800796) and tooth loss, and an interaction between the polymorphism and smoking habits for the loss. Our subjects were 4917 check-up examinees ages 35-69. They reported tooth loss and lifestyle in a questionnaire. We regressed the number of teeth on the IL6 genotype, gender, age, smoking, drinking, diabetes, hypertension, physical activity, energy intake, education, and brushing. We further estimated multivariate-adjusted odds ratios (ORs) for having <20 teeth. Participants with a GG genotype tended to have less teeth than those with CC; β = -0.798 (95% confidence interval [CI] = -1.501--0.096). Subjects with a GG genotype were more likely to have <20 teeth than those with CC; OR was 1.56 (95% CI = 1.08-2.25). Association between current smoking and tooth loss was stronger among those with GG than among those with CC. In a multiple regression analysis, a significant interaction was found between GG genotype and current smoking in the prediction of tooth loss (P = 0.018). The IL6 C-634G polymorphism was significantly associated with tooth loss. Our results suggest greater effects of smoking on tooth loss in GG genotype individuals.

FREQUENCY DISTRIBUTION OF INTRONIC POLYMORPHISMS OF IL1-raVNTR AND IL-4VNTR IN RHEUMATIC MITRAL VALVE DISEASE IN CAUCASIAN POPULATION OF SIBERIA

A search for associations between allelic variations of immune response genes, and mitral stenosis associated with rheumatic heart disease, represents an important task when studying the pathogenesis of cardiovascular disorders among inhabitants of large industrial regions in Western Siberia. Among multiple polymorphisms of interleukin-encoding genes, a particular attention should be paid to association studies of some intronic polymorphisms with variable numbers of tandem repeats (VNTR). In this respect, genotyping of interleukin 1 receptor antagonist genes ( IL-1ra 86bp VNTR ) and interleukin 4 ( IL-4 70bp VNTR ) has shown positive associations between the intron 2 IL-1ra *3R/3R microsatellite polymorphism, intron 3 IL-4 *2R/2R variant, and the risk of mitral stenosis development in patients with rheumatic heart disease (OR = 12.71; p = 0.0001).

Saving more teeth-a case for personalized care.

Background: Certain risk factors such as tobacco use, diabetes, genetic variations on the IL1 gene, and other inflammatory conditions are hypothesized to predict tooth loss in patients treated in a large medical center. Tooth loss trends are hypothesized to be greater in patients with more risk factors. Methods: DNA samples for 881 individuals were taken from the Dental Registry and DNA Repository at University of Pittsburgh School of Dental Medicine. Clinical data for all 4137 subjects in the registry were also available. SNP genotyping was performed on the samples for IL1α (rs1800587) and IL1β (rs1143634). IL1 positive status was determined as having one or more of the recessive alleles for either SNP. Tooth loss status was determined based on dental records and data gathered for age, sex, ethnicity, and self-reported medical history. Various statistical analyses were performed on the data including genetic association analysis by the PLINK software, chi-square, Mann-Whitney U, and ANOVA tests to determine significance. Results: Tooth loss averages increased with age by all risk factors (smoking, diabetes, hypertension, and interleukin genotypes; p = 4.07E-13) and by number of risk factors (p = 0.006). Increased tooth loss is associated with age and number of risk factors including diabetes, tobacco use, IL1+, and cardiovascular disease. Conclusion: These trends suggest that older patients and those with more risk factors should seek further preventive care to reduce future tooth loss.

Clinical significance of interleukin-1 genotype in smoking patients as a predictor of peri-implantitis: A case-control study.

