The G to A polymorphism at -597 of the interleukin-6 gene is extremely rare in southern Han Chinese

Interleukin-6 (IL-6) is a cytokine involved in different physiologic and pathophysiologic processes including essential hypertension (EH). Associations of the IL-6 promoter region polymorphisms with circulating level of IL-6 have been reported in various studies. We detected the IL-6-597G/A polymorphism in 246 EH patients and 194 healthy controls from Jiangsu area (south of China). Individuals all carried the GG wild genotype, no GA or AA genotypes were found. Our results suggest that IL-6-597G/A polymorphism is extremely rare and unlikely to be contributing significantly to disease susceptibility in southern Han Chinese.     

The interleukin-6 G(-174)C polymorphism and the ex vivo interleukin-6 response to endotoxin in severely injured blunt trauma patients

The aim of this study was to evaluate whether the -174 G/C promoter polymorphism of the interleukin-6 (IL-6) gene is associated with the ex vivo, whole blood IL-6 response to endotoxin with the development of severe sepsis in severely injured, blunt trauma patients. Patients with a severe trauma and an injury severity score of 16 were included in the study. The IL-6 -174 G/C promoter polymorphism was determined by real-time polymerase chain reaction (PCR) assay using specific fluorescence-labelled hybridisation probes. Whole blood of the patients was stimulated with endotoxin and the IL-6 concentrations were measured by ELISA. There was no association between the IL-6 -174 genotypes and the ex vivo, stimulated IL-6 response: 25% of the patients developed severe sepsis later in the clinical course. These patients had higher IL-6 concentrations following whole blood stimulation on day 1 (p = 0.046) after the trauma than patients with uncomplicated post-traumatic recovery. The difference was even more significant on day 2 after the trauma (p = 0.02). High IL-6 responses in a whole blood stimulation assay with endotoxin on days 1 and 2 after a trauma are associated with severe post-traumatic sepsis. Genotyping for the IL-6 -174 G/C polymorphism does not allow early identification of trauma patients with a high, ex vivo IL-6 synthesis capacity.     

Effect of G(-174)C polymorphism in interleukin-6 gene on cardiovascular disease in type 2 diabetes patients

Interleukin-6 (IL-6) is an important pro-inflammatory cytokine of relevance to cardiovascular diseases. The aim of this case-control study was to evaluate the association between the G(-174)C functional polymorphism in the IL-6 gene and risk of cardiovascular disease (CVD) in type 2 diabetes patients. We examined 1090 patients with T2DM and 612 controls. All subjects were genotyped for the G(-174)C polymorphism by polymerase chain reaction (PCR) and restriction analysis. There were no significant differences in the distribution of genotypes and alleles between T2DM patients and healthy controls. Significantly higher C allele frequency was observed in CVD+ patients compared to CVD- subgroup (53% vs. 32%, p < 0.0001). The odds ratio for C allele was 2.4 (95% CI 1.99–2.9, p < 0.0001) and for CC genotype 4.55 (95% CI 3.12–6.63, p < 0.000). When the distribution of G(-174)C polymorphism was compared in subgroups with different clinical phenotypes of CVD, a significant association of CC genotype with myocardial infarction was observed. Forty eight percent of patients with MI had the CC genotype compared to 22% of patients without MI (p < 0.0001). In conclusion, type 2 diabetes patients carrying the C allele of the IL-6 G(-174)C polymorphism have a significantly increased risk of CVD.     

Influence of the interleukin-6 -174 G/C gene polymorphism on exercise training-induced changes in glucose tolerance indexes.

