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Gupta A, Gupta P, Singh AK, Gupta V. Association of adipokines with insulin resistance and metabolic syndrome including obesity and diabetes. GHM OPEN 2023; 3:7-19. [PMID: 40143837 PMCID: PMC11933950 DOI: 10.35772/ghmo.2023.01004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/18/2023] [Accepted: 07/25/2023] [Indexed: 03/28/2025]
Abstract
Adipose tissue (AT) acts as a highly active endocrine organ, which secretes a wide range of adipokine hormones. In the past few years, several adipokines (leptin, adiponectin, resistin etc.) have been discovered showing metabolic consequences in relation to insulin resistance (IR), obesity and diabetes. These adipokines are considered to be an important component playing an important role in the regulation of energy metabolism. They have been shown to be involved in the pathogenesis of metabolic syndrome (MetS) and cardiac diseases. The current article provides a holistic summary of recent knowledge on adipokines and emphasizes their importance in association with IR, obesity, diabetes and MetS. Adipokines such as leptin, adiponectin, resistin and tumor necrosis factor-alpha (TNF-α) have been involved in the regulation of an array of metabolic functions and disease associated with it, e.g. appetite and energy balance of the body, suppression of atherosclerosis and liver fibrosis, obesity with type 2 diabetes (T2D) and IR. An important adipokine, Interleukin-6 (IL-6), also correlates positively with human obesity and IR and also the elevated level of IL-6 predicts development of T2D. All of these hormones have important correlation with energy homeostasis, glucose and lipid metabolism, cardiovascular function and immunity. All the possible connections have extended the biological emphasis of AT secreted adipokines as an investigator in the development of MetS, and are now no longer considered as only an energy storage site.
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Affiliation(s)
- Abhishek Gupta
- Department of Physiology, King George's Medical University, Lucknow, India
| | - Priyanka Gupta
- Department of Medicine, King George's Medical University, Lucknow, India
| | - Arun Kumar Singh
- Department of Physiology, King George's Medical University, Lucknow, India
| | - Vani Gupta
- Department of Physiology, King George's Medical University, Lucknow, India
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Idris AB, Idris AB, Gumaa MA, Idris MB, Elgoraish A, Mansour M, Allam D, Arbab BMO, Beirag N, Ibrahim EAM, Hassan MA. Identification of functional tumor necrosis factor-alpha promoter variants associated with Helicobacter pylori infection in the Sudanese population: Computational approach. World J Gastroenterol 2022; 28:242-262. [PMID: 35110948 PMCID: PMC8776532 DOI: 10.3748/wjg.v28.i2.242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/13/2021] [Accepted: 12/31/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) is a ubiquitous bacterium that affects nearly half of the world's population with a high morbidity and mortality rate. Polymorphisms within the tumor necrosis factor-alpha (TNF-A) promoter region are considered a possible genetic basis for this disease. AIM To functionally characterize the genetic variations in the TNF-A 5'-region (-584 to +107) of Sudanese patients infected with H. pylori using in silico tools. METHODS An observational study was carried out in major public and private hospitals in Khartoum state. A total of 122 gastric biopsies were taken from patients who had been referred for endoscopy. Genomic DNA was extracted. Genotyping of the TNF-A-1030 polymorphism was performed using PCR with confronting two-pair primer to investigate its association with the susceptibility to H. pylori infection in the Sudanese population. Furthermore, Sanger sequencing was applied to detect single nucleotide polymorphisms in the 5'-region (-584 to +107) of TNF-A in H. pylori-infected patients. Bioinformatics analyses were used to predict whether these mutations would alter transcription factor binding sites or composite regulatory elements in this region. A comparative profiling analysis was conducted in 11 species using the ECR browser and multiple-sequence local alignment and visualization search engine to investigate the possible conservation. Also, a multivariate logistic regression model was constructed to estimate odds ratios and their 95% confidence intervals for the association between TNF-A-1030, sociodemographic characteristics and H. pylori infection. Differences were statistically significant if P < 0.05. Statistical analyses were performed using Stata version 11 software. RESULTS A total of seven single nucleotide polymorphisms were observed in the TNF-A 5'-region of Sudanese patients infected with H. pylori. Only one of them (T > A, -76) was located at the in silico-predicted promoter region (-146 to +10), and it was predicted to alter transcription factor binding sites and composite regulatory elements. A novel mutation (A > T, +27) was detected in the 5' untranslated region, and it could affect the post-transcriptional regulatory pathways. Genotyping of TNF-A-1030 showed a lack of significant association between -1030T and susceptibility to H. pylori and gastric cancer in the studied population (P = 0.1756) and (P = 0.8116), respectively. However, a significant association was detected between T/C genotype and H. pylori infection (39.34% vs 19.67%, odds ratio = 2.69, 95% confidence interval: 1.17-6.17, P = 0.020). Mammalian conservation was observed for the (-146 to +10) region in chimpanzee (99.4%), rhesus monkey (95.6%), cow (91.8%), domesticated dog (89.3%), mouse (84.3%), rat (82.4%) and opossum (78%). CONCLUSION Computational analysis was a valuable method for understanding TNF-A gene expression patterns and guiding further in vitro and in vivo experimental validation.
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Affiliation(s)
- Abeer Babiker Idris
- Department of Agricultural Science and Technology, Institute of Natural and Applied Sciences, Erciyes University, Kayseri 38039, Turkey
- Department of Medical Microbiology, Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum 11111, Sudan.
| | - Alaa B Idris
- Department of Neurosurgery, Ribat University Hospital, Khartoum 11111, Sudan
| | - Manal A Gumaa
- Department of Medical Microbiology, Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum 11111, Sudan
| | - Mohammed Babiker Idris
- BioMérieux Clinical and Application Advisor, Al-Jeel Medical Co., Riyadh 11422, Saudi Arabia
| | - Amanda Elgoraish
- Department of Epidemiology, Tropical Medicine Research Institute, Khartoum 11111, Sudan
| | - Mohamed Mansour
- Department of Gastroenterology, Ibn Sina Specialized Hospital, Khartoum 11111, Sudan
| | - Dalia Allam
- Department of Gastroenterology, Ibn Sina Specialized Hospital, Khartoum 11111, Sudan
| | - Bashir MO Arbab
- Department of Gastroenterology, Modern Medical Centre, Khartoum 11111, Sudan
| | - Nazar Beirag
- Biosciences, College of Health, Medicine and Life Sciences, Brunel University, London UB8 3PH, Uxbridge, United Kingdom
| | - El-Amin M Ibrahim
- Department of Medical Microbiology, Faculty of Medical Laboratory Sciences, University of Khartoum, Khartoum 11111, Sudan
| | - Mohamed A Hassan
- Department of Bioinformatics, Africa city of technology, Khartoum 11111, Sudan
- Department of Bioinformatics, DETAGEN Genetic Diagnostics Center, Kayseri 38350, Turkey
- Department of Translation Bioinformatics, Detavax Biotech, Kayseri 38350, Turkey
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The association of TNF-α -308G/A and -238G/A polymorphisms with type 2 diabetes mellitus: a meta-analysis. Biosci Rep 2019; 39:221417. [PMID: 31803921 PMCID: PMC6923338 DOI: 10.1042/bsr20191301] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 10/31/2019] [Accepted: 12/04/2019] [Indexed: 12/24/2022] Open
Abstract
Tumor necrosis factor-α (TNF-α) is involved in insulin resistance and has long been a candidate gene implicated in type 2 diabetes mellitus (T2DM), however the association between TNF-α polymorphisms -308G/A and -238G/A and T2DM remains controversial. The present study sought to verify associations between these polymorphisms and T2DM susceptibility using a meta-analysis approach. A total of 49 case-control studies were selected up to October 2018. Statistical analyses were performed by STATA 15.0 software. The odds ratios (ORs) and 95% confidence intervals were calculated to estimate associations. Meta-analyses revealed significant associations between TNF-α -308G/A and T2DM in the allele model (P=0.000); the dominant model (P=0.000); the recessive model (P=0.001); the overdominant model (P=0.008) and the codominant model (P=0.000). Subgroup analyses also showed associations in the allele model (P=0.006); the dominant model (P=0.004) and the overdominant model (P=0.005) in the Caucasian and in the allele model (P=0.007); the dominant model (P=0.014); the recessive model (P=0.000) and the codominant model (P=0.000) in the Asian. There were no associations between TNF-α -238G/A and T2DM in the overall and subgroup populations. Meta-regression, sensitivity analysis and publication bias analysis confirmed that results and data were statistically robust. Our meta-analysis suggests that TNF-α -308G/A is a risk factor for T2DM in Caucasian and Asian populations. It also indicates that TNF-α -238G/A may not be a risk factor for T2DM. More comprehensive studies will be required to confirm these associations.
