Polymorphism in the tumor necrosis factor B gene is associated with Palmoplantar pustulosis

We investigated the allele and genotype distribution of a polymorphism of the tumor necrosis factor (TNF) B gene and the frequency of HLA-DR9 in 49 patients with Palmoplantar pustulosis (PPP) and 51 healthy controls. We found that the frequency of TNFB2 in the PPP patients was significantly higher than that in the controls. Furthermore, the DR9-TNFB2 haplotype was significantly more frequent in the PPP patients (P=0.0045). These results suggest that TNFB2 may confer susceptibility to PPP.     

Polymorphism in the chemokine receptor 7 gene (CCR7) is associated with previous myocardial infarction in patients undergoing elective coronary angiography

Coronary artery disease (CAD) remains a major cause of death in developed countries. Both environmental and, less known, genetic factors contribute to progression of CAD to myocardial infarction (MI). Immune system is activated in patients with CAD through dendritic cells (DCs), which present plaque antigens to T lymphocytes. Production of proinflammatory cytokines by activated T cells contributes to plaque rupture in MI. Chemokine receptor 7 (CCR7) on DCs is required for their chemotaxis from plaque to lymph nodes. This makes possible an interaction of DCs with T lymphocytes and initiation of specific immune response. We hypothesized that single nucleotide polymorphisms (SNPs) in CCR7 gene locus are associated with previous MI in patients with CAD. To test this hypothesis, we genotyped six SNPs from the CCR7 gene locus in 300 consecutive patients, admitted for elective coronary angiography. We performed univariate‐, multivariate‐ (including potential confounders) and haplotype‐based tests of association of SNPs with previous MI and results of angiography. Allele A of rs17708087 SNP was associated with previous MI. This association remained significant after adjustment for age, sex, smoking, hypercholesterolaemia and drugs used by patients (odds ratio 2.13, 95% confidence interval: 1.13–3.86). Therefore, we conclude that CCR7 gene locus harbours a polymorphism that modifies risk of MI in patients with CAD. Replication of this association could be sought in a prospective cohort of initially healthy individuals.     

The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games

The members of the tumour necrosis factor (TNF)/tumour necrosis factor receptor (TNFR) superfamily are critically involved in the maintenance of homeostasis of the immune system. The biological functions of this system encompass beneficial and protective effects in inflammation and host defence as well as a crucial role in organogenesis. At the same time, members of this superfamily are responsible for host damaging effects in sepsis, cachexia, and autoimmune diseases. This review summarizes recent progress in the immunobiology of the TNF/TNFR superfamily focusing on results obtained from animal studies using gene targeted mice. The different modes of signalling pathways affecting cell proliferation, survival, differentiation, apoptosis, and immune organ development as well as host defence are reviewed. Molecular and cellular mechanisms that demonstrate a therapeutic potential by targeting individual receptors or ligands for the treatment of chronic inflammatory or autoimmune diseases are discussed.     

Kinetics of tumour necrosis factor-alpha, soluble tumour necrosis factor receptors, interleukin 1-beta and its receptor antagonist during serious infections

Tumour necrosis factor-α (TNF) and interleukin-1β (IL-1β) are the central mediators in the genesis of sepsis. The proinflammatory effects of these cytokines are counteracted in vivo by natural inhibitors. Soluble TNF receptors (sTNFR) are shed upon inflammatory stimuli such as IL-1β and TNF itself. Circulating TNF can be complexed by these receptors, thus preventing TNF from binding to effector cells. The binding of IL-1β to its receptor can be blocked by high concentrations of interleukin-1 receptor antagonist (IL-1Ra), which is produced and released upon nearly the same stimuli as IL-1β. This review presents some aspects of the kinetic behaviour of native sTNFR and of the production of native IL-1Ra during severe infections. It appears that in fulminant septicaemia, the plasma concentration of TNF is increased only transiently, during the very early stage of the infection. The concentration of sTNFR, in contrast, remains elevated much longer, probably due to a slower clearance. During the acute stage of severe infectious diseases, peripheral blood cells cannot be stimulated to produce IL-1β. The production of IL-1Ra, in contrast, is not affected. Thus, the kinetic behaviour and regulation of TNF and IL-1β, is different from that of their antiinflammatory counterparts.     