A polymorphism in the IL-6 gene, a G-to-C substitution 176 bp upstream of the ATG translation initiation site, has been associated with diabetes prevalence and insulin resistance. Interventions including exercise training are frequently used to modify cardiovascular disease risk factors. Consequently, this project examined associations between the IL-6 -174 genotype and oral glucose tolerance test outcomes in 50- to 75-yr-old sedentary men and postmenopausal women before and after aerobic exercise training. Among the 87 individuals who started the study, 56 were retested after 6 mo of aerobic exercise training. Subject characteristics at baseline did not differ between the IL-6 genotype groups with the exception of fasting glucose, which was higher (P = 0.02, covariates age, gender, and ethnicity) in the CC genotype group. The training-induced change in glucose area under the curve during the oral glucose tolerance test varied between the IL-6 -174 genotype groups (P = 0.05, covariates age, gender, ethnicity, baseline glucose area under the curve, and percent body fat change) with a significant decrease occurring only in the GG genotype group. Insulin outcomes did not differ among the groups at baseline or after training. Training-induced changes in weight, percent body fat, maximal oxygen consumption, fasting glucose, and an insulin sensitivity index also changed similarly among the genotype groups. In conclusion, fasting glucose and the extent to which glucose tolerance changes with exercise training may be influenced by the IL-6 -174 gene polymorphism.     

Interleukin-6 gene polymorphism -174G/C influences plasma lipid levels in women

Elevated levels of the pro-inflammatory cytokine interleukin-6 (IL-6) have been associated with cardiovascular risk factors. The objective of this study was to investigate potential associations between the promoter polymorphism IL-6 -174G/C and the following indices of metabolism: BMI, waist-to-hip ratio, and plasma levels of IL-6, cholesterol, low-density lipoprotein, triglycerides, high-density lipoprotein, leptin, and C-reactive protein in 252 42-year-old women and 245 51-year-old men. Subgroups were also studied 5 years later. The CC genotype of the IL-6 polymorphism was associated with lower levels of cholesterol and low-density lipoprotein (p < 0.001) in women. This finding was replicated in the follow-up, when a significant association between the CC genotype and low triglycerides was also observed. The association between the C allele and lipid pattern found in women was not found in men, where on the contrary, C carriers tended to display elevated triglycerides. IL-6 genotype was not associated with IL-6 plasma levels in either sample. The results suggest different effects of the IL-6 polymorphism on metabolic indices in women and men. None of the associations between IL-6 genotype and lipid pattern seemed to result from an effect of the polymorphism on IL-6 plasma levels.     

The interleukin-6 (-174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in Native Americans and Caucasians

Chronic low-grade activation of the immune system may play a role in the pathogenesis of type-2 diabetes mellitus (T2DM). Interleukin-6 (IL6), a powerful inducer of hepatic acute phase response, has been implicated in the etiology of insulin resistance and T2DM. Recently, an IL6 promoter polymorphism (G/C) at position -174 was found to be associated with measures of insulin sensitivity. Because we have previously found an association between high IL6 levels and insulin resistance in both Pima Indians - a population with high rates of insulin resistance and T2DM - and Caucasians, we aimed to assess whether the IL6 promoter polymorphism is associated with T2DM in these populations. We genotyped the IL6 (-174) G/C polymorphism using pyrosequencing in 463 Native Americans and by PCR-RFLP in 329 Spanish Caucasians. Among the Spanish Caucasian subjects, there was a significant difference in genotypic distribution between diabetic and non-diabetic subjects (P=0.028); the GG genotype was more common in diabetic (0.40) than in non-diabetic (0.29) subjects. The G allele was much more frequent in the Native American sample, and among a sample of 143 cases and 145 controls, the GG genotype was significantly more common in diabetic subjects (P=0.019). When this sample population was stratified according to ethnic heritage, all 211 subjects who were of full Pima Indian heritage had the GG genotype, whereas in the 77 American Indian subjects with non-Pima admixture, T2DM was associated with IL6 genotype (P=0.001). These findings are consistent with a role for genetic determinants of inflammation in the development of T2DM in both Native Americans and Caucasians.     

