Interleukin-10 Promoter Polymorphisms Research Articles

Association of interleukin-18 promoter polymorphisms with WHO pathological classes and serum IL-18 levels in Chinese patients with lupus nephritis

Accumulating evidence indicates that interleukin (IL)-18 has a central role in the pathogenesis of lupus nephritis (LN). Although two recent studies showed that IL-18 promoter gene polymorphisms might be associated with systemic lupus erythematosus (SLE), to our knowledge, there have not been any reports concerning their association with LN. The aim of our study was to investigate the association of IL-18 promoter polymorphisms with World Health Organization pathological classes and identify their functional correlations. Sequence-specific primer polymerase chain reaction and the restriction fragment length polymorphism method were used to analyse the genotypes of IL-18 promoter polymorphism at the position -607 in 101 unrelated patients with LN, 64 non-renal patients with SLE and 174 ethnically matched healthy controls. Serum IL-18 levels were determined using enzyme-linked immunosorbent assay during the active phase. Immunohistochemical analysis was performed for IL-18 expression on renal biopsies from 72 patients with LN. Our results showed that patients with non-renal SLE had significantly higher frequencies of SNP-607/AA when compared to patients with LN (37.5% vs 18.8%, P < 0.05). LN patients with the AA genotype had significantly lower levels of serum IL-18 than those with the CA or CC genotype (P < 0.01) and also had lower levels of glomerular IL-18 expression than those with the CC genotype (P < 0.05). Significantly, higher frequencies of the SNP-607/AA genotype were observed in LN patients with WHO class III than in those with class IV (34.6% vs 15.6%, P < 0.05). The SNP-607/AA genotype was not observed in patients with LN who progressed to end-stage renal failure that required haemodialysis or renal transplantation. In conclusion, the SNP-607/AA genotype that had lower IL-18 levels might be a genetically protective factor against renal involvement in Chinese patients with SLE and against development of severe nephritis in patients with LN.

Clinical relevance of the interleukin 10 promoter polymorphisms in Chinese Han patients with major trauma: genetic association studies.

IntroductionAn excessive inflammatory response is thought to account for the pathogenesis of sepsis and multiple organ dysfunction syndrome (MODS) after severe trauma. The interleukin-10 (IL-10) is a potent anti-inflammatory cytokine. The objectives of this prospective study were to investigate the distribution of IL-10 promoter polymorphisms in a cohort of 308 Chinese Han patients with major trauma, and to identify associations of IL-10 promoter polymorphisms with IL-10 production and incidence of sepsis and MODS.MethodsA total of 308 patients with major trauma were included in this study. The genotypes of polymorphisms -1082, -819 and -592 were determined by polymerase chain reaction-restriction fragment length polymorphism. The IL-10 levels in the supernatants were determined with enzyme-linked immunoabsorbent assay.ResultsThe -1082A and -592A alleles were significantly associated with lower lipopolysaccharide-induced IL-10 production in an allele-dose dependent fashion. There was no significant difference for the -819 polymorphism. Except for the -1082 polymorphism, the -819 and -592 polymorphisms were not significantly associated with sepsis morbidity rate and MOD scores.ConclusionsOur results further confirm the functionality of the IL-10 promoter single nucleotide polymorphisms in relation to IL-10 production. They also suggest that individual difference in IL-10 production in trauma patients might be at least in part related to genetic variations in the IL-10 promoter region.

Interleukin-18 promoter polymorphisms and the disease progression of Hepatitis B virus-related liver disease

In this study, we aimed to explore whether interleukin-18 (IL-18) gene-promoter polymorphisms are associated with the outcome of hepatitis B virus (HBV) infection. In all, 204 chronically HBV-infected patients were recruited in this study. Of the 204 HBV-infected patients, 43 were considered to be inactive HBV carriers based on the sustained normalization of serum alanine aminotransferase (ALT) together with seropositivity for the antibody to hepatitis B e-antigen (anti-HBe). A total of 161 patients were found to have chronic progressive liver disease, which included cirrhosis. In these HBV-infected patients, the frequencies of AA genotype of IL-18 gene-promoter polymorphisms at position -607 and C allele at position -137 were significantly higher in inactive HBV carriers compared with those in patients with chronic progressive liver disease. These polymorphisms of the IL-18 promoter regions (-607 and -137) could be associated with different outcomes of HBV infection.