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Mohanty S, Singh US, Mohanty S, Mohanty AK, Pande V, Das A. Evolutionary interplay of single nucleotide polymorphisms at the promoter region of TNF-α gene in different clinical outcomes of malaria in India. INFECTION GENETICS AND EVOLUTION 2019; 69:107-116. [PMID: 30677532 DOI: 10.1016/j.meegid.2019.01.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 01/16/2019] [Accepted: 01/21/2019] [Indexed: 01/17/2023]
Abstract
Host genetic factors are frequently ascribed to differential malaria outcomes as a by-product of evolutionary adaptation. To this respect, Tumor Necrosis factor alpha (TNF-α), a human cytokine, is known to be associated with malaria through its differential regulation in diverse malaria manifestations. Since diversity in differential malaria outcome is uncommon in every endemic settings, possible association of TNF-α and malaria is not commonly established. In order to check for association between the occurrence of Single Nucleotide Polymorphisms (SNPs) in the TNF-α gene with different malaria manifestations, we have sequenced a 4011 bp region constituting the promoter and the whole gene of human TNF-α in 61 patients [(16 cerebral plus severe (SCM), 21 severe (SM) and 24 uncomplicated (UM)] samples in a highly malaria endemic state (Odisha) of India. Multiple sequence alignment revealed presence of six SNPs (-1031 T > C, -863C > A, -857C > T, -308G > A, -806C > T, +787C > A), out of which the -806C > T and +787C > A are novel in malaria patients in general and the +787C > A was detected for the first time in humans. Although alleles due to six different SNPs segregate differentially in the three groups of malaria (SCM, SM and UM) in the present study, interestingly, for the -1031 T > C position, the frequency of individuals possessing the homozygous rare allele was higher in the SCM group with a higher number of heterozygotes in the UM group. The Tajima's D values considering all the SNPs in a defined group were positive and statistically insignificant conforming no evolutionary constraint. However, statistically significant deviation from expectation under Hardy-Weinberg equilibrium for -1031 T > C SNP in the UM group points towards the probable role of natural selection providing some kind of protection to malaria in Odisha, India.
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Affiliation(s)
- Stuti Mohanty
- Division of Vector Borne Diseases, ICMR-National Institute of Research in Tribal Health, Garha, Jabalpur, Madhya Pradesh, India
| | - Upasana Shyamsunder Singh
- Division of Vector Borne Diseases, ICMR-National Institute of Research in Tribal Health, Garha, Jabalpur, Madhya Pradesh, India; School of Earth and Environmental Sciences, The University of Manchester, Manchester M139PL, United Kingdom
| | - Sanjib Mohanty
- Community Welfare Society Hospital, Rourkela, Odisha, India
| | | | - Veena Pande
- Department of Biotechnology, Kumaun University, Nainital, Uttarakhand, India
| | - Aparup Das
- Division of Vector Borne Diseases, ICMR-National Institute of Research in Tribal Health, Garha, Jabalpur, Madhya Pradesh, India.
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Dittmar D, Schuttelaar ML. Immunology and genetics of tumour necrosis factor in allergic contact dermatitis. Contact Dermatitis 2017; 76:257-271. [DOI: 10.1111/cod.12769] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 12/16/2016] [Accepted: 01/02/2017] [Indexed: 12/27/2022]
Affiliation(s)
- Daan Dittmar
- Department of Dermatology; University Medical Centre Groningen, University of Groningen; 9700 RB Groningen The Netherlands
| | - Marie L. Schuttelaar
- Department of Dermatology; University Medical Centre Groningen, University of Groningen; 9700 RB Groningen The Netherlands
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Wieser F, Fabjani G, Tempfer C, Schneeberger C, Zeillinger R, Huber JC, Wenzl R. Tumor Necrosis Factor-α Promotor Polymorphisms and Endometriosis. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/107155760200900510] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
| | | | | | | | | | - Johannes C. Huber
- Deparment of Obstetrics and Gynecology, Division of Gynecological Endocrinology and Assisted Reproduction, Division of Gynecology and Obstetrics, University of Vienna, Vienna, Asutria
| | - Rene Wenzl
- Department of Obstetrics and Gynecology, Division of Gynecological Endocrinology and Assisted Reproduction, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
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Jamil K, Jayaraman A, Ahmad J, Joshi S, Yerra SK. TNF-alpha -308G/A and -238G/A polymorphisms and its protein network associated with type 2 diabetes mellitus. Saudi J Biol Sci 2016; 24:1195-1203. [PMID: 28855812 PMCID: PMC5562469 DOI: 10.1016/j.sjbs.2016.05.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2015] [Revised: 05/01/2016] [Accepted: 05/15/2016] [Indexed: 01/07/2023] Open
Abstract
Several reports document the role of tumor necrosis factor alpha (TNF-α) and lipid metabolism in the context of acute inflammation as a causative factor in obesity-associated insulin resistance and as one of the causative parameter of type 2 diabetes mellitus (T2DM). Our aim was to investigate the association between -308G/A and -238G/A polymorphisms located in the promoter region of the TNF-α gene in T2DM in the Indian population with bioinformatics analysis of TNF-α protein networking with an aim to find new target sites for the treatment of T2DM. Demographics of 100 diabetes patients and 100 healthy volunteers were collected in a structured proforma and 3 ml blood samples were obtained from the study group, after approval of Institutional Ethics Committee of the hospital (IEC). The information on clinical parameters was obtained from medical records. Genomic DNA was extracted; PCR-RFLP was performed using TNF-α primers specific to detect the presence of SNPs. Various bioinformatics tools such as STRING software were used to determine its network with other associated genes. The PCR-RFLP studies showed that among the -238G/A types the GG genotype was 87%, GA genotype was 12% and AA genotype was 1%. Almost a similar pattern of results was obtained with TNF-α -308G/A polymorphism. The results obtained were evaluated statistically to determine the significance. By constructing TNF-α protein interaction network we could analyze ontology and hubness of the network to identify the networking of this gene which may influence the functioning of other genes in promoting T2DM. We could identify new targets in T2DM which may function in association with TNF-α. Through hub analysis of TNF-α protein network we have identified three novel proteins RIPK1, BIRC2 and BIRC3 which may contribute to TNF-mediated T2DM pathogenesis. In conclusion, our study indicated that some of the genotypes of TNF-α -308G/A, -238G/A were not significantly associated to type 2 diabetes mellitus, but TNF-α -308G/A polymorphism was reported to be a potent risk factor for diabetes in higher age (>45) groups. Also, the novel hub proteins may serve as new targets against TNF-α T2DM pathogenesis.
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Affiliation(s)
- Kaiser Jamil
- Genetics Department, Bhagwan Mahavir Medical Research Centre, 10-1-1, Mahavir Marg, AC Guards, Hyderabad 500004, Telangana, India.,Centre for Biotechnology and Bioinformatics, School of Life Sciences, Jawaharlal Nehru Institute of Advanced Studies (JNIAS), Buddha Bhawan, 6th Floor, M.G. Road, Secunderabad 500003, Telangana, India
| | - Archana Jayaraman
- Centre for Biotechnology and Bioinformatics, School of Life Sciences, Jawaharlal Nehru Institute of Advanced Studies (JNIAS), Buddha Bhawan, 6th Floor, M.G. Road, Secunderabad 500003, Telangana, India
| | - Javeed Ahmad
- Zoology Department, Osmania University, Hyderabad 500007, Telangana, India
| | - Sindhu Joshi
- Mahavir Hospital and Research Centre, 10-1-1, Mahavir Marg, AC Guards, Hyderabad 500004, Telangana, India
| | - Shiva Kumar Yerra
- Cardiology Department, Mahavir Hospital and Research Centre, 10-1-1, Mahavir Marg, AC Guards, Hyderabad 500004, Telangana, India
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Kojima A, Kobayashi T, Ito S, Murasawa A, Nakazono K, Yoshie H. Tumor necrosis factor-alpha gene promoter methylation in Japanese adults with chronic periodontitis and rheumatoid arthritis. J Periodontal Res 2015; 51:350-8. [PMID: 26247485 DOI: 10.1111/jre.12314] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/07/2015] [Indexed: 01/29/2023]
Abstract
BACKGROUND AND OBJECTIVE Over-expression of tumor necrosis factor-alpha (TNF-α) plays a pathological role in chronic periodontitis (CP) and rheumatoid arthritis (RA), which might be regulated by the epigenetic mechanism. The aim of the present study was to evaluate whether there is a unique methylation profile of the TNF-α gene promoter in blood cells of individuals with CP and RA. MATERIAL AND METHODS The study participants consisted of 30 Japanese adults with RA (RA group), 30 race-matched adults with CP only (CP group) and 30 race-matched healthy controls (H group). Genomic DNA isolated from peripheral blood was modified by sodium bisulfite and analyzed, by direct sequencing, to investigate DNA methylation of the TNF-α gene promoter region. The level of TNF-α produced in mononuclear cells stimulated with Porphyromonas gingivalis lipopolysaccharide was determined using ELISA. RESULTS Twelve cytosine-guanine dinucleotide (CpG) motifs were identified in the TNF-α promoter fragment from -343 to +57 bp. The CP group showed a significantly higher methylation rate and frequency at -72 bp than the H group (p < 0.01). The RA group exhibited significantly higher methylation rates at seven CpG motifs (-302, -163, -119, -72, -49, -38 and +10 bp), and significantly higher methylation frequencies at six CpG motifs (-163, -119, -72, -49, -38 and +10 bp), than the H group (p < 0.01 for all comparisons). The levels of TNF-α produced were significantly different between individuals with and without methylation at -163 bp (p = 0.03). CONCLUSION These results suggest that the hypermethylated status of CpG motifs in the TNF-α gene promoter in blood cells may be unique to Japanese adults with CP and RA.