BackgroundInterleukin-1 (IL-1) is a proinflammatory cytokine that plays an important role in the pathogenesis of periodontitis, and so it might be useful to detect high-risk cases of peri-implantitis. It has been reported that IL-1 polymorphisms and smoking habit have a synergic effect, increasing the incidence of peri-implantitis. The aim of the present study was to evaluate the relationship between IL-1 gene polymorphisms and peri-implantitis in smoking patients.Material and MethodsA case-control study was performed in 27 patients with peri-implantitis and 27 patients with healthy implants. All patients included were smokers. IL-1A-C889T, IL-1B+C3953T and IL-1RN+T2018C were identified by polymerase chain reaction (PCR) amplification in order to establish a relation between these variables and the presence of peri-implantitis. A bivariate analysis was performed and odds-ratio (OR) were calculated.ResultsThe incidence of peri-implantitis was significantly higher in patients with previous history of periodontitis (p=0.024; OR=10.9). Both groups were similar regarding IL-1A-C889T, IL-1B+C3953T and IL-1RN+T2018C genotypes. No increased risk in heavy smokers with IL-1 polymorphism was found.ConclusionsIL-1 genotypes do not seem to be good predictors of peri-implantitis in the great majority of smoking patients. Furthermore, no synergic effect was found between IL-1 genotypes and heavy smokers. Patients with a previous history of periodontitis were more prone to peri-implantitis. Key words:Peri-implantitis, interleukin-1 genotype positive, case-control study, smoking.

Interleukin‐6 gene‐174 G/C promoter polymorphism and its association with clinical profile of patients with multiple myeloma

In multiple myeloma (MM), the growth and survival of myeloma cells is controlled by interleukin-6 (IL-6), the plasma levels of which is controlled by a guanine/cytosine substitution occurring in position -174 of IL-6 gene promoter region. We studied the occurrence of IL-6-174 G/C polymorphism in patients of MM and correlated the presence of genotypes with serum IL-6 levels and tumor staging. One hundred three patients with MM and 117 age- and sex-matched healthy controls were staged by International Staging System. IL-6 genotypes were evaluated by polymerase chain reaction and restriction enzyme analysis. Serum levels of IL-6 were assessed by enzyme-linked immunosorbent assay. Frequency of GG, GC and CC genotypes did not differ significantly between cases (GG 52%, GC 40%, CC 9%) and controls. The median serum level of IL-6 was significantly higher among the GC genotype versus other genotypes (24 ng/mL, P = 0.007) as compared with the GG versus other genotypes (12 ng/mL, P = 0.001). GC was associated more with stage 3 disease (27%) than was GG (11%) or CC (22% P = 0.001). At position 174 of the IL-6 promoter, patients with GC genotype had higher serum levels of IL-6 and presented with more severe disease compared with patients with GG or CC genotype.

Interleukin-12 and Interleukin-6 Gene Polymorphisms and Risk of Bladder Cancer in the Iranian Population

Interleukin-12 (IL-12) as an antitumor and interleukin-6 (IL-6) as an inflammatory cytokine, are immunomodulatory products that play important roles in responses in cancers and inflammation. We tested the association between two polymorphisms of IL-12(1188A>C; rs3212227) and IL-6 (-174 C>G) and the risk of bladder cancer in 261 patients and 251 healthy individuals. We also investigated the possible association of these SNPs in patients with high-risk jobs and smoking habits with the incidence of bladder cancer. The genotype distributions of IL-6 (-174 C/G) genotype were similar between the cases and the control groups; however, among patients with smoking habits, the association between IL-6 gene polymorphism and incidence of bladder cancer was significant. After a control adjustment for age and sex, the following results were recorded: CC genotype (OR= 2.11, 95%CI=1.56-2.87, p=0.007), GC genotype (OR=2.18, 95%CI=1.16-4.12, p=0.014) and GC+ CC (OR=2.6, 95%CI=1.43-4.47, p=0.011). A significant risk of bladder cancer was observed for the heterozygous genotype (AC) of IL-12 (OR=1.47, 95%CI=1.01-2.14, p=0.045) in all cases, and among smokers (AC) (OR=3.13, 95%CI=1.82-5.37, p=0.00014), combined AC+CC (OR=3.05, 95%CI=1.8-5.18, p=0.000015). Moreover among high risk job patients, there was more than a 3-fold increased risk of cancer in the carriers of IL-12 beta heterozygous (OR=3.7, 95%CI=2.04-6.57, p=0.000056) and combined AC+CC(OR=3.29, 95%CI=1.58-5.86, p=0.00002) genotypes as compared with the AA genotype with low-risk jobs. As a conclusion, this study suggests that IL-12(3'UTR A>C) and IL-6 (-174 C>G) genotypes are significantly associated with an increased risk of bladder cancer in the Iranian population with smoking habits and/or performing high-risk jobs.