Kinetics of tumour necrosis factor-alpha,soluble tumour necrosis factor receptors,interleukin 1-beta and its receptor antagonist during serious infections

Tumour necrosis factor-α (TNF) and interleukin-1β (IL-1β) are the central mediators in the genesis of sepsis. The proinflammatory effects of these cytokines are counteracted in vivo by natural inhibitors. Soluble TNF receptors (sTNFR) are shed upon inflammatory stimuli such as IL-1β and TNF itself. Circulating TNF can be complexed by these receptors, thus preventing TNF from binding to effector cells. The binding of IL-1β to its receptor can be blocked by high concentrations of interleukin-1 receptor antagonist (IL-1Ra), which is produced and released upon nearly the same stimuli as IL-1β. This review presents some aspects of the kinetic behaviour of native sTNFR and of the production of native IL-1Ra during severe infections. It appears that in fulminant septicaemia, the plasma concentration of TNF is increased only transiently, during the very early stage of the infection. The concentration of sTNFR, in contrast, remains elevated much longer, probably due to a slower clearance. During the acute stage of severe infectious diseases, peripheral blood cells cannot be stimulated to produce IL-1β. The production of IL-1Ra, in contrast, is not affected. Thus, the kinetic behaviour and regulation of TNF and IL-1β, is different from that of their antiinflammatory counterparts.     

Polymorphism in the promoter region of tumor necrosis factor-alpha gene is associated with severe meliodosis

Melioidosis is an important infectious disease endemic in Southeast Asia and the Northern territories of Australia. Septicemic melioidosis, is the leading cause of fatality from community acquired septicemia in northeastern part of Thailand where death often occurs within a few days after hospitalization. The present study was carried out to investigate the polymorphisms of the position -308 promoter region of the TNF-alpha gene, as well as of the intron 1 of the TNF-beta gene in patients with melioidosis compared with normal uninfected controls in the same endemic area. The gene frequency of TNF2 allele was significantly higher in melioidosis patients compared with control subjects (p = 0.0097, relative risk 2.32). The increase in TNF2 allele in melioidosis patients was found in both heterozygous and homozygous forms. In addition, the increase in TNF2 allele was most apparent in patients who had fatal outcome from septicemic melioidosis (p = 0.017), but was also observed with lesser degree in other groups of melioidosis patients. However, no difference in the frequency of TNF-beta polymorphism the melioidosis patients was observed.     

Polymorphism in the insulin-like growth factor 1 gene is associated with age at menarche in caucasian females

BACKGROUND: The insulin-like growth factor 1 (IGF1) gene, which plays a crucial role in hypothalamic-pituitary-ovarian hormone-controlled metabolic processes, may influence the onset of menarche. Our study aimed to test association between IGF1 polymorphisms with the variation of age at menarche (AAM) in Caucasian females. METHODS: We recruited a sample of 1048 females from 354 Caucasian nuclear families and genotyped 19 single-nucleotide polymorphisms (SNPs) spanning the entire IGF1 gene. Pairwise linkage disequilibrium among SNPs was measured, and the haplotype blocks were inferred. Both single SNP markers and haplotypes were tested for association with AAM using the quantitative transmission disequilibrium test. RESULTS: Significant association (P = 0.0153) between AAM and SNP3 (rs6214) in block1 was detected. CONCLUSIONS: Our results suggested a potential effect of SNP3 in the IGF1 gene on AAM variation in Caucasian women for the first time. However, further independent studies are needed to confirm our findings.     

HLA-DRB1*12 is associated with protection against complicated typhoid fever, independent of tumour necrosis factor alpha.