Association of G–137C IL-18 Promoter Polymorphism With Acute Allograft Rejection in Renal Transplant Recipients

Interleukin 18 (IL-18) is a potent proinflammatory cytokine, which is postulated to play a role in mechanism of renal allograft rejection and strongly induces interferon (IFN)-gamma production. The aim of this study was to investigate the association of the G-137C IL-18 promoter polymorphism with acute allograft rejection in renal transplant recipients (RTRs). A total of 226 RTRs and 148 controls were recruited for association analysis. Genotyping was performed by using a real-time polymerase chain reaction. Patients were separated into two groups, the acute rejection (AR) (n=37) or the no AR group (n=189), depending on their history of AR episodes. IL-18 and IFN-gamma serum levels of 73 randomly selected RTRs were measured by ELISA. No significant differences in genotype and allele frequencies were observed between the RTRs and the controls. Significant differences in genotype frequency and allele frequency between the AR and no AR group were observed. The frequency of the -137GG genotype was significantly increased in patients with AR (P=0.015, odds ratio=3.653). Serum levels of IL-18 and IFN-gamma were significantly elevated in the AR group with compared with the no AR group. In the AR group, patients with the -137GG genotype had significantly higher IL-18 serum levels compared to other genotypes. These data demonstrate that the -137GG genotype of the IL-18 gene, encoding higher IL-18 production, seems to be associated with AR and may be a useful marker of AR risk in RTRs.

Interleukin-18 promoter polymorphisms and risk of late onset Alzheimer's disease

Pro- and anti-inflammatory cytokines play an important role in Alzheimer's disease (AD), and common polymorphisms of genes controlling their production have been shown to be associated with the susceptibility to sporadic AD. Interleukin (IL)-18 is a potent pro-inflammatory cytokine of the IL-1 superfamily, and increasing evidences indicate a crucial role for it in the pathogenesis of AD. To clarify the role of IL-18 as a potential cause for AD susceptibility, we investigated the effect of two functional polymorphisms in IL-18 promoter: − 607 C/A (rs1946518) and − 137 G/C (rs187238) for the risk of sporadic late onset Alzheimer's disease (LOAD) in a Han Chinese population of 109 patients and 109 healthy controls matched for sex and age. All 218 subjects were also genotyped for the Apolipoprotein E (ApoE) polymorphisms. The results revealed that both − 607 C allele and − 137 G allele were associated with an increased risk of LOAD (odds ratios/OR = 1.56, P = 0.04, Power = 0.96 and OR = 1.85, P = 0.03, Power = 0.80, respectively), and these associations were influenced by the presence of ApoE ɛ4 alleles. Moreover, they showed a highly significant synergistical interaction with the ApoE ɛ4 allele (OR = 5.70 and 4.64, respectively). Examination of the haplotypes identified the − 607 C/− 137 G haplotype to increase the risk of LOAD (OR = 1.62, P = 0.003, Power = 0.97). These findings suggest that the functional polymorphisms in IL-18 promoter may be involved in the risk of developing sporadic LOAD in the Han Chinese population.