Abstract 4719: Associations between IL-6 genotype and IL-6-related tumor alterations in ER+ breast cancer: results from ECOG2190/Int0121

Abstract Background: Despite overall favorable prognosis, a subset of patients with ER+ breast cancer will subsequently relapse, and there is a need to identify mechanisms associated with recurrence. Interleukin-6 (IL-6) is a cytokine that has been implicated in progression and metastatic behavior in breast cancer. We previously demonstrated that genotypic variants in the IL-6 promotor associated with high IL-6 production are associated with poor prognosis in a subset of non-metastatic, ER+ breast cancers (Cancer Res, 2009). In the current study, we sought to determine whether patients with these “high-producer” (HP) genotypes (GT) had tumors that were enriched for IL-6 related alterations in membrane receptors, signaling pathways and cell cycle control. Methods: We identified patients with tumor blocks available from the ECOG 2190/INT0121 trial subjects in which we previously had obtained germline DNA and performed GT/haplotype (HT) analysis, and tumor microarrays (TMAs) were prepared. Expression of IL-6/gp130 membrane receptors, tumoral IL-6 content, cytoplasmic signaling through expression of phosphorylated signaling proteins (p-STAT3, p-AKT and p-ERK) and alterations in nuclear cell cycle marker expression (cyclin D, cyclin E and p27) were assessed by immunohistochemistry. Patients had previously been GT for IL-6-174, -572, -597 and the -373 variable repeat as well as assigned HT combining the HP alleles. Chi2 and Fishers exact tests were used to compare proportions. All tests were 2-sided. Results: From the previously GT ER+ patients in E2190 (n=205), we recovered assessable tumor in 84 (41%) patients. Those with tumor did not differ from the overall or ER+ GT cohorts by any tumor/patient characteristics, genotype frequencies or recurrence rate at 10 years (63% with tumor vs. 60% overall). Gp130 membrane receptor positivity was significantly associated with all IL-6 HP GT (-174GG p=0.012; -572GG p=0.01; -597GG p=0.007 and -373non8A12T p=0.008), though IL-6 receptor or IL-6 tumor content were not, and none were associated with HT. Tumor expression of p-STAT3 was seen exclusively in tumors of patients with any of the four IL-6 HP genotypes (rate 10 - 14% for HP GT vs. 0% for all other GT) and within those with the intermediate and HP HT (p=0.03), and p-AKT expression was significantly higher among those with IL6-174GG (p=0.06) and -373non8A12T (p=0.04) GT. Tumor cyclin D levels were significantly higher in those with IL6-174GG (p=0.02), -597GG (p=0.02) and HT (p=0.04). No associations were seen with p-ERK, cyclin E or p27 expression. Conclusions: These data suggest that patients with ER+ breast cancer who have “high-producer” IL-6 genotypes and poor prognosis have tumors enriched for the IL-6 gp130 receptor, JAK/STAT signaling and cyclin D overexpression, suggesting targets for intervention in these patients. Citation Format: Angela M. Demichele, Michelle Donelson, Sara Komrokian, Christopher Colameco, Jinbo Chen, Lu Chen, Robert Gray, Jennifer Nnoli, William Vaughan, Karen Anderson, Jacqueline Bromberg. Associations between IL-6 genotype and IL-6-related tumor alterations in ER+ breast cancer: results from ECOG2190/Int0121. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4719. doi:10.1158/1538-7445.AM2014-4719

The effect of IL-4 and MTHFR gene variants in ankylosing spondylitis.