We investigated whether HLA-DR2 or -DR12 alleles in 63 Javanese patients with complicated or non-complicated typhoid fever were associated with severity of disease. No association was observed between HLA type and susceptibility to disease. However, in patients we did find a negative association of DR12 (DRB1*12021) with complicated typhoid fever (P = 0.05; OR = 0.3; 95% CI: 0.1-1.0). No effect of DR2 (DRB1*1502) on outcome (P = 0.46; OR = 1.5; 95% CI: 0.5-4.5) was demonstrated. The odds ratio for DR12 remained unchanged after adjusting for DR2. Tumour necrosis factor alpha (TNF-alpha) production capacity in lipopolysaccharide (LPS)-stimulated whole blood culture, as measured by non-equilibrium radioimmunoassay, was significantly lower in complicated than in non-complicated cases (P = 0.02), confirming previous data. No significant correlation of either DR12 (P = 0.47) or DR2 (P = 0.89) was found with TNF-alpha production capacity. Apparently, protection against complications by DR12 is attributable to other mechanisms.     

R497K polymorphism in epidermal growth factor receptor gene is associated with the risk of acute coronary syndrome

Background  

Previous studies suggested that genetic polymorphisms in the epidermal growth factor receptor (EGFR) gene had been implicated in the susceptibility to some tumors and inflammatory diseases. EGFR has been recently implicated in vascular pathophysiological processes associated with excessive remodeling and atherosclerosis. Acute coronary syndrome (ACS) is a clinical manifestation of preceding atherosclerosis. Our purpose was to investigate the association of the EGFR polymorphism with the risk of ACS. In this context, we analyzed the HER-1 R497K and EGFR intron 1 (CA)_n repeat polymorphisms in 191 patients with ACS and 210 age- and sex-matched controls in a Chinese population, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy and direct sequencing.     

Genetic variation in tumour necrosis factor and lymphotoxin is not associated with endometriosis in an Australian sample

BACKGROUND: Tumour necrosis factor (TNF) is a pleiotropic cytokine with a wide range of immunoregulatory effects. Variation in the promoter region of TNF and the neighbouring lymphotoxin alpha (LTA) gene might be associated with endometriosis. METHODS: We examined the association between endometriosis and common single-nucleotide polymorphisms (SNPs) or haplotypes in the TNF/LTA region in an Australian sample by analysing 26 SNPs in 958 endometriosis cases and 959 unrelated controls. We selected functional SNPs in the coding and the promoter region of the TNF gene and HapMap tagging SNPs and typed them on a Sequenom MassARRAY platform. A key SNP (rs1800630) in the promoter region typed in previous studies did not give reliable results. Therefore, we also examined a statistically identical (r(2) = 1) SNP (siSNP) (rs2844482), identified using the web based program ssSNPer. RESULTS: Genotype completion rate was 99.5% for SNPs spanning a region of 15.5 kb across the TNF/LTA locus. There was no evidence for association between endometriosis and TNF/LTA SNPs or SNP haplotypes in our case-control study. CONCLUSIONS: Our data suggest both TNF and LTA genes are not major susceptibility genes for endometriosis.     

Serum interleukin-18 and soluble tumour necrosis factor receptor 2 are associated with disease severity in patients with paracoccidioidomycosis

Interleukin (IL)-18 is a proinflammatory cytokine of the IL-1 superfamily that exhibits broad functional effects in innate and acquired immune responses and which has been found in high levels in several chronic inflammatory and autoimmune diseases. Over-expression of IL-18 may promote early resolution of infection or could promote a detrimental exaggerated immune response. The aim of this study was to determine serum levels of IL-18 and other inflammatory mediators [IL-12, soluble intercellular adhesion molecule 1 (sICAM-1), soluble tumour necrosis factor receptor 1 (TNF-RI), sTNF-RII, CXC chemokine ligand 9 (CXCL9), CXCL10] at baseline and after anti-fungal therapy in serum from patients with juvenile (JF) and adult (AF) forms of paracoccidioidomycosis (PCM), as well as in healthy controls (C), and to assess their possible relationships to the severity of disease. IL-18 and sTNF-RII levels in patients with the JF of PCM were significantly higher than those in the AF and controls. In relation to sICAM-1, no difference was observed between JF and AF patients but both presented higher levels than controls. sTNF-RI levels were higher in patients with PCM than in controls, and significantly higher concentrations were detected in AF patients compared to JF patients. Moreover, IL-12 and chemokines CXCL9 and CXCL10 were also higher in patients than in controls. In JF patients IL-18 levels correlated significantly with sICAM-1 (r=0 x 62, P<0 x 0001), sTNF-RI (r=0 x 63, P<0 x 0001), sTNF-RII (r=0 x 51, P=0 x 02), as well as with clinical severity. The results suggest the value of serum IL-18 and sTNF-Rs levels as a parameter of PCM severity and may support a possible role for them in the pathogenesis of the disease.     