Body Composition and -174G/C Interleukin-6 Promoter Gene Polymorphism: Association with Progression of Insulin Resistance in Normal Weight Obese Syndrome

Insulin resistance and obesity are intimately related to a chronic low grade systemic inflammation. Interleukin-6 (IL-6) may influence the pathogenesis of obesity-related diseases. The aim of this study is to investigate the effect of body's fat mass on the relationships between -174G/C IL-6 promoter gene polymorphism, IL-6 circulating level and insulin resistance. A population of 150 Caucasian women was studied, subdivided according to their body composition in non-obese (NW), Normal Weight Obese (NWO) and preobese-obese (OB). The NWO subjects were found in an intermediate position between the NW and OB subjects in terms of body weight, fat mass percentage (FM%), abdominal FAT%, hs-CRP and plasma triglyceride level. Fasting plasma IL-6 concentration was positively correlated with the homeostasis model assessment for insulin resistance (HOMA-IR) in all subjects analyzed (P=0.0014). In NWO and OB women a significantly increased IL-6 mean value was observed compared with NW subjects. In G/G population, the IL-6 plasma level of NWO and OB was significantly higher with respect to NW. No significant differences of IL-6 concentrations were observed in the three groups carrying G/C genotype. NWO and OB women homozygous for the allele C have significantly lower value of IL-6 with respect to NW subjects. IL-6 concentration was positively correlated with FM% in G/G (R(2)=0.397, P<0.001) and was negatively correlated in C/C (R(2)=0.459, P=0.002). No significant correlation was observed in G/C genotype (R(2)=0.041, P=0.173). In conclusion our study confirms that, at least in Italian Caucasian females, the FM% is a major determinant of an increase in IL-6 production and insulin resistance. -174 G/C IL-6 promoter polymorphism represents a marker which could help to identify, time in advance, "vulnerable" individuals at risk of age and obesity related diseases.

Association of interleukin-6 (− 174G>C) promoter polymorphism with risk of squamous cell esophageal cancer and tumor location: An exploratory study

Chronic inflammation plays a role in transformation from normal cell to malignant state. Interleukin-6 (IL-6) regulates inflammation and various physiological processes. IL-6 promoter polymorphism (− 174G>C) is associated with transcription differences in vitro and in vivo. High expression of IL-6 may result in oxidative DNA damage and enhance risk of carcinogenesis. Therefore, we aimed to evaluate association of IL-6 − 174G>C polymorphism with predisposition to esophageal cancer (EC) in 369 subjects (168 patients with EC and 201 controls). We observed significant association of IL-6 − 174C non-carrier genotype with risk of EC, (OR = 2.29; P = 0.001), with squamous cell carcinoma (SCC) histology (OR = 2.26; P = 0.001) and tumor at upper and lower anatomical locations (OR = 5.97; P = 0.009 and OR = 2.34; P = 0.034). Patients having IL-6 − 174C non-carrier genotype were at elevated risk of metastasis (OR = 2.49; P = 0.005). In conclusion, IL-6 − 174G>C gene polymorphism may confer high risk for EC and its clinical characteristics.

Identification of interleukin-6 promoter polymorphisms in the Chinese Han population and their functional significance*

Interleukin-6 (IL-6) is a pivotal cytokine in both innate and adaptive immunity. Several polymorphisms in the IL-6 promoter have been reported in Western populations. However, little is known about their occurrence in the Chinese population. The functionality of IL-6 promoter polymorphisms remains controversial. Genetic, functional, and association studies. National key laboratory of trauma and departments of traumatic surgery in two teaching hospitals. A total of 348 healthy blood donors and 105 patients with major trauma. None. Identification of polymorphisms in the IL-6 promoter was performed using sequencing and restriction fragment length polymorphism methods. Their functionality was assessed by observation of transcription activity, IL-6 production, and their clinical relevance in 105 patients with major trauma. Only one variant (C-572G) was identified in IL-6 promoter in Chinese Han population. This polymorphism was associated with IL-6 production by peripheral leukocytes in response to ex vivo lipopolysaccharide stimulation in an allele-dose-dependent effect. The C-->G variation at position -572 could reduce transcriptional activity of the IL-6 promoter as shown in both U-937 and K562 cell lines. Moreover, the -572 polymorphism was associated with lower risk of sepsis in major trauma patients. The -572 polymorphism, a unique variation in the IL-6 promoter in the Chinese Han population, may be used as a relevant risk estimate for sepsis in trauma patients.

