Association of IL1β and IL4 gene polymorphisms with nasal polyps in a Polish population

Imbalance between proinflammatory and anti-inflammatory cytokines may regulate the inflammatory reaction in the nasal polyps. Polymorphisms in the regulatory regions of the cytokines genes may influence their expression. The aim of this study was to investigate the relationship between an IL-1β and IL-4 promoter polymorphisms and nasal polyps. The C-511T promoter polymorphism of the IL-1β gene and C-590T promoter polymorphism of the IL-4 gene were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis in 208 Polish patients with nasal polyps and 200 healthy Polish subjects. The risk of susceptibility to NP was significantly higher in patients with NP who had ?511 T/T genotype of IL1β than in controls (OR 3.07; 95 % CI 1.18–7.99). No statistically significant differences were found between NP patients and the control group with regard to genotype distribution and allele frequencies of C/T polymorphism of IL4 gene. Our study demonstrated that the TT genotype for C-511T mutation associated with the risk of developing NP in a Polish population.     

The polymorphisms G(−174)C in IL6 gene and G(−1082)A in IL10 gene are associated with poor outcomes in patients with acute coronary syndrome

Association between the rates of poor outcomes in the patient cohort with acute coronary syndrome and polymorphisms G(?174)C in the IL6 gene and G(?1082)A in the IL10 gene were determined. In total, 1145 patients hospitalized for coronary artery disease to cardiological hospitals of Moscow, St. Petersburg, Kazan, Chelyabinsk, Perm, Stavropol, and Rostov-on-Don were examined. The mean observation period was 9.10 ± 5.03 months (maximal, 18 months). Analysis of the survival of the patients with acute coronary syndrome that carried allele A has demonstrated that the presence of IL10 gene polymorphism G(?1082)A is associated with more frequent poor outcomes as compared with GG genotype. The survival time to endpoint for the carriers of GA and AA genotypes was 11.68 ± 0.67 months versus 12.69 ± 0.65 months for the carriers of GG genotype in IL10 gene (χ² = 4.13, p = 0.042). As for the IL6 gene polymorphism G(?174)C, survival rate analysis did not detect any significant association with the risk for poor outcome. However, joint analysis of these polymorphisms in both genes has demonstrated that characteristic of the patients with acute coronary syndrome that carry GG genotype of IL6 gene and GA and AA genotypes of IL10 is a higher rate of poor outcomes (time to endpoint, 11.01 ± 1.24 months) as compared with the carriers of IL6 gene CC and CG genotypes and IL10 gene GG genotype (time to endpoint, 13.28 ± 0.83 months (ξ² = 10.23, p = 0.017). These data suggest that the genes IL6 and IL10, whose products are involved in the control of inflammatory response, play an important role by increasing the probability of poor outcomes in the patients with acute coronary syndrome.     

Assessment of IL-10, IL-1ß and TNF-α gene polymorphisms in patients with peri-implantitis and healthy controls

Molecular Biology Reports - Peri-implantitis (PI) is a multifactorial condition caused by the interactions of pathogens and the host immune response. Previous studies have demonstrated a...     

IgE,TNFα, IL1 β, IL4 and IFNγ gene polymorphisms in sheep selected for resistance to fleece rot and flystrike

Investigation of restriction fragment length polymorphisms (RFLPs) associated with immunoglobulin E (IgE) and cytokine genes in the sheep genome revealed polymorphisms in the IgE constant heavy chain, interferon γ and interleukin 4 genes. No polymorphisms were found in interleukin 1β or tumour necrosis factor α. PstI and BamHI RFLPs in the IgE gene showed differences in frequency between animals selected for resistance or susceptibility to fleece rot and blowfly strike.     

Association of FcγRIIB and FcγRIIA R131H gene polymorphisms with renal involvement in Egyptian systemic lupus erythematosus patients

Identification of the genetic basis of systemic lupus erythematosus (SLE) may contribute to the discovery of effective drugs before renal involvement. Our aim of this study was to estimate the association between Fc gamma receptor (FcγR) polymorphisms and SLE and renal involvement in Egyptian patients. FcγRIIB and FcγRIIA R131H gene polymorphisms were genotyped in 180 Egyptian adults. Genotyping for FcγRIIA R131H was performed using allele-specific PCR and FcγRIIB-Ile232 Thr polymorphism was genotyped using polymerase chain reaction restriction fragment length polymorphism (PCR–RFLP). The study showed that the homozygous genotype (Thr/Thr) of FcγRIIB significantly increased in all SLE patients (90 patients) and in SLE patients complicated with nephritis (61 patients). The Thr allele was significantly associated with an increased risk of the disease in all the patients and in patients complicated with nephritis. Our study demonstrated an association of FcγRIIB polymorphisms with SLE and lupus nephritis and a lack of association of FcγRIIA polymorphisms with SLE in the Egyptian patients.     