Ankylosing Spondylitis (AS) is a chronic inflammatory rheumatic disease that characteristically affects the sacroiliac joints and the spine. The exact pathogenesis of AS remains poorly understood, but genetic factors play a key role in disease development. Several genes have been consistently associated with susceptibility to AS. This study was conducted in Turkish AS patients to determine the frequency of the methylenetetrahydrofolate reductase (MTHFR) gene C677T and interleukin-4 (IL-4) gene 70bp variable number of tandem repeats (VNTR) variants, as well as their association with clinical characteristics. Genomic DNA obtained from 272persons (122AS patients and150healthy controls) was used in this study. Genomic DNA was isolated and genotyped using a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay for the MTHFR C677T and IL-4 70bp VNTR gene variants, which were determined using specific PCR primers. There was statistically significant difference between the groups with respect to MTHFR genotype distribution (p = 0.02) and allele frequencies (p < 0.001). When we examined MTHFR and IL-4 genotype frequencies according to clinical characteristics, we found an association between the homozygous MTHFR TT genotype and ocular involvement, although this did not reach statistical significance (p = 0.02). However, we did not find any difference between the groups with respect to IL-4 genotype distribution or allele frequencies and clinical characteristics (p > 0.05). Our findings suggest that there is an association of the MTHFR gene C677T polymorphism with the susceptibility of a person for development of AS. However, the IL-4 gene is not associated with AS within the same population.

Synergistic effect of anti and pro-inflammatory cytokine genes and their promoter polymorphism with ST-elevation of myocardial infarction.

The single-gene approach in association studies of polygenic diseases such as acute myocardial infarction (AMI) is likely to provide limited value. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) plasma levels may be genetically influenced. We evaluate the impact of single nucleotide polymorphism of the promoter region of these genes, as well as reciprocal interaction of these genes with ST-elevation of myocardial infarction (STEMI). In a case-control study 500 STEMI patients and 500 age- and sex-matched controls were studied. Three single-nucleotide polymorphism genotypes were evaluated by polymerase chain reaction and restriction enzyme analysis and assessed their association with STEMI. The synergistic effects of IL-6, TNF-α and IL-10 gene polymorphisms were evaluated by using logistic regression analysis. We found that IL-6 and TNF-α concentrations of studied population were significantly different (p<0.0001) in each genotype of IL-6 -174G>C and TNF-α -308G>A gene polymorphisms respectively. A significant association was found in multivariate analysis for the IL-6 -174G>C [odds ratio (OR): 0.390; 95% confidence interval (CI): 0.176-0.865, p=0.020] and TNF-α -308G>A [OR: 0.372; 95% CI: 0.171-808, p=0.012] gene polymorphisms with STEMI. In contrast, IL-10 -592C>A gene polymorphism was no longer significant in the multivariate model (OR: 0.678; 95% CI: 0.288 to 1.594, p=0.373) whereas significant in univariate analysis (OR: 0.697; 95% CI: 0.523-0.929, p=0.014). Our findings suggest that IL-6, TNF-α and IL-10 gene polymorphisms all contribute in the association with STEMI whereas the association persisted only for IL-6 and TNF-α but not for IL-10 gene polymorphism with this disease in the multivariate analysis.