The interleukin-6 gene -572G&gt;C promoter polymorphism is related to intracranial aneurysms in Chinese Han nationality

There is evidence suggesting that inflammation plays an important role in the pathogenesis of intracranial aneurysms (IAs). Interleukin-6 (IL-6) is an important pro-inflammatory cytokine, and some authors have demonstrated that IL-6 promoter polymorphism -572G>C is associated with IAs in Caucasian population. We performed a case-control study to investigate whether this single nucleotide polymorphism (SNP) might affect the development of IAs in Chinese Han population. The study groups comprised 240 Chinese Han nationality aneurysmal patients and 240 controls. Differences in genotype and allele frequencies between patients and controls were tested by the chi-square method. The results showed that among the Chinese Han subjects, there were significant differences in genotypic distribution and allele frequencies between aneurysmal patients and controls. The GG genotype was significantly more common in patients than in controls (24.5% vs. 3.7%, p<0.001, odds ratio 8.366, 95% CI: 4.040-17.324), and the G allele was much more frequent in patients than in controls (51.7% vs. 20.8%, p<0.001, odds ratio 4.062, 95% CI: 3.058-5.395).

Association of interleukin‐18 polymorphisms and plasma level with the outcome of chronic HCV infection

Hepatitis C virus (HCV) infection is the main cause of chronic liver disease throughout the world, and may progress to cirrhosis and hepatocellular carcinoma (HCC). Immunological factors, especially cytokines and some host genetic variations, rather than direct HCV action, seem to play an important role in the pathogenesis of HCV infection. Elevated levels of interleukin-18 (IL-18) were described previously for chronically (HCV)-infected patients. This study is aimed at investigating IL-18 promoter polymorphisms (-607C/A and -137G/C) in HCV-infected patients with different disease severities (chronic hepatitis C, liver cirrhosis and HCC) and establishing an association between these polymorphisms and IL-18 plasma concentration with the outcome of chronic HCV infection. The carriage of at least one C allele at position -607 (CC + CA) was associated with a higher risk of cirrhosis and HCC (P = 0.032). Compared with controls, HCV-infected patients had significantly higher levels of IL-18 (P = 0.0001) that correlate with disease severity (P = 0.01, P = 0.001, P = 0.0006, respectively). In conclusion, we supposed a possible implication of IL-18 promoter polymorphisms in the pathogenesis of chronic HCV infection.

Interleukin-10 promoter polymorphisms influence susceptibility to ulcerative colitis in a gender-specific manner

Objective. Pathological evidence supports a potential role of the pro- and anti-inflammatory cytokine network in the pathogenesis of inflammatory bowel disease (IBD). Moreover, associated studies suggest a possible involvement of cytokine-related genes in IBD susceptibility. In this study, we evaluated the effect of the anti-inflammatory interleukin-10 (IL10) gene on ulcerative colitis (UC). Material and methods. Two functional single nucleotide polymorphisms (−1082 G/A, −819 T/C) in the IL10 promoter in 203 Italian sporadic UC patients and 391 controls were determined using high-resolution melting analysis. Results. The frequency of the −1082A allele was significantly higher in the UC patients than in controls (p=0.00003); −1082 genotype frequencies were also significantly different between UC patients and controls (p=0.0001). Allele and genotype frequencies of −819 T/C were not significantly associated with UC. Furthermore, the frequencies of haplotypes −1082A/−819C and −1082A/−819T, which have been reported to have a lower promoter activity, were significantly higher in UC patients than in controls (p=0.0004). After gender stratification, we found a significant difference in the −1082A allele (p=0.00004) and genotype (p=0.0002) frequencies only between female UC patients and controls; the same result was obtained for the −1082A/−819C and −1082A/−819T haplotypes (p=0.0006). Conclusions. A gender effect is observed, with women of AG/AA IL10 genotypes and AC/AT haplotypes having a higher risk of developing UC at a younger age. This finding could be related to the previously documented lower IL10 production associated with the −1082A allele and to the IL10 down-regulating effect of estrogens.