MMP-2, TNF-α and NLRP1 polymorphisms in Chinese patients with ankylosing spondylitis and rheumatoid arthritis

Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are autoimmune, inflammatory diseases with substantial genetic contributions. Matrix metalloproteinase (MMP)-2, tumor necrosis factor (TNF)-α and NLR family pyrin domain-containing 1 (NLRP1) play important roles in the immune response. We studied the MMP-2 rs243865 C/T, TNF-α rs1800629 A/G, NLRP1 rs878329 C/G and NLRP1 rs6502867 C/T polymorphisms in a Chinese cohort of 520 patients with RA, 100 with AS and 520 controls. Genotyping was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Using the MMP-2 rs243865 CC homozygote genotype as the reference group, the CT and TT/CT genotypes were associated with significantly reduced risks of AS. However, logistic regression analyses revealed that the MMP-2 rs243865 C/T polymorphism was not associated with risk of RA. TNF-α rs1800629 A/G, NLRP1 rs878329 C/G and NLRP1 rs6502867 C/T polymorphisms were not associated with risk of RA or AS. These findings suggest that the MMP-2 rs243865 C/T polymorphism is associated with AS development.     

Association of HS6ST3 gene polymorphisms with obesity and triglycerides: gene × gender interaction

The heparan sulfate 6-O-sulfotransferase 3 (HS6ST3) gene is involved in heparan sulphate and heparin metabolism, and has been reported to be associated with diabetic retinopathy in type 2 diabetes. We hypothesized that HS6ST3 gene polymorphisms might play an important role in obesity and related phenotypes (such as triglycerides). We examined genetic associations of 117 single-nucleotide polymorphisms (SNPs) within the HS6ST3 gene with obesity and triglycerides using two Caucasian samples: the Marshfield sample (1442 obesity cases and 2122 controls), and the Health aging and body composition (Health ABC) sample (305 cases and 1336 controls). Logistic regression analysis of obesity as a binary trait and linear regression analysis of triglycerides as a continuous trait, adjusted for age and sex, were performed using PLINK. Single marker analysis showed that six SNPs in the Marshfield sample and one SNP in the Health ABC sample were associated with obesity (P?<?0.05). SNP rs535812 revealed a stronger association with obesity in meta-analysis of these two samples (P?=?0.0105). The T–A haplotype from rs878950 and rs9525149 revealed significant association with obesity in the Marshfield sample (P?=?0.012). Moreover, nine SNPs showed associations with triglycerides in the Marshfield sample (P?<?0.05) and the best signal was rs1927796 (P?=?0.00858). In addition, rs7331762 showed a strong gene × gender interaction (P?=?0.00956) for obesity while rs1927796 showed a strong gene × gender interaction (P?=?0.000625) for triglycerides in the Marshfield sample. These findings contribute new insights into the pathogenesis of obesity and triglycerides and demonstrate the importance of gender differences in the aetiology.     

TGFB1 polymorphisms and TGF-β1 plasma levels identify gastric adenocarcinoma patients with lower survival rate and disseminated disease

TGF-β1 is involved in tumour growth. Four TGFB1 SNPs and TGF-β1 production by stimulated PBMC were determined in seventy-eight gastric adenocarcinoma patients. In addition, TGF-β1 levels were measured in the plasma of further thirty patients. rs1800471-G/C genotype was prevalent in patients (20.7%) compared to controls (8.4%), as it also was the rs1800468 SNP-G/A genotype in stage IV patients (20.7%) compared to stage I, II and III patients, combined (10.3%). Conversely, the T/T rs1800469 SNP-T/T genotype was absent in the former group and present in 19.0% in the latter. Furthermore, the rs1800469-C/rs1800470-T (CT) haplotype was found in 15.0% of stage IV patients as compared to 3.0% of the remaining patients (3.0%) and also identifies patients with worse five-year life expectancy (P = .03). TGF-β1 synthesis by stimulated PBMCs was significantly lower in patients with the risk SNPs or haplotype, compared to the alternative genotype. Finally, TGF-β1 plasma levels were lower in patients with worse life expectancy. Analysis of TGFB1 SNPs and measurement of plasma TGF-β1 levels serves to identify patients at risk of developing a more aggressive disease.     