Association of interleukin‐1 gene variations with moderate to severe chronic periodontitis in multiple ethnicities

Background and ObjectiveGenetic markers associated with disease are often non-functional and generally tag one or more functional “causative” variants in linkage disequilibrium. Markers may not show tight linkage to the causative variants across multiple ethnicities due to evolutionary divergence, and therefore may not be informative across different population groups. Validated markers of disease suggest causative variants exist in the gene and, if the causative variants can be identified, it is reasonable to hypothesize that such variants will be informative across diverse populations. The aim of this study was to test that hypothesis using functional Interleukin-1 (IL-1) gene variations across multiple ethnic populations to replace the non-functional markers originally associated with chronic adult periodontitis in Caucasians.Material and MethodsAdult chronic periodontitis cases and controls from four ethnic groups (Caucasians, African Americans, Hispanics and Asians) were recruited in the USA, Chile and China. Genotypes of IL1B gene single nucleotide polymorphisms (SNPs), including three functional SNPs (rs16944, rs1143623, rs4848306) in the promoter and one intronic SNP (rs1143633), were determined using a single base extension method or TaqMan 5′ nuclease assay. Logistic regression and other statistical analyses were used to examine the association between moderate to severe periodontitis and IL1B gene variations, including SNPs, haplotypes and composite genotypes. Genotype patterns associated with disease in the discovery study were then evaluated in independent validation studies.ResultsSignificant associations were identified in the discovery study, consisting of Caucasians and African Americans, between moderate to severe adult chronic periodontitis and functional variations in the IL1B gene, including a pattern of four IL1B SNPs (OR = 1.87, p < 0.0001). The association between the disease and this IL1B composite genotype pattern was validated in two additional studies consisting of Hispanics (OR = 1.95, p = 0.04) or Asians (OR = 3.27, p = 0.01). A meta-analysis of the three populations supported the association between the IL-1 genotype pattern and moderate to severe periodontitis (OR 1.95; p < 0.001). Our analysis also demonstrated that IL1B gene variations had added value to conventional risk factors in predicting chronic periodontitis.ConclusionThis study validated the influence of IL-1 genetic factors on the severity of chronic periodontitis in four different ethnicities.

Polymorphisms of interleukin 6 and interleukin 10 in Egyptian people with Behcet's disease

Cytokines play critical roles in the pathogenesis of Behçet's disease (BD). They mediated many of the effectors and regulatory functions of immune and inflammatory responses. Many studies have linked Interleukin-6 (IL-6) and Interleukin-10 (IL-10) pathologically to BD. Thus, this study aimed to investigate the associations between IL-6 and IL-10 promoter single-nucleotide polymorphisms (SNPs) and the susceptibility to BD and their implication on plasma levels. We genotyped IL-6 −174 G/C (rs1800795) using Mutagenically Separated Polymerase Chain Reaction PCR (MS-PCR) and IL-10 −1082 G/A (rs1800896) and −819 C/T (rs1800871) using Sequence Specific Primer PCR (SSP-PCR) in 87 Egyptian patients and 97 controls. The plasma levels of IL-6 and IL-10 were measured using Enzyme-linked Immunosorbent Assay (ELISA). Significant increase in the frequency of −1082 GG genotype (P<0.05, OR=2.25, 95%CI=1.03–4.91) and significant decrease in the frequency of −1082 GA genotype (P<0.05, OR=0.53, 95%CI=0.29–0.96) was demonstrated in BD patients compare to controls. Patients with genital ulcer had significantly lower frequency of −1082 GG (P<0.05, OR 0.2, 95% CI=0.04–0.99) and G allele (P<0.05, OR=0.28, 95%CI=0.08–0.93), while patients with ocular manifestations had significantly higher frequency of −1082 G allele (P<0.01, OR=2.28, 95%CI=1.19–4.36). BD patients had significantly higher level of IL-6 (P<0.001) and significantly lower level of IL-10 (P<0.001) compared to controls. The changes in the level of cytokines were independent of any genotype of IL-6 or any genotype/haplotype of IL-10. Patients with active disease state had significantly higher level of IL-6 compared to patients in remission (P<0.05). In conclusion, our preliminary study indicates that the polymorphism at IL-10 −1082 G/A may play a role in BD susceptibility. The significant increase in IL-6 level and the significant decrease in IL-10 level in BD patients were independent of any particular genotype in IL-6 or any particular genotype/haplotype in IL-10.