Association of interleukin-6 (IL-6) haplotypes with plaque-induced gingivitis in children

Objectives. The proinflammatory cytokine interleukin-6 (IL-6) is a key regulator of the host response to microbial infection and major modulator of extracellular matrix catabolism and bone resorption. The aim of this case-control study was to test differences between children with and without gingivitis in the distribution of IL-6 alleles at positions −174, −572, and −597 and their haplotypes. Material and methods. A total of 455 Caucasian children, aged 11 to 13 years, were enrolled in this study. According to gingival bleeding on probing indices, 183 were classified as healthy subjects and 272 as children with plaque-induced gingivitis. DNA for genetic analysis was obtained from buccal epithelial cells and PCR-RFLP methods were used for genotyping three selected IL-6 promoter polymorphisms. Results. Complex analysis revealed significant differences in haplotype frequencies between patients and healthy subjects (p<0.01). The CGA haplotype was significantly more frequent in children with gingivitis than in healthy subjects (41.5% versus 34.1%). In subanalyses, we found that IL-6 −174C allele was more frequent in patients (44.3%) than in healthy children (36.1%, p=0.016, Pcorr<0.05). Multivariate logistic regression analysis showed that allele C remained a risk factor for gingivitis in children (p=0.03) regardless of plaque or gender. However, the proportions of the IL-6 −597 and −572 genotypes were comparable between the two groups. Conclusions. Our results indicate that the three promoter polymorphisms in the IL-6 gene act in a cooperative fashion and suggest that IL-6 haplotypes could play a role in the pathogenesis of gingivitis in Caucasian children.

Involvement of Interleukin‐10 Promoter Polymorphisms in Nonmelanoma Skin Cancers—A Case Study in Non‐Caucasian Skin Cancer Patients†

Interleukin 10 (IL-10) is a potent immunosuppressive cytokine, therefore elevated IL-10 expression has been implicated in inhibition of antitumor immune response. IL-10 gene promoter polymorphism has been shown to be involved in susceptibility to skin cancers, but there has been no report focusing on susceptibility to skin cancers among non-Caucasian populations. We enrolled 129 patients with skin cancers and 50 age- and sex-matched healthy controls between April 2004 and March 2007. Genomic DNA was extracted from patients' blood samples and IL-10 promoter polymorphisms were identified using polymerase chain reaction-restriction fragment length polymorphism or direct sequencing. The distribution of the frequency of allele or haplotype of IL-10 gene promoter in Japanese was quite different from that of Europeans. No significant differences could be demonstrated in the frequency of allele or haplotype of IL-10 gene promoter between the patient group and the control group. However, the frequency of the low-IL-10 expression haplotype was significantly high in Bowen's disease subgroup. The frequency of low expression IL-10 promoter genotype was significantly less (P = 0.009, chi(2) = 6.74) in the group of nonmelanoma skin cancer generated on sun-exposed areas in comparison with that on covered areas. Our results indicated that low expression haplotype of IL-10 in Bowen's disease may inhibit the escape of tumor cells from immune surveillance, resulting in suppression of tumor growth and tumor invasion to the dermis. Moreover, high IL-10-expressing haplotype of IL-10 promoter may be a risk factor for photocarcinogenesis.

IL-10-592 Polymorphism Predicts the Clinical Outcome of Japanese Patients with Multiple Myeloma and MGUS.