Association between -174 G/C promoter polymorphism of the interleukin-6 gene and progression of prostate cancer in North Indian population

The cellular alterations that give rise to cancer initiate changes in cytokine expression. Though IL-6 is known to play a major role in proliferation of tumor cells, IL-4 upregulates androgen receptors and prostate-specific antigen (PSA). The present study was undertaken to evaluate the association of IL-4 and IL-6 gene polymorphisms for the susceptibility to prostate cancer (PCa) risk. Our study included 200 controls and 200 histologically confirmed cases of PCa. Polymorphisms in IL-4 (intron 3, by VNTR analysis) and IL-6 (-174 G/C, by amplification refractory mutation system, i.e., ARMS-PCR) were genotyped in all the subjects. There was no significant association of IL-4 and IL-6 gene polymorphisms with the risk of PCa. Nevertheless, twofold risk with progression to bone metastasis (odds ratio = 2.09; 95% confidence interval = 1.16-3.75; p = 0.014) in PCa patients was observed. No association with other confounding factors such as PSA level, Gleason score, and lifestyle-associated risk factors like tobacco chewing and cigarette smoking was seen. Our study suggests that an IL-6 gene variant may be associated with prostate progression and bone metastasis.     

IL6-174 G/C gene polymorphism and its relation to serum IL6 in Egyptian children with community-acquired pneumonia

Cytokines are involved in the pathogenesis of community acquired pneumonia (CAP). The aim of this study is to investigate the association of IL6-174 G/C gene polymorphism with CAP in Egyptian children, to assess its effect on CAP outcome and to determine its effect on the serum IL6 levels in these children.IL6-174 G/C gene polymorphism was genotyped in 210 Egyptian children (100 patients with CAP and 110 healthy controls) using PCR-RFLP, while the serum IL6 levels were measured by ELISA method.We found a significant association between the GG genotype, G allele of IL6-174 G/C SNP and susceptibility to CAP (P = 0.02, 0.01 respectively). However, GG genotype and G allele were protective against severe sepsis (p = 0.004), acute respiratory failure (p < 0.001) and hospital mortality (p < 0.001). Serum IL6 levels were significantly increased in these children while there was no relation between GG genotype and serum IL6.In conclusion, IL6-174 G/C gene polymorphism may contribute to susceptibility to CAP in Egyptian children.     

Association of the IL-6 -174G/C gene polymorphism with knee osteoarthritis in a Thai population

Osteoarthritis is a chronic progressive degenerative joint disease characterized by age-related regressive change in articular cartilage. A single nucleotide polymorphism has been described at position -174 of the interleukin-6 (IL-6) promoter region, leading to three possible genotypes, GG, GC, and CC. We investigated a possible association of the IL-6 -174G/C gene polymorphism with knee osteoarthritis in a Thai population. Genotype distributions and allelic frequencies of the IL-6 -174G/C polymorphism were investigated in 115 knee osteoarthritis patients and 100 healthy controls. Genotyping was performed using PCR-RFLP. The genotype distribution of IL-6 was 79 GG, 36 GC, 0 CC in knee osteoarthritis patients and 88 GG, 12 GC, 0 CC in controls. The frequency of the GC genotype in subjects with knee osteoarthritis was higher than in controls (P< 0.001). Logistic regression analysis showed that the GC genotype was independently associated with increased risk of knee osteoarthritis (odds ratio = 3.3, 95% confidence interval = 1.6-6.9, P = 0.001). These findings suggest that the -174G/C polymorphism of the IL-6 gene promoter plays a role in the pathogenesis of knee osteoarthritis.     

Association between the interleukin-6 promoter polymorphism -174G/C and serum lipoprotein(a) concentrations in humans

Background

Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease. The interleukin-6 (IL-6) receptor antagonist tocilizumab has been shown to lower serum Lp(a) concentrations. We investigated whether the IL-6 single nucleotide polymorphism −174G/C is associated with baseline serum Lp(a) concentrations.

Methodology/Principal Findings

We divided 2321 subjects from the Lipid Analytic Cologne (LIANCO) cohort into 2 groups, the ones with substantially elevated Lp(a), defined as concentrations ≥60 mg/dl (n = 510), and the ones with Lp(a) <60 mg/dl (n = 1811). The association with the genotypes GG (33.7%), GC (50.75%) and CC (15.55%) was investigated. The GC and the CC genotype were associated with a significantly increased odds ratio of having substantially elevated Lp(a) concentrations (OR = 1.3, 95% CI 1.04 to 1.63, P = 0.02 and OR = 1.44, 95% CI 1.06 to 1.93, P = 0.018). These associations remained significant after adjusting for age, sex, smoking behavior, body mass index, serum lipoproteins, hypertension and diabetes. Of these covariates, only LDL cholesterol was significantly and independently associated with elevated Lp(a) concentrations.