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.

Role of Proinflammatory Cytokines (Interferon Gamma) and Anti-Inflammatory Cytokine (Interleukin-10) Gene Polymorphisms in Chronic Hepatitis B Infection: An Indian Scenario

Immune-mediated mechanisms have been found to play an important role in the progression of hepatitis B virus (HBV) infection. The outcomes of infection do not appear to be determined by viral strains. Instead, allelic variants in human genome are likely to affect the disease progression. Allelic variation of proinflammatory cytokines such as interferon gamma (IFN-γ) participates in the elimination of HBV, and interleukin-10 (IL-10) helps in inhibition of Th1 effector mechanisms for host defense. The aim of this study was to determine the influence of host genetic factors in chronic HBV infection and gene promoter polymorphism or single-nucleotide polymorphism analysis of IFN-γ+874 and IL-10 (-1082, -592, and -819) on disease progression and persistence. A total of 232 patients along with 76 healthy controls were included. Allele-specific primers for IFN-γ and restriction fragment length polymorphism for IL-10 were used. The study indicated that low IFN-γ expression probably impairs host immune response to HBV, rendering these subjects more prone to HBV infection. No significant differences were detected between the 2 groups in the distributions of IL-10 genotype at the -1082, -819, and -592 positions. Odds ratio indicated that heterozygosity of genotypes -819 CT and -592 AC was more strongly associated with liver chronicity. Significantly, AA homozygous genotype was dominant in chronic hepatitis B cases in IFN-γ+874 and IL-10 (-1082 and -592) and is associated with increased risk of persistent infection.

Cytokine gene polymorphism (interleukin-1β +3954, Interleukin-6 [-597/-174] and tumor necrosis factor-α -308) in chronic periodontitis with and without type 2 diabetes mellitus.

Pro-inflammatory cytokine gene polymorphisms are potential candidates for susceptibility for both type 2 diabetes mellitus (DM) and chronic periodontitis (CHP). This study explored the association of interleukin-1 beta (IL-1 β) +3954, interleukin-6 (IL-6) -597/-174 and tumor necrosis factor-alpha (TNF-α) -308 single nucleotide polymorphisms in CHP with and without type 2 DM in Malayalam speaking subjects of Dravidian ethnicity. This case control study consisted of 51 chronic periodontitis with type 2 diabetes mellitus (CHPDM) and 51 CHP patients as cases and 51 healthy subjects as controls. Polymorphisms were identified by polymerase chain reaction amplification followed by restriction enzyme digestion and gel electrophoresis. IL-1 β (+3954) TT genotype and T allele were significantly associated with CHPDM group when compared with CHP (P = 0.001), whereas CC genotype and allele C was higher in CHP subjects (P = 0.001). For IL-6 (-597) frequency of genotype GA/AA (P = 0.04) and allele A (P = 0.01) was lower in CHPDM group, and for TNF-α -308 the frequency of genotype GA (P = 0.01) and allele A (P = 0.01) was higher in CHP subjects when compared with controls. In Malayalam speaking Dravidian population, IL-6 (-597) genotype GA/AA and allele A appears to be protective for CHP with type 2 DM. Allele C of IL-1 β +3954 and allele A of TNF-α -308 appears to be risk factors for CHP individuals.