Introduction: Interleukin 10 (IL-10) has been reported as an anti-inflammatory cytokine and B-cell proliferation factor, and has been implicated in autoimmunity, tunorigenesis and stem cell transplantation tolerance. IL-10 is also reported to be involved in multiple myeloma (MM) cell proliferation and survival. The polymorphism of position-592, -819, and -1082 in the promoter of IL-10 gene is a strong determinant of IL-10 expression. However, it is unclear whether IL-10 polymorphisms alter the incidence and clinical outcome of MM. We examined the single nucleotide polymorphism (SNPs) located within the promoter region of IL-10 genes in patients with MM, monoclonal gammopathy of undetermined significance (MGUS) and healthy controls in Japan.Methods: Seventy nine patients with MM [age range, 40–83 years; stage I (n=9), stage II (n=20), stage III (n=50); IgG(n=47), IgA(n=12), IgD(n=1), non-secretory (n=3), Bence Jones(n=16)], 46 patients with MGUS (age range, 44–86 years), and 200 healthy controls were included. Fifteen patients with transformation of MGUS to MM were included in MM group. Genotyping in IL-10 -1082G/A, -819C/T, -592A/C was determined by the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. Genotype and allele frequencies were compared between the study groups using χ2-test. The characteristics and laboratory features of MM patients with each IL-10 promoter polymorphism were compared using χ2-tests and student t-tests. Probability values <0.05 were considered statistically significant. The Kaplan-Meier method was used in the calculation of overall survival. Overall survival curves were compared with the log-rank test.Results: IL-10-592 A/A, A/C and C/C genotype frequencies were not significantly different between MM patients (51%, 34%, and 15%) and controls (42%, 43%, and 15%). Higher frequency of −592A/A genotype was seen in our Asian control compared with Caucasian. The frequency of IL-10 -1082 and -819 were also not significantly different between MM patients and healthy controls. The IL-10-592A/C genotype was detected in 10 of 16 patients (63%) with transformation of MGUS to MM and 20 of 46 patients (43%) with MGUS who did not progress to MM (odds ratio [OR], 2.2; 95% confidence interval [95% CI], 0.7–7.0; p=0.15). In MM patients who received autologous stem cell transplantation (ASCT), the overall survival was similar among 3 genotype groups. However, in patients who did not received ASCT, patients with IL-10-592A/C and C/C genotype had shorter overall survival compared with patients with IL-10-592A/A genotype (median survival, 32 months vs. not reached).Conclusion: It is reported that IL-10-592 A/C and C/C genotype are high producer of IL-10. Our results suggested that the IL-10-592 A/C and C/C genotype was not associated with the susceptibility to MM, however associated with poor prognosis in MM patients who did not receive ASCT. In addition, IL-10-592 A/C and C/C genotype may contribute to transformation of MGUS to MM. According these data, IL-10 may be implicated in the progression of MM and MGUS, and SNPs of IL-10 is one of prognostic factors in patients with MGUS and MM.

Association Between IL-6 and MMP-3 Gene Polymorphisms and Adolescent Idiopathic Scoliosis

Case-control study. As inflammation plays a key role in the etiology of intervertebral disc degeneration, we suggest a possible contribution of pro-inflammatory gene polymorphisms in the pathogenesis of adolescent idiopathic scoliosis (AIS). The nucleus pulposus of scoliotic discs responds to exogenous stimuli by secreting interleukin-6 (IL-6) and other inflammatory cytokines. The association between matrix metalloproteinases (MMPs) and disc degeneration has been reported by several investigators. A human MMP-3 promoter 5A/6A gene polymorphism regulates MMP-3 genes expression, while the G/C polymorphism of the promoter region of IL-6 gene influences levels and functional activity of the IL-6 protein. We conducted a case-control study to investigate whether the 5A/6A polymorphism of the MMP-3 gene and the G/C polymorphism of the promoter region of IL-6 gene were associated with susceptibility to AIS. The frequency of the 5A/5A genotype of MMP-3 gene polymorphism in patients with scoliosis was almost 3 times higher than in controls (30.2% vs. 11.2%, p 0.001), and the frequency of the G/G genotype of IL-6 gene polymorphism in patients with scoliosis was almost 2 times higher than in controls (52.8% vs. 26.2%, P < 0.001). 5A/5A genotype of MMP-3 gene polymorphism and G/G genotype of IL-6 gene polymorphism are independently associated with a higher risk of scoliosis (odds ratio, respectively, 3.34 and 10.54). This is the first study that has evaluated the possibility that gene variants of IL-6 and MMPs might be associated with scoliosis and suggests that MMP-3 and IL-6 promoter polymorphisms constitute important factors for the genetic predisposition to scoliosis.