Conclusions/Significance

The IL-6 single nucleotide polymorphism −174G/C is associated with increased odds of having elevated Lp(a). Whether this association plays a role in the Lp(a)-lowering effects of IL-6 receptor antagonists remains to be established.     

The interleukin-6 -174 promoter polymorphism is associated with extrapulmonary bacterial dissemination in Streptococcus pneumoniae infection

Interleukin-6 (IL-6) is required for the clearance of bacteria in pneumococcal pneumonia. The abundance of endogenous IL-6 production on infectious stimuli is associated with genotypic differences in the -174 promoter region of IL-6 (-174 G-->C), showing increased IL-6 levels in patients carrying the GG genotype. One hundred patients with culturally proven pneumococcal disease were analyzed for distribution of the G-/C-alleles in the IL-6 -174 promoter region in comparison to 50 age-matched controls. Extrapulmonary pneumococcal dissemination, including septic metastasis, endocardial and meningeal infection, was used as parameter for impaired clearance of the bacteria. No significant differences in the allele distribution were observed between patients and controls. Within the patient group, the interleukin-6 GG homozygous carriers were less likely to develop extrapulmonary pneumococcal infection (10.3% versus 30.9%; OR 0.26, 95% CI 0.07-0.94, p=0.04). The IL-6 GG genotype, encoding for enhanced IL-6 secretion on bacterial stimuli, reduces the risk of bacterial spread to extrapulmonary sites in pneumococcal infection, possibly due to a more effective clearance of the pathogen from the blood and the respiratory tract.     

Association between -174 interleukin-6 gene polymorphism and biological response to rituximab in several systemic autoimmune diseases

Rituximab has become a pivotal treatment for systemic autoimmune diseases. The aim of this study was to determine whether the genetic variant -174 IL-6 contributes to differences in the response to rituximab in patients with systemic autoimmune diseases, including systemic lupus erythematosus (SLE), inflammatory myopathies, anti-neutrophil cytoplasmic antibody-mediated vasculitis, systemic sclerosis, Sj?egren's syndrome, rheumatoid arthritis, and autoimmune hemolytic anemia. DNA samples from 144 Spanish patients with different systemic autoimmune diseases receiving rituximab were genotyped for -174 IL-6 (rs1800795) gene polymorphism using the TaqMan(?) allelic discrimination technology. Six months after the first infusion with rituximab, we evaluated the response to the drug: 60.4% of the patients showed a complete response, partial 27.8%, and 11.8% did not respond to the treatment. The CC genotype frequency was significantly increased in nonresponders with respect to responders (23.5% vs. 7.1%, respectively; p=0.049; odds ratio (OR)=4.03, 95% confidence intervals (CI) 0.78-16.97). According to the genotype distribution, rituximab was effective in 69.2% of the CC carriers, 91.9% of the CG carriers, and 88.4% of the GG carriers. A similar trend was observed when SLE patients were analyzed separately (27.3% carried CC homozygosis in nonresponders and 6.9% in responders; p=0.066; OR=5.10, 95% CI 0.65-31.73). Rituximab was effective in 62.5% of the CC carriers, 88.9% of the GC carriers, and 90% of the GG carriers. These results suggest that -174 IL-6 (rs1800795) gene polymorphism plays a role in the response to rituximab in systemic autoimmune diseases. Validation of these findings in independent cohorts is warranted.     