Association of IL-6, TNF-α and IL-10 gene polymorphisms with type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a metabolic pro-inflammatory disorder characterized by chronic hyperglycemia and increased levels of circulating cytokines suggesting a causal role of inflammation in its etiology. Polymorphism of cytokine genes including interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were studied in T2DM patients as well as in normal healthy controls. Genomic DNA was isolated from both T2DM patients and controls followed by quantification and genotyping by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) using suitable primers. The genotypic, allelic and carriage rate frequency distribution in patients and controls were analyzed by SPSS (version 15.0). Odd ratios with 95 % confidence interval was determined to describe the strength of association by logistic regression model. Double and triple combinations of genotypes were analyzed by χ² test. Gene–gene interaction and linkage disequilibrium tests were performed using SHEsis software. Individually, IL-6, TNF-α and IL-10 did not show any association. In double combination, IL-6 ?597 GA and TNF-α ?308 GG genotypes increased the risk up to 21 times and in triple combination IL-6 ?597 AA, TNF-α ?308 GG and IL-10 ?592 CA increased the risk of T2DM up to 314 times. In gene–gene interaction allele ‘A’ of all studied polymorphisms increased the risk of T2DM up to 1.41 times. Our results suggest that individuals having a haplotype combination of AA, GG and CA for IL-6, TNF-α and IL-10 gene polymorphisms will have higher susceptibility and be at greater risk of developing T2DM.     

Association studies of CTLA-4, CD28, and ICOS gene polymorphisms with type 1 diabetes in the Japanese population

Co-stimulatory molecules of CD28, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and the newly identified inducible co-stimulator (ICOS) are expressed on cell surfaces and provide regulatory signals for T-cell activation. Their genes are candidate susceptibility genes for type 1 diabetes because they co-localize to Chromosome 2q33 with the IDDM12 locus. After determining the genomic structure and screening for polymorphisms of the ICOS gene, we performed association studies between newly identified polymorphisms of the ICOS gene, together with known polymorphisms of CD28 and CTLA-4 genes, and type 1 diabetes. The 49A/G dimorphism in exon 1 and the (AT)n in the 3' untranslated region of the CTLA-4 gene were significantly associated with type 1 diabetes. Evaluation of the CTLA-4 49A-3'(AT)n 86-bp haplotype frequency in patients and controls confirmed the results from the analysis of each polymorphic site. Dimorphism in intron 3 of the CD28 gene was associated with type 1 diabetes only in the early-onset group. In contrast, there was no association with the microsatellite polymorphisms in the ICOS gene or dimorphisms in the promotor region of CTLA-4. Of the three genes encoding co-stimulatory molecules, the CTLA-4 gene appears to confer risks for the development of type 1 diabetes.     

Association of interleukin-6 and transforming growth factor-β1 gene polymorphisms with developmental hip dysplasia and severe adult hip osteoarthritis: a preliminary study

Developmental hip dysplasia (DDH) greatly contributes to occurrence of severe hip osteoarthritis (OA) in adulthood, but the association between the two is not a perfect one. Both conditions are known to have a strong genetic component. Transforming growth factor β1 (TGF-β1) and interleukin-6 (IL-6) are two pro-inflammatory cytokines included in pathogenesis of OA, bone remodeling and development of bone and joint tissues. TGF-β1 gene has a polymorphic site in the signal sequence ((29)T→C) and "C allele carriage" is associated with higher circulating TGF-β1 levels. IL-6 gene has several polymorphic sites in the promoter region including -572T→C transition associated with higher circulating IL-6 levels. As a preliminary investigation on possible association between these polymorphisms and severe adult hip OA secondary to DDH, 28 consecutive patients and 20 healthy controls were genotyped at these loci. With adjustment for sex, "C allele carriage" in the TGF-β1 signal sequence and CC genotype ("transition homozygous") at locus -572 in the IL-6 promoter were each associated with severe OA secondary to DDH (OR=13.4, p=0.016 and OR=6.2, p=0.024, respectively). The combination of these genotypes was particularly strongly associated with the disease (OR=11.1, p<0.001). Data support feasibility of larger-scale studies on potential association between TGF-β1 signal sequence and IL-6 promoter polymorphisms and occurrence of DDH and (un)related severe OA.     

Excretion of 6-keto-PGF1α and PGE2 in rats with hereditary hypothalamic diabetes insipidus

We measured the urinary excretion of a stable metabolite of prostacyclin, 6-keto-PGF_1α, and of PGE₂ in homozygous Brattleboro rats, a strain with hereditary hypothalamic diabetes insipidus. Excretion of both prostaglandins was largely increased compared to both heterozygous Brattleboro rats and Long-Evans rats. These results are in contrast to previously published observations demonstrating a subnormal excretion of PGE₂ in Brattleboro rats. It is suggested that prostaglandin synthesis may be under tonic inhibitory control by vasopressin both in the kidney and in the endothelial cells of blood vessels. The findings further support the view that prostaglandins play an important role in the regulation of water excretion and in the pathogenesis of polyuric conditions.     