The interleukin‐10 promoter haplotype ATA is a putative risk factor for aggressive periodontitis

Interleukin-10 has been described as an anti-inflammatory cytokine and a B-cell proliferation factor. Promoter polymorphisms of the interleukin-10 gene have been associated with altered interleukin-10 expression. Therefore, the aim of this study was to evaluate three polymorphisms at positions -1082G>A, -819C>T and -590C>A in patients with generalized chronic periodontitis (n = 27) and generalized aggressive periodontitis (n = 32) in comparison with periodontitis-free controls (n = 34). Interleukin-10 promoter polymorphisms were analyzed by polymerase chain reaction with sequence-specific primers (PCR-SSP). Distributions of single alleles, genotypes and haplotypes were calculated by the chi-square test. Risk factor analyses were carried out by logistic regression. Subgingival bacteria were subjected to molecular biological analyses using the micro-Ident test. The combination ATA/ATA was found only in patients with aggressive periodontitis (15.6 vs. 0.0%, p = 0.023). Taking into account age, gender, smoking and plaque level, an increased odds ratio (3.7, p = 0.04) for aggressive periodontitis was shown for subjects with the haplotype ATA. Prevotella intermedia was found to be decreased in ACC- positive (41.3 vs. 66.7%, p = 0.022), ATA-positive (33.3 vs. 57.1%, p = 0.032) and ACC/ATA-positive (20.0 vs. 55.9%, p = 0.002) individuals. In GCC/GCC-positive subjects, P. intermedia occurred more frequently (86.7 vs. 42.3%, p = 0.002). The haplotype ATA, which is known as a 'low interleukin-10 producer' is a putative risk indicator for generalized aggressive periodontitis.

Interleukin-18 promoter polymorphism associates with the occurrence of sudden cardiac death among Caucasian males: The Helsinki Sudden Death Study

Objective The increased plasma concentrations of pro-atherogenic and cardiomyocyte hypertrophic cytokine interleukin 18 (IL-18) predict mortality in patients with coronary heart disease (CHD) in addition to predicting the outcome of heart failure. The IL-18 gene has a functional −137 G/C polymorphism (rs187238) in the promoter region. The C allele carriage is associated with attenuated IL-18 production. The effect of IL-18 genotype on SCD is unknown. We studied the association of the IL-18 gene −137 G/C polymorphism with the occurrence of sudden cardiac death (SCD). Methods Using the TaqMan 5′ nuclease assay, we genotyped two independent consecutive and prospective autopsy series which were included in the Helsinki Sudden Death Study. Results Of the 663 men, 359 (54.1%) had the wild-type GG-genotype, 261 (39.4%) were heterozygotes (CG) and 43 (6.5%) were CC homozygotes. Compared to the GG homozygotes, the C allele carriers (i.e. subjects having CC or CG genotypes) had a lower adjusted risk for SCD from any cause (odds ratio [OR] 0.49; 95% confidence interval [CI], 0.31–0.77, p = 0.002), for SCD due to CHD (OR 0.51; 95% CI, 0.32–0.82, p = 0.005), and for SCD caused by non-coronary heart diseases (OR 0.34; 95% CI 0.13–0.90, p = 0.030). Conclusion IL-18 promoter −137 G/C polymorphism, which regulates the expression of IL-18, is an important predictor of SCD from any cause as well as SCD in patients with and without underlying CHD.