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Affiliation(s)
- A Kojima
- Division of Periodontology, Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - T Kobayashi
- Division of Periodontology, Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.,General Dentistry and Clinical Education Unit, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - S Ito
- Niigata Rheumatic Center, Shibata, Japan
| | - A Murasawa
- Niigata Rheumatic Center, Shibata, Japan
| | - K Nakazono
- Niigata Rheumatic Center, Shibata, Japan
| | - H Yoshie
- Division of Periodontology, Department of Oral Biological Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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Gichohi-Wainaina WN, Melse-Boonstra A, Feskens EJ, Demir AY, Veenemans J, Verhoef H. Tumour necrosis factor allele variants and their association with the occurrence and severity of malaria in African children: a longitudinal study. Malar J 2015; 14:249. [PMID: 26088606 PMCID: PMC4474355 DOI: 10.1186/s12936-015-0767-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 06/07/2015] [Indexed: 12/16/2022] Open
Abstract
Background Tumour necrosis factor (TNF) is central to the immune response to Plasmodium infection. Its plasma concentration is influenced by allele variants in the promoter region of TNF. The study’s objectives were to assess TNF allele variants (TNF−1031, TNF−308): (1) modulation of malaria rates in young Tanzanian children; (2) modulation of the severity of malaria as indicated by haemoglobin concentrations at the time of presentation with febrile episodes; and (3) the association between Plasmodium infection and haemoglobin concentration in symptomless parasite carriers. Methods Data from a placebo-controlled trial in which 612 Tanzanian children aged 6–60 months with height-for-age z-score in the range −3 SD to 1.5 SD was utilised. Those with Plasmodium infection at baseline were treated with artemether-lumefantrine. An episode of malaria was predefined as current Plasmodium infection with an inflammatory response (axillary temperature ≥37.5°C or whole blood C-reactive protein concentration ≥8 mg/L) in children reported sick. Linkage disequilibrium (LD) pattern assessment as well as haplotype analysis was conducted using HAPLOVIEW. Cox regression models used in the primary analysis accounted for multiple episodes per child. Results Genotyping of 94.9% (581/612) children for TNF−1031 (TNF−1031T>C); allele frequency was 0.39. Corresponding values for rs1800629 (TNF−308G>A) were 95.4% (584/612) and 0.17. Compared to the wild type genotype (TT), malaria rates were increased in the TNF−1031CC genotype (hazard ratio, HR [95% CI]: 1.41 [1.01‒1.97] and 1.31 [0.97‒1.76] for crude analysis and adjusting for pre-specified baseline factors, respectively) but decreased in those with the TNF−308AA genotype (corresponding HR: 0.13 [0.02‒0.63] and 0.16 [0.04‒0.67]). These associations were weaker when analysing first episodes of malaria (P value −0.59 and 0.38, respectively). No evidence that allele variants of TNF−1031 and TNF−308 affected haemoglobin concentration at first episode of malaria, or that they modified the association between Plasmodium infection and haemoglobin concentrations at baseline was observed. Conclusion In this cohort of Tanzanian children, the TNF−1031CC genotype was associated with increased rates of malarial episodes, whereas the TNF−308AA genotype was associated with decreased rates.
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Affiliation(s)
| | - Alida Melse-Boonstra
- Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.
| | - Edith J Feskens
- Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.
| | - Ayse Y Demir
- Laboratory for Clinical Chemistry, Meander Medical Centre, Amersfoort, The Netherlands.
| | - Jacobien Veenemans
- Laboratory for Microbiology and Infection Control, Amphia Hospital, Breda, The Netherlands.
| | - Hans Verhoef
- Cell Biology and Immunology Group, Wageningen University, Wageningen, The Netherlands. .,Medical Research Council (MRC) International Nutrition Group, London School of Hygiene & Tropical Medicine, London, UK. .,Medical Research Council (MRC), Keneba, The Gambia.
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Golshani H, Haghani K, Dousti M, Bakhtiyari S. Association of TNF-α 308 G/A Polymorphism With Type 2 Diabetes: A Case-Control Study in the Iranian Kurdish Ethnic Group. Osong Public Health Res Perspect 2015; 6:94-9. [PMID: 25938018 PMCID: PMC4411339 DOI: 10.1016/j.phrp.2015.01.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 11/20/2014] [Accepted: 01/15/2015] [Indexed: 12/03/2022] Open
Abstract
Objectives Tumor necrosis factor-α (TNF-α) plays roles in the development of obesity, insulin resistance, and possibility of Type 2 diabetes mellitus (T2DM). The objective of the current study was to evaluate the association of TNF-α promoter−308 G/A polymorphism with T2DM. Methods In all, 1038 patients with T2DM and 1023 normoglycemic controls were included in this study. All participants were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. Genotypic and allelic frequencies were then analyzed in each group. Serum lipids, fasting glucose, fasting serum insulin, homeostatic model assessment of insulin resistance, and hemoglogin A1c levels were determined by conventional methods. Results The allelic frequency of the A allele was significantly different between case and control participants (p = 0.006). Genotypes GA and AA were found to be significantly associated with 2.24- and 3.18-fold increased risk for T2DM, respectively. Similarly, the dominant model of -308 G/A polymorphism was found to have a higher risk for T2DM (odds ratio = 2.34, p = 0.001). Individuals with T2DM carrying the GA + AA genotypes of -308 G/A variation had significantly lower fasting plasma insulin than those carrying GG genotype. Conclusion Our findings revealed that there is an association between the TNF-α promoter -308 G/A polymorphism and T2DM in this population.
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Affiliation(s)
- Hasan Golshani
- Student Research Committee, Ilam University of Medical Sciences, Ilam, Iran
| | - Karimeh Haghani
- Department of Clinical Biochemistry, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Majid Dousti
- Department of Parasitology, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - Salar Bakhtiyari
- Department of Clinical Biochemistry, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
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Sefri H, Benrahma H, Charoute H, Lakbakbi el Yaagoubi F, Rouba H, Lyoussi B, Nourlil J, Abidi O, Barakat A. TNF A -308G>A polymorphism in Moroccan patients with type 2 diabetes mellitus: a case-control study and meta-analysis. Mol Biol Rep 2014; 41:5805-11. [PMID: 24952604 DOI: 10.1007/s11033-014-3454-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Accepted: 06/12/2014] [Indexed: 11/27/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is one of causes of mortality and morbidity in Moroccan population. The identification of genes implicated in this disease can help to found a specific treatment and to improve the quality of life for type 2 diabetic patients. In this study we analyze the association between a polymorphism (-308G>A) of TNF A promoter gene and T2DM in Moroccan patients. Five hundred and fifty-one individuals (307 patients with T2DM and 244 controls) were genotyped for this polymorphism by PCR-RFLP. This association was further reconsidered by a meta-analysis on 21 studies including 8,187 cases and 7,811 controls. We found that in Moroccan patients the -308A allele is strongly associated with T2DM (p = 0.000002; odds ratio 1.79, 95 % confidence interval 1.41-2.28). Based on our meta-analysis, there was no significant association detected between the TNF A -308G>A polymorphism and risk for T2DM. Our results suggest that the -308G>A polymorphism is a genetic risk factor for the development of T2DM in Moroccan population. On the other hand the meta analysis results led to controversial conclusions in other ethnicities.