A functional Sp1/Egr1-tandem repeat polymorphism in the 5-lipoxygenase gene is not associated with myocardial infarction

Arachidonate 5-lipoxygenase is an enzyme encoded by the ALOX5 gene, and plays an important role in the synthesis of leukotrienes. These are inflammatory mediators, and have been involved in atherosclerosis and other pathological processes that require proinflammatory activities. Human and animal studies have suggested a role for the ALOX5 gene in atherosclerosis, including a significant association between a promoter polymorphism and a carotid intimal-medial thickness in response to dietary fat. This polymorphism was three- to six-tandem repeats of a Sp1/Egr1 binding motif (GGGCGG)(n), and the number of repeats has been linked with the amount of gene expression. We hypothesized that this ALOX5 polymorphism could influence the risk for myocardial infarction (MI). First, we analysed the effect of the four alleles on gene expression by transfecting the HEK-293 cell line with luciferase reporter-constructs. We found that luciferase activities are dependent on the number of the Sp1/Egr1 repeats, with the three and six repeats having the lowest and highest values. We genotyped 312 male MI survivors, aged < 55 years, and 376 healthy controls matched with patients for sex, age, and ethnicity. Ninety-six per cent of the patients were smokers, compared to only 42% among the controls (P < 0.001; OR = 31.84). The 55 + 56 repeat genotypes were less frequent in patients (55 = 56%, 56 = 0.6%) compared to controls (55 = 60%, 56 = 3%). However, these were non-significantly different frequencies. In addition, no difference in MI-onset age and biochemical values was found between the allele and genotypes. In conclusion, we confirmed the effect of the ALOX5-promoter polymorphism on gene expression, but our data did not support a significant effect of this functional variation on MI risk.     

HLA‐DRB1*12 is associated with protection against complicated typhoid fever,independent of tumour necrosis factor α

We investigated whether HLA‐DR2 or ‐DR12 alleles in 63 Javanese patients with complicated or non‐complicated typhoid fever were associated with severity of disease. No association was observed between HLA type and susceptibility to disease. However, in patients we did find a negative association of DR12 (DRB1*12021) with complicated typhoid fever (P = 0.05; OR = 0.3; 95% CI: 0.1–1.0). No effect of DR2 (DRB1*1502) on outcome (P = 0.46; OR = 1.5; 95% CI: 0.5–4.5) was demonstrated. The odds ratio for DR12 remained unchanged after adjusting for DR2. Tumour necrosis factor α (TNF‐α) production capacity in lipopolysaccharide (LPS)‐stimulated whole blood culture, as measured by non‐equilibrium radioimmunoassay, was significantly lower in complicated than in non‐complicated cases (P = 0.02), confirming previous data. No significant correlation of either DR12 (P = 0.47) or DR2 (P = 0.89) was found with TNF‐α production capacity. Apparently, protection against complications by DR12 is attributable to other mechanisms.     

Association of arginase 1 gene polymorphisms with the risk of myocardial infarction and common carotid intima media thickness

Background

Recently, it was suggested that arginase (ARG)1 plays an important role in atherogenesis. However, because of its complex functions depending on vascular cell type, its impact on atherogenesis remains unclear.

Objective

To evaluate the association between ARG1 polymorphisms and phenotypes related to atherosclerosis.