Alcohol consumption, interleukin-6 and apolipoprotein E genotypes, and concentrations of interleukin-6 and serum amyloid P in older adults

Background: Whether alcohol intake is associated with concentrations of interleukin-6 (IL-6) and serum amyloid P (SAP) is uncertain.Objective: We determined how alcohol intake and apolipoprotein E (apo E) and IL-6 promoter (IL-6 −174G→C) polymorphisms interact for concentrations of IL-6 and SAP.Design: In the Cardiovascular Health Study, 2454 older adults reported their intake of beer, wine, and liquor and underwent measurements of circulating IL-6 and SAP.Results: Alcohol intake was not associated with IL-6 concentrations among apo E4-negative or IL-6C-positive participants but was positively associated among both apo E4-positive and IL-6C-negative participants (P for trend = 0.02 for both). The corresponding interactions on SAP were not significant for alcohol overall but were similar for liquor intake.Conclusions: Among older adults free of clinical cardiovascular disease, specific IL-6 promoter and apo E alleles appeared to confer positive associations of alcohol consumption with IL-6 concentrations. Genetic heterogeneity should be considered in understanding the cardiovascular effects of alcohol intake.

Interleukin‐18 promoter polymorphism in patients with atopic asthma

Allergic asthma is a chronic inflammatory disease in which interleukin-18 (IL-18) plays an important role. However, there are controversial reports on IL-18 promoter polymorphism as an independent marker of asthma susceptibility. The aim of the present study was to examine the IL-18 promoter polymorphism in patients with allergic asthma. Two hundred and thirty-one patients with allergic asthma from a Polish population diagnosed according to the National Heart, Lung, and Blood Institute (NHLBI)/WHO guidelines were examined. An allele-specific polymerase chain reaction was used to analyse polymorphisms at positions -137 and -607 in the promoter region of the IL-18 gene. Neither in the -607 C>A nor in the -137 G>C promoter polymorphism were there any differences observed between the total group of asthmatic patients and the controls in the frequencies of genotypes, alleles, diplotypes or haplotypes. In patients with severe asthma, the -607 CC and -137 GG genotypes were observed significantly more frequently (P = 0.03 for both), whereas in patients with mild and moderate asthma, the -137 CC genotype was more prevalent than in the former group. The strongest difference between mild to moderate and severe asthma was observed in -137 allele frequencies (P = 0.006). The results of the present study suggest that the -137 G allele and the C-G/C-G diplotype seem to be involved in the pathogenesis of the severe form of asthma.

Polymorphisms of IL-10 gene promoter and rheumatoid arthritis in a Colombian population

Rheumatoid arthritis is an inflammatory disease driven by TH1 CD4+ cells. Interleukin-10 is present in higher concentrations in serum and synovial fluid from patients with rheumatoid arthritis and has a marked anti-inflammatory activity. Furthermore, it is capable of stimulating B cells and increasing autoantibody production. Interleukin-10 synthesis is under genetic control. Three polymorphisms of the promoter region were analyzed for interleukin-10 genes -1082, -819 and -592. Subjects were patients with rheumatoid arthritis compared with a control population for these genes. One hundred two patients with rheumatoid arthritis and 102 matched healthy controls were studied. The following data were taken from the rheumatoid arthritis patients: age of disease onset, presence and titers of rheumatoid factor, and history of replacement joint surgery. Genotypes were obtained by polymerase chain reaction and sequence-specific primer method. The three polymorphisms are in strong linkage-disequilibrium and form three haplotypes -1082A/-819C/-592C, -1082A/-819T/-592A y -1082G/-819C/-592C. No association was detected between Interleukin-10 alleles, haplotypes/genotypes and rheumatoid arthritis. No significant differences occurred between interleukin-10 polymorphisms and age of disease onset, presence and titer of rheumatoid factor and history of major joint replacement. Interleukin-10 is an important regulator of the immune response and likely plays a role in the pathogenesis of rheumatoid arthritis. The current results suggested that Interleukin-10 promoter polymorphisms were not important for development or severity of rheumatoid arthritis.