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Affiliation(s)
- Hajar Sefri
- Laboratoire de Génétique Moléculaire Humaine, Département de Recherche Scientifique, Institut Pasteur du Maroc, 1, Place Louis Pasteur, 20360, Casablanca, Morocco
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The TNF-alpha -308G/A polymorphism is associated with type 2 diabetes mellitus: an updated meta-analysis. Mol Biol Rep 2013; 41:73-83. [DOI: 10.1007/s11033-013-2839-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 10/26/2013] [Indexed: 12/28/2022]
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Liu ZH, Ding YL, Xiu LC, Pan HY, Liang Y, Zhong SQ, Liu WW, Rao SQ, Kong DL. A meta-analysis of the association between TNF-α -308G>A polymorphism and type 2 diabetes mellitus in Han Chinese population. PLoS One 2013; 8:e59421. [PMID: 23527193 PMCID: PMC3601959 DOI: 10.1371/journal.pone.0059421] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 02/14/2013] [Indexed: 12/21/2022] Open
Abstract
Objective A meta-analysis was applied to evaluate the associations between tumor necrosis factor-α (TNF-α) −308G>A (rs1800629) polymorphism and type 2 diabetes mellitus (T2DM). Methods Hardy-Weinberg equilibrium (HWE) was employed to test genetic equilibrium among the genotypes of the selected literature. Power analysis was performed with the Power and Sample Size Calculation (PS) program. A fixed or random effect model was used on the basis of heterogeneity. Publication bias was quantified and examined with the Begg's funnel plot test and Egger's linear regression test. The meta-analysis was performed with Review Manager 5.1 and Stata 11.0. Results There were 10 studies including 1425 T2DM patients and 1116 healthy control subjects involved in this meta-analysis. No significant publication bias was found in the studies. The pooled ORs (95% CIs) for TNF-α −308G>A of A vs. G allele and GA+AA vs. GG genotype were 1.63 (1.17–2.25) and 1.47 (1.17–1.85), respectively. Conclusion This meta-analysis result suggested that TNF-α −308G>A polymorphism was strongly associated with T2DM risk, and A allele at this locus might be a susceptibility allele for the development of T2DM in Han Chinese population.
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Affiliation(s)
- Zheng-hui Liu
- Department of Epidemiology and Medical Statistics, School of Public Health, Guangdong Medical College, Dongguan, Guangdong, China
| | - Yuan-lin Ding
- Department of Epidemiology and Medical Statistics, School of Public Health, Guangdong Medical College, Dongguan, Guangdong, China
| | - Liang-chang Xiu
- Department of Epidemiology and Medical Statistics, School of Public Health, Guangdong Medical College, Dongguan, Guangdong, China
| | - Hai-yan Pan
- Department of Epidemiology and Medical Statistics, School of Public Health, Guangdong Medical College, Dongguan, Guangdong, China
| | - Yan Liang
- Department of Endocrinology and Metabolism, Maoming People’s Hospital, Maoming, Guangdong, China
| | - Shou-qiang Zhong
- Department of Endocrinology and Metabolism, Maoming People’s Hospital, Maoming, Guangdong, China
| | - Wei-wei Liu
- Department of Epidemiology and Medical Statistics, School of Public Health, Guangdong Medical College, Dongguan, Guangdong, China
| | - Shao-qi Rao
- Department of Epidemiology and Medical Statistics, School of Public Health, Guangdong Medical College, Dongguan, Guangdong, China
- * E-mail: (S-qR); (D-lK)
| | - Dan-li Kong
- Department of Epidemiology and Medical Statistics, School of Public Health, Guangdong Medical College, Dongguan, Guangdong, China
- * E-mail: (S-qR); (D-lK)
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Mustapic M, Popovic Hadzija M, Pavlovic M, Pavkovic P, Presecki P, Mrazovac D, Mimica N, Korolija M, Pivac N, Muck-Seler D. Alzheimer's disease and type 2 diabetes: the association study of polymorphisms in tumor necrosis factor-alpha and apolipoprotein E genes. Metab Brain Dis 2012; 27:507-12. [PMID: 22580620 DOI: 10.1007/s11011-012-9310-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2012] [Accepted: 04/24/2012] [Indexed: 12/18/2022]
Abstract
Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two progressive disorders with high prevalence worldwide. Polymorphisms in tumor necrosis factor-alpha (TNF-α) and apolipoprotein E (ApoE) genes might be associated with both T2D and AD, representing possible genetic markers for the development of the AD in subjects with T2D. The aim was to determine ApoE and G-308A TNF-α gene polymorphisms in unrelated Croatian Caucasians: 207 patients with sporadic AD, 196 T2D patients and 456 healthy controls. Patients with AD had higher frequency of ApoE4 allele compared to T2D patients and controls. The significant association, observed between ApoE2 allele and T2D, disappeared after the data were adjusted for age and sex. The genotype or allele frequencies of G-308A TNF-α gene polymorphism were similar among the patients with AD, T2D and healthy controls. In conclusion, these results do not support the hypothesis that the A allele of G-308A TNF-α gene polymorphism is associated either with AD or T2D. Our data confirm the association between the ApoE4 allele and AD, and point out the E2 allele of ApoE gene as the possible risk factor for T2D.
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15
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Sookoian SC, González C, Pirola CJ. Meta-analysis on theG-308ATumor Necrosis Factor α Gene Variant and Phenotypes Associated with the Metabolic Syndrome. ACTA ACUST UNITED AC 2012; 13:2122-31. [PMID: 16421346 DOI: 10.1038/oby.2005.263] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The G-308A tumor necrosis factor (TNF) alpha gene variant has been associated with obesity, insulin resistance, and hypertension. We performed a systematical review of the literature by means of a meta-analysis to assess the association of the G-308A TNFalpha polymorphism with the components of the metabolic syndrome. RESEARCH METHODS AND PROCEDURES Studies were identified by searches of the literature for reports using the terms: diabetes, insulin resistance, hypertension, obesity or metabolic syndrome and TNF, variants or polymorphism or alleles, and Nco or -308. From 824 reports, we included 31 observational studies, case control and cohort at baseline, which analyzed the association between the TNFalpha polymorphism and one or more components of the metabolic syndrome. A fixed effect model was used to pool data from individual studies. RESULTS Obesity [odds ratio, 1.23; 95% confidence interval (CI), 1.045 to 1.45; p = 0.013] in a total of 3562 individuals from eight homogeneous studies, systolic arterial blood pressure (standardized difference, 0.132; 95% CI, 0.016 to 0.25; p < 0.03) in a total of 1624 individuals from four homogeneous studies and plasma insulin levels (standardized difference, 0.095; 95% CI, 0.020 to 0.17; p = 0.013) in a total of 3720 subjects from 16 homogeneous studies were positively associated with the -308A variant. DISCUSSION These results indicate that individuals who carried the -308A TNFalpha gene variant are at 23% risk of developing obesity compared with controls and showed significantly higher systolic arterial blood pressure and plasma insulin levels, supporting the hypothesis that the TNFalpha gene is involved in the pathogenesis of the metabolic syndrome.
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Affiliation(s)
- Silvia C Sookoian
- Molecular Cardiology, Institute of Medical Research, A. Lanari, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
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Gupta V, Gupta A, Jafar T, Gupta V, Agrawal S, Srivastava N, Kumar S, Singh AK, Natu SM, Agarwal CG, Agarwal GG. Association of TNF-α promoter gene G-308A polymorphism with metabolic syndrome, insulin resistance, serum TNF-α and leptin levels in Indian adult women. Cytokine 2012; 57:32-36. [PMID: 21616679 DOI: 10.1016/j.cyto.2011.04.012] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2010] [Revised: 04/18/2011] [Accepted: 04/19/2011] [Indexed: 10/18/2022]
Abstract
BACKGROUND Tumour necrosis factor alpha is a multifunctional proinflammatory cytokine involved in the pathogenesis of metabolic syndrome, insulin resistance, and obesity. Aim of this study is to investigate in a North Indian female population the impact of the G-308A TNF-α variant on various components of the metabolic syndrome, Insulin Resistance, serum TNF-α and Leptin levels. METHODS The G-308A TNF-α polymorphism has been studied in 269 females with metabolic syndrome (NCEP ATP III criteria) (age 31.91±6.05) and 272 healthy females without metabolic syndrome (age 30.96±7.01). The G-308A variant was detected by PCR amplification and Nco-1 digestion. RESULTS Homozygous mutant genotype (AA) (p=<0.001: OR=3.24: 95% CI=2.15-4.89) and mutant allele (A) (p=<0.001: OR=3.04: 95% CI=2.08-4.43) of TNF-α was significantly less frequently observed in the control population as compared to study group. Furthermore, on dividing the subjects into two groups according to the absence (TNF-1 allele) or presence of the mutant A (TNF-2) allele, significant results were obtained in most of the metabolic risk factors. CONCLUSIONS Our results suggest that the G-308A polymorphism of the TNF-α gene may be independently associated with hypertension, leptin level and hypercholesterolemia leading to metabolic syndrome independent of Insulin resistance and hyperglycemia.