Methods

Among 10 ARG1 polymorphisms selected from databases, 4 single‐nucleotide polymorphisms (rs2781666; rs2781667; rs2781668; rs17599586) were tested for association with myocardial infarction (MI) in a case–control study (350 cases vs 581 controls), and with common carotid artery (CCA) intima–media thickness (CCA‐IMT) in an independent sample of 963 subjects (Etude du Vieillissement Artériel (EVA) study).

Results

The genotype distribution of the rs2781666 G/T polymorphism differed significantly between MI cases and controls (p = 0.005), and the risk of MI was consistently increased for both GT heterozygotes (OR (95% CI) 1.5 (1.1 to 2.0)) and TT homozygotes (OR (95% CI) 2.2 (1.1 to 4.4)). In the EVA study, the rs2781666 polymorphism was also associated with an increase in CCA‐IMT (p = 0.010), a surrogate marker of MI.

Conclusions

The ARG1 rs2781666 polymorphism was consistently associated with MI and an increased CCA‐IMT. These findings reinforce the hypothesis of a significant role of ARG1 in vascular pathophysiology.The aetiology of coronary artery disease (CAD) is complex, and results from interactions between environmental risk factors and individual genetic predispositions. As the overall genetic contribution to CAD has been estimated to range from 20% to 60%,¹ it is essential to establish the genetic basis of CAD to understand the pathophysiology of this disease.Some very recent studies support a role for arginase (ARG)1 in the initiation, development and complications of CAD.^2,3,4,5,6 In hepatocytes, as a partner of the urea cycle, ARG1 catalyses the synthesis of l‐ornithine and urea from l‐arginine, but the ARG1 gene (ARG1) has also been shown to be expressed in various cell types. Teupser et al² designated ARG1, located on 6q23, as a candidate gene that might modulate individual susceptibility to atherosclerosis. In that study, subtractive suppression hybridisation was used to screen for genes that were differentially expressed in macrophages obtained from two strains of rabbits with genetically determined high and low predisposition to atherosclerosis. ARG1 was shown to be expressed at higher levels in macrophages with low atherosclerotic response than in those with high atherosclerotic response, and the level of expression was correlated with increased enzymatic activity. These results suggested a protective role for ARG1 overexpression in the development of atherosclerosis. Consistent with these findings, Thomas et al⁷ showed evidence for a decreased ARG1 gene expression in foam cells compared with non‐foamy cells obtained from rabbits. Both studies were of particular interest because ARG1 was identified as a candidate gene following strategies without any preconceptions about the genes potentially involved in atherogenesis. Nevertheless, other studies suggested that ARG1 overexpression might be deleterious. Notably, it has been proposed that enhanced ARG expression and/or activity may contribute to endothelial dysfunction in various cardiovascular disorders including atherosclerosis.^3,6,8 Finally, the role of ARG1 in atherogenesis may result from conflicting actions in the different vascular cell types.In this context, we attempted to approach the putative role of ARG1 in humans by evaluating its potential implication in clinical manifestations of CAD. First, we searched for associations between ARG1 polymorphisms and myocardial infarction (MI) in a case–control study (350 cases and 581 controls).⁹ Second, in the longitudinal Etude du Vieillissement Artériel (EVA) study (n = 963), we examined whether genetic variations in ARG1 were associated with common carotid artery (CCA) intima–media thickness (CCA‐IMT), considered as an indicator of generalised atherosclerosis.^10,11,12,13     

Polymorphism in the epidermal growth factor gene is associated with birthweight in Sinhalese and white Western Europeans