A study on the association of TNF-α-308, IL-6-174, IL-10-1082 and IL-1RaVNTR gene polymorphisms with rheumatic heart disease in Pakistani patients

Inflammation is an important contributor to the pathogenesis of rheumatic heart disease (RHD), a disorder of heart valves caused by a combination of immune, genetic and environmental factors. Cytokines are important mediators of inflammatory and immune responses. The aim of this study was to investigate the role of cytokine gene polymorphisms and their potential usefulness as biomarkers in RHD patients from Pakistan. We screened 150 RHD patients and 204 ethnically matched controls for tumor necrosis factor (TNF)-α^-308G/A, interleukin (IL)-10^?1082 G/A, interleukin (IL)-6^-174 G/C and a variable number of tandem repeats (VNTRs) polymorphism of the IL-1Ra gene using polymerase chain reaction. The results showed that TNF-α^-308 A and IL-6^-174 G alleles were associated with susceptibility to RHD (p = 0.000; OR = 2.81; CI = 1.5–5.14 and p = 0.025; OR = 1.50; CI = 1.04–2.16 respectively). The TNF-α^-308 AA and GA genotypes were associated with susceptibility to RHD (p = 0.012; OR = 9.94; CI; 1.21–217.3 and p = 0.046; OR = 1.97; CI = 0.98–3.97 respectively) while the GG genotype seemed to confer resistance (p = 0.003; OR = 0.39; CI = 0.20–0.76). The GG genotype for IL-6^-174 was significantly associated with predisposition to RHD (p = 0.015; OR = 2.6; CI = 1.17–5.85). The A1 (four repeats) and A2 (two repeats) alleles at the IL-1Ra VNTR polymorphism were associated with resistance and susceptibility to RHD respectively. However, this polymorphism deviated from Hardy–Weinberg equilibrium in both patients and controls in our population. TNF-α^-308 and IL-6^-174 polymorphisms may be useful markers for the identification of individuals susceptible to RHD in Pakistan. These individuals could be provided aggressive prophylactic intervention to prevent the morbidity and mortality associated with RHD.     

DNA polymorphisms in north Sardinian newborns and their linkage with abnormal γ globin gene arrangements and with βo-thalassemia

Fetal hemoglobin analysis and globin gene mapping have identified one type of beta(0)-thalassemia and four different gamma globin gene arrangements among newborn babies from the northern part of Sardinia. The beta(0)-thalassemia with a nonsense mutation at codon 39 was found on two chromosomes, each with a distinct pattern of polymorphic restriction sites; one had the A gamma T (A gamma 75 Ile----Thr) mutation, while the second did not. Four closely related haplotypes were identified for chromosomes with the A gamma T mutation. The gamma-thalassemia heterozygosity with the -GA gamma- hybrid gene fell into two categories. One apparently originated through crossing-over between mismatched chromosomes characterized by the most common haplotype, while the other had polymorphisms resembling those of a less frequently occurring chromosome. Chromosomes with the -G gamma-AG gamma-A gamma- triplication had polymorphic sites to be expected for this condition, being complimentary to the -GA gamma- thalassemias. Of the two additional gamma globin gene variations the -G gamma- G gamma- arrangement was associated with the chromosome with the most commonly occurring haplotype, while the chromosome with the -A gamma-A gamma- arrangement had a haplotype characteristic for that with the A gamma T mutation, which identified an -A gamma-A gamma T- arrangement. The incidental discovery of a silent beta-chain mutant, Hb Hamilton, with the Val----Ile substitution at position beta 11, in five newborns was also reported.     

DNA polymorphisms in the ψβ1- and β-globin gene regions in asian macaques

DNA polymorphisms in the ₁--globin gene region in nine Asian macaques(Macaca fuscata, M. mulatta, M. nemestrina, M. cyclopis, M. fascicularis, M. arctoides, M. radiata, M. maura, andM. assamensis) were examined using several restriction endonucleases and the human ₁, IVS2, and IVS2 probes. TheBamHI site 3 to the -globin gene was polymorphic inM. fuscata andM. mulatta, while the HincII site and the EcoRI site in the ₁-globin gene region was highly polymorphic inM. fuscata andM. mulatta, respectively. These polymorphic sites also seem to be present in other Asian macaques. The present study of the polymorphism at theBamHI site 3 to the -globin gene in Asian macaques supports, at the nuclear DNA level, the idea that thefascicularis group includingM. fuscata, M. mulatta, M. cyclopis, andM. fascicularis is different from other Asian macaque groups.This study was supported in part by the Cooperation Research Program of the Primate Research Institute, Kyoto University.