40-OR

Genetic control of cytokine production is a feature of variation in cytokine gene regulatory regions that produce low, moderate, or high cytokine production profiles. We have earlier shown that renal allograft recipients carrying low Interleukin-10 (IL-10) producing genotypes have high incidence of chronic allograft failure and graft inflammation. In the present study of a 15-year post transplant follow up, we report the impact of IL-10 gene variants on renal allograft survival. A total of 218 renal transplant recipients with a maximum of 15-year follow-up were recruited. Three variants of IL-10 promoter region (-1082G/A, -819C/T, -592C/A) were analyzed by Luminex based sequence-specific oligonucleotide probe method. Kaplan-Meir (with Log-rank test) and Cox-regression survival analyses using confounding factors like HLA matching, acute rejection as independent variables were performed to assess the impact of IL-10 gene variants on graft survival. Renal transplant recipients carrying low IL-10 producing genotypes had significantly lower graft survival than recipients carrying high IL-10 producing genotypes (65% v/s 92%; p = 0.001; Hazard ratio = 4.35) [Fig. 1]. Renal transplant recipients carrying high IL-10 genotypes have significant better allograft survival. The likely explanation is high IL-10 production contributing to an efficient regulatory immune environment leading to controlled allo-immune responses and better allograft survival.

Interleukin 6(-174G/C) Variant and its Circulating Levels in Coronary Artery Disease Patients and Their First Degree Relatives

Interleukin-6 (IL-6) a pleiotropic cytokine is a central mediator of inflammation in the pathogenesis of coronary artery disease (CAD). Our aim is to evaluate the serum levels of IL-6 and C-reactive protein (CRP) and to analyze the IL-6 polymorphism in CAD patients and to identify the first-degree relatives (FDRs) at risk of the disease in comparison with healthy controls. Estimation of IL-6 levels by enzyme-linked immunosorbent assay (ELISA) and CRP by latex reagent kit method, and genotyping of IL6 gene variants -174 (G>C) was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 600 subjects. IL-6 and CRP levels were significantly high in patients followed by FDRs compared to controls. The frequency of the IL-6 genotype was significantly different between cases, FDRs and controls and association of serum IL-6 levels with genotype found to be significant in CC genotype compared to GC and GG at p < 0.01 in CAD patients and FDRs, while there is no significant difference observed in controls. The study shows the importance of inflammation in the pathogenesis of CAD and predicts the risk of future coronary events in healthy asymptomatic FDRs.

Lack of an Association BetweenInterleukin-6−174G/C Polymorphism and Circulating Interleukin-6 Levels in Normal Population: A Meta-Analysis

Interleukin-6 (IL-6) signaling may play a causal role in the development of coronary heart disease. However, the relationship between IL-6 genotypes and plasma levels of IL-6 appears to be complex. To help clarify the inconsistent findings, we conducted a meta-analysis of the published genetic association studies of the -174 G/C polymorphisms in the IL-6 gene and the circulating IL-6 levels in a normal population. In this meta-analysis, no significant association of IL-6 -174G/C polymorphism and circulating IL-6 levels in a normal population was observed. However, when compared among GG, GC, and CC genotypes, heterogeneity existed among the studies. Sensitivity analysis revealed that, the independent study by Shen et al. influenced the heterogeneity in the homozygous and heterozygous comparison. Although Shen et al.'s study was excluded, no significant association was observed between IL-6 -174G/C polymorphism and circulating IL-6 levels in a normal population [homozygous comparison (GG vs. CC): the pooled standard mean difference (SMD) was -0.01, 95% confidence interval (CI): -0.1-0.08; heterozygous comparison (GC vs. GG or CC): the pooled SMD (GG vs. GC) was -0.05, 95%CI: -0.11-0.01, and the pooled SMD (CC vs. GC) was 0.03, 95%CI: -0.03-0.1]. Under the dominant model, the pooled SMD was -0.05, 95%CI: -0.11-0.01). The meta-analysis provides evidence that the -174G/C polymorphism in the IL-6 gene is not significantly associated with circulating IL-6 levels in a normal population.