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Affiliation(s)
- Vani Gupta
- Department of Physiology, CSMMU UP, Lucknow, UP, India.
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Perez-Luque E, Malacara JM, Garay-Sevilla ME, Fajardo ME. Association of the TNF-α -308G/A polymorphism with family history of type 2 diabetes mellitus in a Mexican population. Clin Biochem 2011; 45:12-5. [PMID: 22015686 DOI: 10.1016/j.clinbiochem.2011.09.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2011] [Revised: 09/02/2011] [Accepted: 09/25/2011] [Indexed: 12/20/2022]
Abstract
AIMS We examined the possible association of the -308G/A polymorphism of the TNF-α promoter gene in type 2 diabetes mellitus (DM2) patients and in non-diabetic subjects with and without family history of DM2. METHODS We studied 87 non-diabetic subjects without DM2 family history in at least one of two generations, 48 non-diabetic subjects with DM2 family history and 95 DM2 patients. Genotyping was carried out by PCR-RFLP. RESULTS The frequency of TNF-α -308G/A genotype was significantly lower in non-diabetic subjects without DM2 relatives (6%) as compared to DM2 patients (24%) (odds ratio (OR)=5.24; 95% confidence interval (CI)=1.9-15.8, p<0.0005), but similar to non-diabetic subjects with DM2 relatives (29%) (OR=0.77; CI=0.3-1.7, p=0.4). Logistic regression analysis showed the association of TNF-α -308G/A polymorphism with DM2 family history (OR=5.80; CI=1.77-18.98, p<0.0003). CONCLUSIONS Our results suggest that TNF-α -308G/A polymorphism is associated with DM2 family history and is a risk factor for DM2.
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Affiliation(s)
- Elva Perez-Luque
- Departamento de Ciencias Medicas, Universidad de Guanajuato, Mexico.
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18
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Tumor necrosis factor alpha gene polymorphism is associated with the outcome of trauma patients in Chinese Han population. ACTA ACUST UNITED AC 2011; 70:954-8. [PMID: 20805766 DOI: 10.1097/ta.0b013e3181e88adf] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a major role in the sepsis and multiple organ dysfunction secondary to major trauma. The purpose of this article was to research the clinical relevance of the TNF gene polymorphism in patients with major trauma. METHODS Three hundred six patients with major trauma were prospectively recruited. The TNF gene polymorphisms were genotyped using restriction fragment length polymorphism analysis. Plasma TNF-α levels were determined with enzyme-linked immunosorbent assay. Sepsis morbidity rate and multiple organ dysfunction scores were accessed. RESULTS The TNF-α/-308 polymorphism was shown to be well associated with increased capacity of peripheral leukocytes to produce TNF-α in response to ex vivo lipopolysaccharide stimulation in trauma patients at admission. Results from association study indicated that trauma patients carrying the TNF-α/-308/A allele were more likely complicated with sepsis. CONCLUSIONS The TNF-α/-308 polymorphism might be used as a biomarker for the assessment of outcome of trauma patients, but the TNF-β/252 gene polymorphism might not influence the development of complications in patients with major trauma.
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19
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Feng RN, Zhao C, Sun CH, Li Y. Meta-analysis of TNF 308 G/A polymorphism and type 2 diabetes mellitus. PLoS One 2011; 6:e18480. [PMID: 21494616 PMCID: PMC3072982 DOI: 10.1371/journal.pone.0018480] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Accepted: 03/01/2011] [Indexed: 12/12/2022] Open
Abstract
Background and Objectives Many investigations have focused the association between TNF 308 G/A polymorphism and risk for type 2 diabetes mellitus (T2DM). However, the sample sizes of most of the studies were small. The aim of this study is to evaluate the precise association between this variant and risk for T2DM in a large-scale meta-analysis. Methods All publications were searched on the association between TNF 308 G/A polymorphism and T2DM. The key words were as follows: diabetes, tumor necrosis factor and polymorphism/variant/genotype. This meta-analysis was assessed by Review manager 5.0. Results There were 18 studies identified. The odd ritos (ORs) and 95% confidence intervals (CI) for GA+AA versus GG genotype of TNF 308 G/A polymorphism were 1.03 (0.95–1.12), 1.03 (0.94–1.13) and 1.03 (0.78–1.36) in overall, Caucasian and Asian populations, respectively. The sensitivity analysis further strengthened the validity of this association. No publication bias or heterogeneity was observed in this study. Conclusion In summary, there was no significant association detected between the TNF 308 G/A polymorphism and risk for T2DM.
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Affiliation(s)
- Ren-Nan Feng
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, China
| | - Chen Zhao
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, China
| | - Chang-Hao Sun
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, China
- * E-mail: (YL); (C-HS)
| | - Ying Li
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, China
- * E-mail: (YL); (C-HS)
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20
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Veloso S, Olona M, Peraire J, Viladés C, Pardo P, Domingo P, Asensi V, Broch M, Aguilar C, López-Dupla M, Aragonés G, Garcia-Pardo G, Sirvent JJ, Vendrell J, Richart C, Vidal, for the HIV Lipodystrophy St F. No relationship between TNF-α genetic variants and combination antiretroviral therapy-related lipodystrophy syndrome in HIV type 1-infected patients: a case-control study and a meta-analysis. AIDS Res Hum Retroviruses 2011; 27:143-52. [PMID: 20854131 DOI: 10.1089/aid.2009.0312] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Tumor necrosis factor alpha (TNF-α) is thought to be involved in the pathogenic and metabolic events associated with HIV-1 infection. We assessed whether carriage of the TNF-α gene promoter single nucleotide polymorphism (SNP) is associated with lipodystrophy and metabolic derangements in HIV-1-infected patients treated with cART. We also assessed variations in TNF-α receptor plasma levels. The study group comprised 286 HIV-1-infected patients (133 with and 153 without lipodystrophy) and 203 uninfected controls (UC). TNF-α -238G > A, -308G > A, and -863 C > A SNP were assessed using PCR-RFLPs on white cell DNA. Plasma sTNF-α R1 and R2 levels were measured by ELISA. Student's t test, the χ(2) test, Pearson correlations, and the logistic regression test were performed for statistical analysis. The TNF-α -308G > A SNP was significantly associated with lipodystrophy in the univariate analysis (p = 0.04). This association, however, was no longer significant in the multivariate analysis. A meta-analysis of the published literature and our own data, which included 284 patients with lipodystrophy and 338 without lipodystrophy, showed that there was no relationship between the TNF-α -238G > A and -308G > A SNP and lipodystrophy (p > 0.05 for all comparisons). HIV-1-infected patients had greater sTNF-α R2 plasma levels than UC (p = 0.001) whereas sTNF-α R1 and R2 levels were not significantly different in both the HIV-1-infected cohorts, lipodystrophy vs. nonlipodystrophy (p = NS). In our cohort of white Spaniards the TNF-α -238G > A, -308G > A, and -863C > A SNP were not associated with lipodystrophy in HIV-1-infected patients treated with cART. This finding was replicated in a meta-analysis of the published data, which showed no associations between the TNF-α -238G > A and -308G > A SNP and lipodystrophy. In HIV-1-infected patients under cART there is a systemic overproduction of sTNF-α R2, which is unrelated to the presence of lipodystrophy.