Meta-analysis: Interleukin 6 gene -174G/C polymorphism associated with type 2 diabetes mellitus and interleukin 6 changes

The gene coding interleukin 6 (IL-6) is a promising candidate in predisposition to type 2 diabetes mellitus (T2DM). This study aimed to meta-analytically examine the association of IL-6 gene −174G/C polymorphism with T2DM and circulating IL-6 changes across −174G/C genotypes. Odds ratio (OR) and standard mean difference (SMD) with 95% confidence interval (CI) were calculated. Twenty-five articles were meta-analysed, with 20 articles for T2DM risk and 9 articles for circulating IL-6 changes. Overall, there was no detectable significance for the association between −174G/C polymorphism and T2DM, and this association was relatively obvious under dominant model (OR: 0.82, 95% CI: 0.56-1.21). Improved heterogeneity was seen in some subgroups, with statistical significance found in studies involving subjects of mixed races (OR: 0.63, 95% CI: 0.46-0.86). Begg's and filled funnel plots, along with Egger's tests revealed week evidence of publication bias. In genotype-phenotype analyses, carriers of −174CC and −174CG genotypes separately had 0.10 and 0.03 lower concentrations (pg/mL) of circulating IL-6 than −174GG carriers. Albeit no detectable significance for the association of −174G/C with T2DM, our findings provided suggestive evidence on a dose-dependent relation between −174G/C mutant alleles and circulating IL-6 concentrations, indicating possible implication of this polymorphism in the pathogenesis of T2DM.     

The C-174G promoter polymorphism of the interleukin-6 (IL-6) gene that affects insulin sensitivity in Caucasians is not involved in the pathogenesis of Taiwanese type 2 diabetes mellitus

Interleukin-6 (IL-6) is a pleiotropic cytokine which regulates the immune response, the acute-phase response, hematopoiesis and body energy balance. Genetic polymorphism at -174 position of IL-6 promoter has been recently reported to be linked with insulin resistance, however, with conflicting results. The C allele at IL-6 -174 position is associated with increased insulin sensitivity, and has a protective role for the development of type 2 diabetes, in a Spanish study. Whereas, according to a Finnish study, it is correlated with lower insulin sensitivity and may encourage the development of type 2 diabetes. Ethnic differences play certain roles in the distribution of IL-6 promoter polymorphisms because the distribution of the IL-6 -174 C allele is diverse among study subjects with different racial origins. Therefore, we examined IL-6 C-174G polymorphism in Taiwanese type 2 diabetic subjects to clarify the relationship of this polymorphism with Taiwanese type 2 diabetes mellitus in the context of the aforementioned mentioned contradictory results. All of our 101, type 2 diabetic patients and 112, non-diabetic, healthy individuals carried homologous G alleles. No C allele was found. Our study suggested that the C allele at the IL-6 -174 position was rare in Taiwanese people. Furthermore, our results demonstrated that IL-6 C-174G polymorphism is unlikely to play a role in the development of Taiwanese type 2 diabetes, regardless of its protective or promoting role.     

The effect of IL6-174C/G polymorphism on postprandial triglyceride metabolism in the GOLDN studyboxs

Chronically elevated interleukin-6 (IL-6) affects lipid and lipoprotein metabolism. Individuals genetically predisposed to higher IL-6 secretion may be at risk of dyslipidemia, especially during the postprandial phase. We investigated the effect of genetic variants at the IL6 locus on postprandial lipemia in US Whites participating in the Genetics of Lipid Lowering Drugs and Diet Network study. Subjects were given a single fat load composed of 3% of calories as protein, 14% as carbohydrate, and 83% as fat. Blood was drawn at 0 h, 3.5 h, and 6 h to determine plasma triglyceride (TG), TG-rich lipoprotein (TRL) and lipoprotein particle size. Homozygotes (GG) and heterozygotes (CG) of the -174C/G variant displayed higher plasma IL-6 concentrations compared with major allele homozygotes (CC) (P = 0.029). GG and CG subjects showed higher fasting plasma TG (P = 0.025), VLDL (P = 0.04), and large VLDL (P = 0.02) concentrations than did CC subjects. Moreover, GG and CG subjects experienced greater postprandial response of TG (P = 0.006) and TRL, including chylomicrons (P = 0.005), total VLDL (P = 0.029), and large VLDL (P = 0.017) than did CC subjects. These results suggest that the functional polymorphism -174C>G at the IL6 locus determines the difference in both fasting and postprandial TG metabolism. This phenomenon could be responsible for the observed association of this genetic variant with cardiovascular disease risk.     