Birthweight predicts health later in life and is influenced by inherited factors. We investigated the association of the c.61G > A, and c.2566G > A polymorphisms in the epidermal growth factor (EGF) gene [GenBank NM_001963] with birthweight in three groups of healthy pregnant women, and in women with pregnancies affected by fetal growth restriction (FGR). Subjects comprised 171 Sinhalese women with normal pregnancies (Group A), 64 white Western European women with normal pregnancies (Group B), 101 white Western European women with normal pregnancies and their babies (Group C) and 107 women with pregnancies affected by FGR, their partners and their babies (Group D). Maternal EGF genotypes were associated with birthweight of healthy babies of women in Groups A (P = 0.03), B (P = 0.001) and C (P = 0.01). The association persisted following adjustment for confounding by gestational age, sex, maternal weight, parity and smoking habit. The trend from heaviest to lightest birthweights in all these groups was c.61AA > c.61GA > c.61GG and c.2566GG > c.2566GA > c.2566AA. The EGF haplotype associated with lower birthweight (c.61G, c.2566A) was transmitted at increased frequency from heterozygous parents to babies affected by FGR in Group D (P = 0.02). These findings support the hypothesis that growth factors expressed by the feto-maternal unit affect birthweight, and implicates polymorphism in the EGF gene in the aetiology of birthweight variability.     

Polymorphism in the gene regulatory region of MCP-1 is associated with asthma susceptibility and severity.

BACKGROUND: Chemokines play an important role in the pathophysiology of asthma and allergy. Recently, polymorphisms in the gene regulatory region of monocyte chemoattractant protein 1 (MCP-1) and in the promoter region of RANTES have been found; these polymorphisms increase the expression of the chemokines. OBJECTIVE: We investigated whether the presence of the polymorphisms was associated with atopy or asthma and whether these alleles influenced the severity of asthma in affected individuals. METHODS: Three groups of subjects-160 children with asthma (disease severity being classified according to the Global Initiative for Asthma guidelines, modified for children), 151 children with nonasthmatic but allergic phenotype, and 303 children without allergic or asthmatic disorders-were screened with a PCR-based assay for genotyping. RESULTS: The frequency of the -2518G polymorphism in the gene regulatory region of MCP-1 was significantly higher in asthmatic children than in controls (P <.001; odds ratio [OR] = 2.0 [1.4-2.6]) and nonasthmatic atopic children (P <.001; OR = 2.0 [1.4-2.9]). The MCP-1 G/G genotype correlated with asthma severity. In asthmatic children, the MCP-1 -2518G allele was also associated with an increased blood eosinophil level. The promoter polymorphisms in the RANTES gene did not have a detectable effect on the susceptibility to asthma or allergy or on the blood eosinophil count. CONCLUSION: In this cohort of children, there are associations between carrying G at -2518 of the MCP-1 gene regulatory region and the presence of asthma as well as between asthma severity and homozygosity for the G allele. In asthmatic children, the MCP-1 -2518G polymorphism correlated with increased eosinophil levels. This variant of MCP-1 might belong to the predictor gene set for asthma.     

Tumor necrosis factor, tumor necrosis factor receptors type 1 and 2, lymphotoxin-alpha, and HLA-DRB1 gene polymorphisms in human T-cell lymphotropic virus type I associated myelopathy

We studied tumor necrosis factor (TNF), lymphotoxin-alpha (LT-alpha), and TNF receptors type 1 (TNFR-1) and type 2 (TNFR-2) gene polymorphisms as well as HLA class II DRB1 alleles in Japanese patients with human T-cell lymphotropic virus type I (HTLV-I) associated myelopathy (HAM) (n = 51), patients with adult T-cell leukemia/lymphoma (ATL) (n = 48), asymptomatic HTLV-I carriers (n = 50), and HTLV-I seronegative, normal controls (n = 112). There were significant differences between HAM patients and normal controls in the distributions of TNF promoter region polymophism at position --857, the LT-alpha gene NcoI polymorphism, and the T-G substitution in exon 6 of the TNFR-2 gene. The distribution of the NcoI polymorphism of the LT-alpha gene was also significantly different between HAM patients and asymptomatic HTLV-I carriers. In contrast, we failed to detect any difference in the frequency of DRB1, TNF promoter at position --1031, --863, or the TNFR-1 promoter --383 polymorphism. The results suggest that the TNF/LT-alpha gene region within the HLA class III of chromosome 6 and the TNFR-2 gene region located on chromosome 1p36 might contribute to susceptibility to HAM, and that aberrant expression or function of these cytokines and the receptor could be involved in the development of HAM.