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Affiliation(s)
- Sergi Veloso
- Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
- IISPV, Tarragona, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
| | - Montserrat Olona
- Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
- IISPV, Tarragona, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
| | - Joaquim Peraire
- Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
- IISPV, Tarragona, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
| | - Consuelo Viladés
- Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
- IISPV, Tarragona, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
| | - Pedro Pardo
- IISPV, Tarragona, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
- Hospital Universitari de Sant Joan, Reus, Spain
| | - Pere Domingo
- Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Victor Asensi
- Hospital Universitario Central de Asturias, Oviedo, Spain
- Universidad de Oviedo, Oviedo, Spain
| | - Montserrat Broch
- IISPV, Tarragona, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
- CIBER Fisiopatologia de la Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Madrid, Spain
| | - Carmen Aguilar
- IISPV, Tarragona, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
- CIBER Fisiopatologia de la Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Madrid, Spain
| | - Miguel López-Dupla
- Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
- IISPV, Tarragona, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
| | - Gerard Aragonés
- IISPV, Tarragona, Spain
- Hospital Universitari de Sant Joan, Reus, Spain
| | - Graciano Garcia-Pardo
- Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
- IISPV, Tarragona, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
| | - Joan-Josep Sirvent
- Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
- IISPV, Tarragona, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
| | - Joan Vendrell
- Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
- IISPV, Tarragona, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
- CIBER Diabetes y Enfermedades Metabólicas Asociadas (CB07/08/0012), Instituto de Salud Carlos III, Madrid, Spain
| | - Cristóbal Richart
- Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
- IISPV, Tarragona, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
- CIBER Fisiopatologia de la Obesidad y Nutrición (CB06/03), Instituto de Salud Carlos III, Madrid, Spain
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Chatterjee K. Host genetic factors in susceptibility to HIV-1 infection and progression to AIDS. J Genet 2010; 89:109-16. [DOI: 10.1007/s12041-010-0003-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Wienzek S, Kissel K, Breithaupt K, Lang C, Nockher A, Hackstein H, Bein G. Tumor necrosis factor alpha gene variants do not display allelic imbalance in circulating myeloid cells. Cell Immunol 2010; 262:127-33. [PMID: 20206339 DOI: 10.1016/j.cellimm.2010.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2009] [Revised: 02/01/2010] [Accepted: 02/04/2010] [Indexed: 11/30/2022]
Abstract
Carriage of the TNF -308 A allele (rs1800629 A) has been associated with increased serum TNF-alpha levels, the development of sepsis syndrome, and fatal outcome, in severely traumatized patients (Menges et al., 2008 [1]). Herein, we analysed the putative allelic imbalance of TNF-alpha release from myeloid cells. Circulating peripheral blood cells from healthy human blood donors (n=104) and monocyte-derived macrophages (n=158) were analysed for their ex vivo capacity of TNF-alpha expression. Our findings indicate that carriage of the TNF -308 A allele is not associated with high TNF-alpha expression in circulating human leucocytes and monocyte-derived macrophages. Other cellular sources, e.g. tissue-resident cells like mast cells and/or tissue specific macrophages might be the cellular source of high TNF-alpha serum levels shortly after trauma.
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Affiliation(s)
- Sandra Wienzek
- Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University Giessen, Giessen, Germany.
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23
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Bouhaha R, Baroudi T, Ennafaa H, Vaillant E, Abid H, Sassi R, Vatin V, Froguel P, Gaaied ABE, Meyre D, Vaxillaire M. Study of TNFalpha -308G/A and IL6 -174G/C polymorphisms in type 2 diabetes and obesity risk in the Tunisian population. Clin Biochem 2010; 43:549-52. [PMID: 20132806 DOI: 10.1016/j.clinbiochem.2010.01.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2009] [Revised: 01/08/2010] [Accepted: 01/23/2010] [Indexed: 12/17/2022]
Abstract
OBJECTIVES We investigated two genetic markers in pro inflammatory molecules : TNFalpha -308G/A and IL6 -174G/C in order to assess their effect on type 2 diabetes (T2D) and obesity in the Tunisian population. DESIGN AND METHODS The study sample includes 228 patients with T2D and 300 healthy controls. Genotyping of IL6 -174G/C (rs1800795) was performed using Automated Dye Terminator Sequencing and of TNFalpha -308G/A (rs1800629) using the LightTyper technology. RESULTS SNPs IL6 -174G/C and TNFalpha -308G/A are associated neither with T2D (p=0.89, p=0.34 respectively) nor with risk for overweight (p=0.86, p=0.12 respectively) in Tunisian population. Bonferroni correction showed that the founded association of IL6 -174G/C SNP with T2D susceptibility restricted to overweight patients (p(nominal)=0.03, p(corrected)=0.0033) is likely to be a random result. CONCLUSION SNPs IL6 -174G/C and TNFalpha -308G/A are not major contributors to T2D or obesity risk in our Tunisian population.
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Affiliation(s)
- Rym Bouhaha
- Laboratory of Genetics, Immunology and Human Pathologies, Faculty of Sciences of Tunis, 2092 Tunis, Tunisia.
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Feng R, Li Y, Zhao D, Wang C, Niu Y, Sun C. Lack of association between TNF 238 G/A polymorphism and type 2 diabetes: a meta-analysis. Acta Diabetol 2009; 46:339-43. [PMID: 19367363 DOI: 10.1007/s00592-009-0118-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Accepted: 03/24/2009] [Indexed: 10/20/2022]
Abstract
The aim of this meta-analysis was to determine the nature of the association between TNF 238 G/A polymorphism and the risk for T2D. We searched databases updated on January 2009 for all publications on the association between this variation and T2D. Data on genotypes and the numbers of cases and controls were assessed using Review Manager 4.2. Meta-analysis of the overall and specific populations was conducted, and odds ratios (OR) and 95% confidence intervals (95% CI) were calculated in the fixed-effect model. I(2) statistic was calculated to examine heterogeneity, and publication bias was evaluated by Egger test. The overall OR (95% CI) for AA and GA genotypes versus GG genotype for TNF-alpha-238 was 1.15 (0.92-1.44), which in European and Asian populations were 1.18 (0.92-1.51) and 1.13 (0.62-2.04), respectively. This first meta-analysis of data from the current and published studies did not detect any association between the polymorphism of TNF 238 G/A and risk for T2D.
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Affiliation(s)
- Rennan Feng
- Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, Harbin, People's Republic of China
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Association of tumor necrosis factor alpha and IL-10 promoter polymorphisms with rheumatoid arthritis in North Indian population. Rheumatol Int 2009; 30:1211-7. [PMID: 19779724 DOI: 10.1007/s00296-009-1131-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2009] [Accepted: 09/13/2009] [Indexed: 12/13/2022]
Abstract
Rheumatoid arthritis is a chronic autoimmune disorder associated with altered expression of pro- and anti-inflammatory cytokines in the affected tissues. The aim of this study was to investigate the association between promoter polymorphisms of TNFalpha and IL-10 gene with susceptibility, age of disease onset and disease severity in North Indian patients with rheumatoid arthritis (RA). SNPs at position -308 and -863 of TNF gene and -819/-592 and -1082 position of IL-10 gene were determined in 222 patients and 208 healthy controls using RFLP or ARMS method. Polymorphism TNF -308A was less prevalent among the patients (1.7%) than controls (4.9%; p = 0.01, OR: 0.32, 95% CI: 0.13-0.76). Among female patients, IL-10 -592A allele associated with higher baseline disease activity scores (5.77 +/- 1.99) than -592C (5.57 +/- 1.19; p = 0.04). Female patients carrying allele A of TNFalpha -863 had earlier age of onset of RA (33.99 +/- 9.6 years) than those with allele C (36.15 +/- 11.21 years; p = 0.043). In conclusion, allele A at TNFalpha -308 locus provides protection against RA in North Indian population while another TNF allele A at -863 position had weak association with earlier onset of disease in female patients. On the other hand promoter polymorphisms of IL-10 did not affect susceptibility but polymorphism at -819/-592A was associated with higher disease activity scores at baseline.
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Hayashi N, Imamura Y, Hiyoshi Y, Takamori H, Beppu T, Hirota M, Baba H. Rapid genotyping of tumor necrosis factor alpha with fluorogenic hybridization probes on the LightCycler. Clin Exp Med 2008; 8:217-24. [PMID: 18815866 DOI: 10.1007/s10238-008-0009-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2007] [Accepted: 07/15/2008] [Indexed: 11/27/2022]
Abstract
Genotyping of tumor necrosis factor alpha (TNF-alpha) has become an important procedure in the selection of high-risk population of septic shock and prevention from death due to septic shock. We present a single-tube method for TNF-alpha genotyping that performed on the LightCycler by melting curve analysis with allele-specific fluorescent probe. A fragment covering the polymorphic site is amplified in the presence of two fluorescently labeled hybridization probes. During amplification, probe hybridization is observed as fluorescence increases every cycle as the product accumulates during amplification. A single base mismatch resulted in a melting temperature (Tm) shift of 7-8 degrees C, allowing for the easy distinction of a common type allele from the polymorphic allele. Using this method, genotyping of 104 samples was completed within 1 h without the need for any post-PCR sample manipulation, thereby eliminating the risks of end-product contamination and sample tracking errors. The genotypes determined with the LightCycler were identical when compared with a conventional sequencing. The simplicity, speed, and accuracy of real-time PCR analysis using FRET probes make it the method of choice in the clinical laboratory for genotyping of a variety of human DNA polymorphisms and mutations.