Interleukin-6 − 174G/C gene polymorphism affects muscle damage response to acute eccentric resistance exercise in elderly obese women

The IL-6 gene polymorphism has been associated with disease prevalence and different physiological responses to exercise. Eccentric resistance exercise (ERE) is considered a nonpharmacological tool to prevent the chronic degenerative profile associated with aging and obesity. Consequently, the aim of the present study was to investigate the influence of IL-6 −174G/C polymorphism on acute interleukin-6 (IL-6) and creatine kinase (CK) temporal response to ERE in elderly obese women. Ninety women completed seven sets of ten repetitions (eccentric only) of an acute ERE session at 110% of the ten repetitions maximum (10RM). IL-6 genotypes displayed no difference at baseline. ERE induced changes in CK concentration over time occurred only in the GG group, F(2.619, 136.173)=5.199, p=0.003, with CK activity increased from 106.8±6.9U/l pre-intervention to 122.7±11.2U/l at 24h and 131.9±14.4U/l at 48h post-exercise. IL-6 concentration in the GG group was lower than the CC/CG group only at 0h post-exercise (3.78±0.58pg/ml versus 6.51±1.91pg/ml, p=0.030). Only the GG genotype group had higher CK activity 24–48h following ERE and greater CK integral values, while IL-6 activity over 48h was higher in the CC/CG genotype group. In conclusion, IL-6 genotype affects CK and IL-6 in response to ERE. It is of interest that the ERE protocol induced an elevation in CK, indicating possible muscle damage without exacerbating IL-6 and CK for the GG genotype.

Association between interleukin 6 and interleukin 16 gene polymorphisms and coronary heart disease risk in a Chinese population

To investigate the role of interleukin 6 (IL6) and IL16 single nucleotide polymorphisms (SNPs) in coronary artery disease (CAD) risk in a Chinese population. Patients with CAD and healthy control subjects were recruited. IL6 (rs1800795 and rs1800796) and IL16 (rs8034928, rs3848180, rs4577037, rs1131445, rs4778889 and rs11556218) genotyping was performed on the MassARRAY® platform (Sequenom®, San Diego, CA, USA). Frequencies of rs8034928 variant C allele and rs11556218 variant T allele were higher in patients with CAD (n = 326) than controls (n = 341). The rs8034928 C/C genotype (odds ratio [OR] 2.03; 95% confidence intervals [CI] 1.16, 3.62) and C allele (OR 1.97; 95%CI 1.15, 3.45) were associated with increased risk of CAD compared with wild type. Similarly, the rs11556218 T/T genotype (OR 2.44; 95%CI 1.15, 5.44) and T allele (OR 2.37; 95%CI 1.13, 5.24) were associated with increased CAD risk compared with wild type. The SNPs rs8034928 and rs11556218 are associated with CAD risk in the Chinese population, and may be useful predictive markers for CAD susceptibility.

Patient Stratification for Preventive Care in Dentistry

Prevention reduces tooth loss, but little evidence supports biannual preventive care for all adults. We used risk-based approaches to test tooth loss association with 1 vs. 2 annual preventive visits in high-risk (HiR) and low-risk (LoR) patients. Insurance claims for 16 years for 5,117 adults were evaluated retrospectively for tooth extraction events. Patients were classified as HiR for progressive periodontitis if they had ≥ 1 of the risk factors (RFs) smoking, diabetes, interleukin-1 genotype; or as LoR if no RFs. LoR event rates were 13.8% and 16.4% for 2 or 1 annual preventive visits (absolute risk reduction, 2.6%; 95%CI, 0.5% to 5.8%; p = .092). HiR event rates were 16.9% and 22.1% for 2 and 1 preventive visits (absolute risk reduction, 5.2%; 95%CI, 1.8% to 8.4%; p = .002). Increasing RFs increased events (p < .001). Oral health care costs were not increased by any single RF, regardless of prevention frequency (p > .41), but multiple RFs increased costs vs. no (p < .001) or 1 RF (p = .001). For LoR individuals, the association between preventive dental visits and tooth loss was not significantly different whether the frequency was once or twice annually. A personalized medicine approach combining gene biomarkers with conventional risk factors to stratify populations may be useful in resource allocation for preventive dentistry (ClinicalTrials.gov, NCT01584479).