Allele frequency distributions of -174G/C polymorphism in regulatory region of interleukin 6 gene (IL6) in Russian and worldwide populations

Allele and genotype frequencies of the ?174G/C polymorphism (rs1800795) in the regulatory region of the IL6 gene, which encode anti-inflammatory cytokine interleukin 6, were determined in seven populations representing five ethnic groups from the European part of Russia (440 individuals), as well as in small cohorts that represent populations from 24 countries of Africa and Eurasia (365 individuals). The maps of the geographic distribution of the ?174G/C allele frequencies were constructed based on personal (22 populations) and the literature data (66 populations), and the data from dbSNP database obtained by the HapMap project (10 populations). The frequency of the ?174G allele varied from 45 to 100% and was characterized by nonrandom geographic distribution. These data could reflect the adaptive load of the alleles examined, which was different in different regions of the world. It is suggested that the level of pathogen prevalence is one of the environmental factors that determine different adaptive values of the IL6*-174G/C alleles. This suggestion is supported by a positive correlation between the ?174G allele frequency and level of pathogen prevalence calculated based on historical data (R = 0.768; p < 0.0001).     

The lack of association between interleukin-6 gene − 174 G/C polymorphism and the risk of type 1 diabetes mellitus: A meta-analysis of 18,152 subjects

Epidemiological studies have evaluated the association between interleukin-6 (IL-6) gene − 174 G/C polymorphism and type 1 diabetes mellitus (T1DM) risk, but results of different studies have been inconsistent. The present meta-analysis was therefore designed to clarify these controversies. PubMed, Embase and Web of Science were searched from the first available year to March 25, 2012, as well as hand searching of the references of identified articles were performed. All studies investigating the association between IL-6 gene − 174 G/C polymorphism and T1DM risk were included. Data analyses were carried out by Review Manager 5.1.2 and Stata 11.0. Seven studies were included in the final meta-analysis, covering a total of 9697 T1DM cases and 8455 controls. The results showed no evidence for significant association between IL-6 gene − 174 G/C polymorphism and T1DM risk (for C/C + C/G vs. G/G: OR = 1.30, 95% CI = 0.84–2.00, p = 0.24; for C/C vs. C/G + G/G: OR = 1.10, 95% CI = 0.75–1.60, p = 0.63; for C/C vs. G/G: OR = 1.34, 95% CI = 0.75–2.42, p = 0.33; for C allele vs. G allele: OR = 1.16, 95% CI = 0.88–1.53, p = 0.30). In addition, the similar results were obtained in the subgroup analysis based on ethnicity. In summary, the present meta-analysis suggests that IL-6 gene − 174 G/C polymorphism is not associated with T1DM risk. However, due to the small sample size in most of the included studies and the selection bias existed in some studies, the results should be interpreted with caution.     

Il6 gene promoter polymorphism (-174G/C) influences the association between fat mass and cardiovascular risk factors

During the last decades, the prevalence of obesity has increased rapidly among young people. A polymorphism in the promoter region of the IL6 gene (-174G/C), has been previously reported to be involved in obesity and metabolic syndrome development. Therefore, the aim of the study was to examine whether the IL6-174G/C polymorphism influence the association of body fat with low-grade inflammatory markers and blood lipids and lipoproteins in Spanish adolescents. 504 Spanish adolescents participating in the AVENA study were genotyped for the-174G/C polymorphism of the IL6 gene. Anthropometric and body composition measurements were taken and blood samples were collected for plasma molecules determinations. No differences between genotypes were observed in anthropometric values, body composition measurements and plasma markers concentration. Physical activity level differ between genotypes with subjects carrying the C allele of the polymorphism being significantly (p<0.05) more active than GG subjects. The association between body fat mass and plasma glucose was influenced by the -174G/C polymorphism of the IL6 gene. Subjects carrying the C allele of the mutation seem to have higher values of lipoprotein (a) and C-reactive protein as their percentage of body fat mass increase. Our results suggest that this promoter polymorphism influences the association between adiposity and some plasma markers.