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Affiliation(s)
- Naoko Hayashi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
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Sohail M, Kaul A, Bali P, Raziuddin M, Singh M, Singh O, Dash A, Adak T. Alleles −308A and −1031C in the TNF-α gene promoter do not increase the risk but associated with circulating levels of TNF-α and clinical features of vivax malaria in Indian patients. Mol Immunol 2008; 45:1682-92. [DOI: 10.1016/j.molimm.2007.10.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2007] [Revised: 09/28/2007] [Accepted: 10/01/2007] [Indexed: 11/16/2022]
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Baena A, Mootnick AR, Falvo JV, Tsytsykova AV, Ligeiro F, Diop OM, Brieva C, Gagneux P, O'Brien SJ, Ryder OA, Goldfeld AE. Primate TNF promoters reveal markers of phylogeny and evolution of innate immunity. PLoS One 2007; 2:e621. [PMID: 17637837 PMCID: PMC1905939 DOI: 10.1371/journal.pone.0000621] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2007] [Accepted: 06/12/2007] [Indexed: 11/18/2022] Open
Abstract
Background Tumor necrosis factor (TNF) is a critical cytokine in the immune response whose transcriptional activation is controlled by a proximal promoter region that is highly conserved in mammals and, in particular, primates. Specific single nucleotide polymorphisms (SNPs) upstream of the proximal human TNF promoter have been identified, which are markers of human ancestry. Methodology/Principal findings Using a comparative genomics approach we show that certain fixed genetic differences in the TNF promoter serve as markers of primate speciation. We also demonstrate that distinct alleles of most human TNF promoter SNPs are identical to fixed nucleotides in primate TNF promoters. Furthermore, we identify fixed genetic differences within the proximal TNF promoters of Asian apes that do not occur in African ape or human TNF promoters. Strikingly, protein-DNA binding assays and gene reporter assays comparing these Asian ape TNF promoters to African ape and human TNF promoters demonstrate that, unlike the fixed differences that we define that are associated with primate phylogeny, these Asian ape-specific fixed differences impair transcription factor binding at an Sp1 site and decrease TNF transcription induced by bacterial stimulation of macrophages. Conclusions/significance Here, we have presented the broadest interspecies comparison of a regulatory region of an innate immune response gene to date. We have characterized nucleotide positions in Asian ape TNF promoters that underlie functional changes in cell type- and stimulus-specific activation of the TNF gene. We have also identified ancestral TNF promoter nucleotide states in the primate lineage that correspond to human SNP alleles. These findings may reflect evolution of Asian and African apes under a distinct set of infectious disease pressures involving the innate immune response and TNF.
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Affiliation(s)
- Andres Baena
- The CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Alan R. Mootnick
- Gibbon Conservation Center, Santa Clarita, California, United States of America
| | - James V. Falvo
- The CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Alla V. Tsytsykova
- The CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Filipa Ligeiro
- The CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Ousmane M. Diop
- Laboratoire de Rétrovirologie, Institut Pasteur, Dakar, Senegal
| | - Claudia Brieva
- Unidad de Rescate y Rehabilitación de Animales Silvestres, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional de Colombia, Bogotá, Colombia
| | - Pascal Gagneux
- Project for Explaining the Origin of Humans, Glycobiology Research and Training Center, Department of Medicine and Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, United States of America
| | - Stephen J. O'Brien
- Laboratory of Genomic Diversity, National Cancer Institute, Frederick, Maryland, United States of America
| | - Oliver A. Ryder
- Conservation and Research for Endangered Species, Zoological Society of San Diego, San Diego, California, United States of America
- Division of Biological Sciences, University of California at San Diego, La Jolla, California, United States of America
| | - Anne E. Goldfeld
- The CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts, United States of America
- * To whom correspondence should be addressed. E-mail:
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Yoshioka K, Yoshida T, Takakura Y, Umekawa T, Kogure A, Toda H, Yoshikawa T. Relationship between polymorphisms 804C/A and 252A/G of lymphotoxin-alpha gene and -308G/A of tumor necrosis factor alpha gene and diabetic retinopathy in Japanese patients with type 2 diabetes mellitus. Metabolism 2006; 55:1406-10. [PMID: 16979413 DOI: 10.1016/j.metabol.2006.06.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2005] [Accepted: 06/12/2006] [Indexed: 10/24/2022]
Abstract
To clarify whether polymorphisms of the lymphotoxin-alpha (LTA) gene and tumor necrosis factor alpha (TNF-alpha) gene were related to diabetic retinopathy (DR), we performed a case-control study in 251 Japanese patients with type 2 diabetes mellitus participating in a multicenter research protocol. Genetic analyses were performed by using a fluorescent allele-specific DNA primer assay system. Diabetic retinopathy was diagnosed in a masked manner by an independent ophthalmologist using fundus photographs and was classified as nondiabetic retinopathy (NDR), nonproliferative retinopathy (NPDR), and proliferative retinopathy (PDR). The results showed that the genotype frequencies of 804C/A in exon 3 and 252A/G in intron 1 of the LTA gene were not significantly different among patients with NDR, NPDR, and PDR. A allelic frequency of the TNF-alpha gene (-302A/G in promoter) was also identical among NDR, NPDR, and PDR groups. Multivariate logistic regression analyses showed that significant associations with DR were glycosylated hemoglobin level and diabetes duration, but not polymorphisms of the LTA gene or TNF-alpha gene. In conclusion, the present study showed no association between polymorphisms 804C/A and 252A/G of the LTA gene and -302A/G of the TNF-alpha gene and DR in Japanese type 2 diabetic patients.
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Affiliation(s)
- Keiji Yoshioka
- Department of Diabetes and Endocrinology, Matsushita Memorial Hospital, Moriguchi, Osaka 570-8540, Japan.
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González-Sánchez JL, Martínez-Calatrava MJ, Martínez-Larrad MT, Zabena C, Fernández-Pérez C, Laakso M, Serrano-Ríos M. Interaction of the -308G/A promoter polymorphism of the tumor necrosis factor-alpha gene with single-nucleotide polymorphism 45 of the adiponectin gene: effect on serum adiponectin concentrations in a Spanish population. Clin Chem 2005; 52:97-103. [PMID: 16254197 DOI: 10.1373/clinchem.2005.049452] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND We investigated whether interactions of the -308G/A polymorphism in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene with single-nucleotide polymorphisms (SNPs) 45 and 276 of the adiponectin gene are associated with circulating adiponectin and soluble TNF-alpha receptor 2 (sTNFR2) concentrations in a Spanish population. METHODS We performed anthropometric and physiologic measurements in 809 unrelated participants recruited with a simple random sampling approach from respondents to a cross-sectional population-based epidemiologic survey in the province of Segovia in central Spain (Castille). RESULTS The 2-h postload glucose and serum insulin concentrations were higher in -308A allele carriers than in -308G/G individuals homozygous for the TNF-alpha gene. Plasma concentrations of sTNFR2 were positively correlated with body mass index, waist-to-hip ratio, and sagittal abdominal diameter among individuals with type 2 diabetes. Individuals with type 2 diabetes and the -308A allele had higher sTNFR2 and lower adiponectin concentrations than -308G homozygotes. Moreover, individuals carrying both the TNF-alpha -308A allele and the G allele of SNP 45 in the adiponectin gene had the highest prevalence of impaired glucose tolerance (adjusted odds ratio, 1.26; 95% confidence interval, 1.01-1.56; P = 0.038) and had lower adiponectin concentrations (beta = -0.090; P = 0.005) than individuals without these genotypes. CONCLUSIONS Our findings are the first to indicate that a higher incidence of impaired glucose tolerance and low circulating adiponectin concentration may be associated with interaction between the -308G/A promoter polymorphism of the TNF-alpha gene and SNP 45 in the adiponectin gene.
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Ateş A, Kinikli G, Düzgün N, Duman M. Lack of association of tumor necrosis factor-alpha gene polymorphisms with disease susceptibility and severity in Behçet’s disease. Rheumatol Int 2005; 26:348-53. [PMID: 15875188 DOI: 10.1007/s00296-005-0610-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2004] [Accepted: 03/03/2005] [Indexed: 10/25/2022]
Abstract
Although it has been reported that the MHC class I molecule, HLA-B51, is a risk factor for Behçet's disease (BD), contribution of the tumor necrosis factor (TNF) genes, which are located in the vicinity of the HLA-B locus, to the genetic susceptibility for BD has yet to be elucidated. The purpose of this study was to analyze the effect of TNF-alpha promoter polymorphisms at positions -308, -238 and -376 on the susceptibility, severity and clinical features of BD. The TNF-alpha gene sequences from 107 patients with BD and 102 healthy subjects were amplified by the polymerase chain reaction. Sequence analysis of the TNF-alpha gene locus, which contains promoter polymorphisms at positions -376, -308, and -238, was performed with a DNA sequencing kit on automated sequencer. The patients were classified according to disease severity and clinical features. Serum TNF-alpha level in the study groups was measured by sandwich enzyme immunoassay. In patients with BD the frequencies of TNF-alpha -308 (19.4% vs 18.4%), -238 (3.7% vs 5.9%), and -376 (0.9% vs 2.9%) gene polymorphisms were not found to be significantly different from those in healthy subjects. The TNF-alpha gene polymorphisms did not show any association with disease severity or clinical features. Serum TNF-alpha level was significantly higher in patients with BD than in healthy controls (3.10 +/- 1.45 pg/ml vs 2.43 +/- 1.94 pg/ml, P < 0.01). Serum TNF-alpha level was not found to be significantly associated with disease severity, activity, clinical findings and TNF-alpha genotypes. The results of this study suggest that the TNF-alpha gene polymorphisms are unlikely to play an important role in the pathogenesis and severity of BD.
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Affiliation(s)
- Aşkin Ateş
- Department of Clinical Immunology and Rheumatology, Faculty of Medicine, Ankara University, Refik Belendir sokak, 57/5 Y. Ayranci, 06540 Ankara, Turkey.
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Bayley JP, Ottenhoff THM, Verweij CL. Is there a future for TNF promoter polymorphisms? Genes Immun 2005; 5:315-29. [PMID: 14973548 DOI: 10.1038/sj.gene.6364055] [Citation(s) in RCA: 182] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The in vitro study of TNF promoter polymorphism (SNP) function was stimulated by the numerous case-control (association) studies of the polymorphisms in relation to human disease and the appearance of several studies claiming to show a functional role for these SNPs provided a further impetus to researchers interested in the role of TNF in their disease of interest. In this review we consider case-control studies, concentrating on the autoimmune and inflammatory diseases rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, and asthma, and on infectious diseases including malaria, hepatitis B and C infection, leprosy and sepsis/septic shock. We also review the available evidence on the functional role of the various TNF promoter polymorphisms. In general, case-control studies have produced mixed results, with little consensus in most cases on whether any TNF polymorphisms are actually associated with disease, although results have been more consistent in the case of infectious diseases, particularly malaria. Functional studies have also produced mixed results but recent work suggests that the much studied -308G/A polymorphism is not functional, while the function of other TNF polymorphisms remains controversial. Studies of the TNF region are increasingly using extended haplotypes that can better capture the variation of the MHC region.
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Affiliation(s)
- J-P Bayley
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
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Sotgiu S, Pugliatti M, Fois ML, Arru G, Sanna A, Sotgiu MA, Rosati G. Genes, environment, and susceptibility to multiple sclerosis. Neurobiol Dis 2004; 17:131-43. [PMID: 15474351 DOI: 10.1016/j.nbd.2004.07.015] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2004] [Revised: 07/01/2004] [Accepted: 07/20/2004] [Indexed: 11/22/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic disease of the central nervous system affecting young adults and thus representing a major burden also for their families and communities. The etiology of MS is obscure and its pathogenesis is yet incompletely depicted. Increased evidences indicate a strong genetic contribution to MS susceptibility, although others support the view that it is also influenced by environmental factors, possibly related to still unidentified pathogens. MS appears to be more heterogeneous than previously believed at the immunological level, and new pathological studies indicate a series of subset of conditions under the common denominator MS. The use of genetically homogeneous and geographically isolated populations at high MS risk, such as that of Sardinia, insular Italy, becomes in principle a vital requirement to reduce biological variables and the intrinsic complexity of the disease. This review will focus on recent findings on the peculiarity of Sardinian MS concerning epidemiological, genetic, and environmental aspects. Epidemiological studies reveal a clear heterogeneous distribution of MS cases in the Northern province of Sassari which may not be uniquely assigned to genetic variations. Furthermore, a different immunogenetic profile, including the association with other immunomediated diseases, and a progressive change in clinical phenotype, including age at onset, are present in this island which gives us unexpected variations at the level of patients' cohort and territorial distribution, especially when the northern province is compared to the southern one. This renders MS etiopathogenesis more complex than formerly thought even in this selected and genetically stable population.
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Affiliation(s)
- Stefano Sotgiu
- Institute of Clinical Neurology, University of Sassari, 07100 Sassari, Italy.
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Zouari Bouassida K, Chouchane L, Jellouli K, Chérif S, Haddad S, Gabbouj S, Danguir J. Polymorphism of stress protein HSP70-2 gene in Tunisians: susceptibility implications in type 2 diabetes and obesity. DIABETES & METABOLISM 2004; 30:175-80. [PMID: 15223990 DOI: 10.1016/s1262-3636(07)70104-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
OBJECTIVES Tumor necrosis factor alpha (TNFalpha) is expressed primarily in adipocytes and elevated levels of this cytokine have been linked to obesity and insulin resistance. Several studies have shown statistical evidence of linkage between obesity and the chromosomal region encompassing the TNFalpha gene, suggesting that TNF alpha and/or a nearby gene is involved in the pathogenesis of obesity. Recently we analyzed the -308 TNFalpha polymorphism and that of HSP70-2 gene in Tunisian patients with obesity and no significant difference in allele frequencies of the -308 TNFalpha polymorphism was found between obese patients and controls. In contrast, polymorphism in HSP70-2 gene was found to be highly associated with obesity. Both TNFalpha and HSP70-2 genes have been mapped within the major histocompatibility complex (MHC). We designated a case-controlled study to investigate a potential association of genetic variation of the TNFalpha and that of the heat shock protein 70-2 (HSP70-2) with type 2 diabetes. METHODS We used the polymerase chain reaction and restriction enzyme to characterize the variation of the TNFalpha promoter region and that of the HSP70-2 gene in 280 unrelated Tunisian patients with type2 diabetes and 274 healthy control subjects. RESULTS Analysis of the -308 TNFalpha polymorphism in patients with type 2 diabetes and in control subjects revealed that the heterozygous TNF1/TNF2 genotype was significantly less frequent in the patient group (p=0.003), suggesting that TNF1/TNF2 may be considered as a protective marker against type 2 diabetes (OR=0.58). In contrast, a significant relative risk of type 2 diabetes was found associated with the P2-HSP70-2 homozygous genotype in non obese diabetic subjects (OR=1.97; p=0.0012). CONCLUSION These results along with those showing high frequency of P2-HSP70-2 genotype in obese Tunisians, suggest that HSP70-2 polymorphism has susceptibility implications in both obesity and diabetes.
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Affiliation(s)
- K Zouari Bouassida
- Service de Nutrition expérimentale, Institut de Nutrition, Tunis, Tunisie
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Schwab SG, Mondabon S, Knapp M, Albus M, Hallmayer J, Borrmann-Hassenbach M, Trixler M, Gross M, Schulze TG, Rietschel M, Lerer B, Maier W, Wildenauer DB. Association of tumor necrosis factor alpha gene -G308A polymorphism with schizophrenia. Schizophr Res 2003; 65:19-25. [PMID: 14623370 DOI: 10.1016/s0920-9964(02)00534-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Tumor necrosis factor alpha (TNFalpha), a cytokine involved in inflammatory processes, has been implicated in the pathophysiology of schizophrenia. The chromosomal location in the major histocompatibility complex (MHC) region on 6p21.1-21.3, a region with evidence for linkage, suggests a role in susceptibility to schizophrenia. Association of the minor (A) allele of the -G308A TNFalpha gene polymorphism with schizophrenia has been reported [Mol. Psychiatry 6 (2001) 79]. METHODS Association of the -G308A TNFalpha gene and the lymphotoxin alpha (LTalpha)+A252G gene polymorphisms with schizophrenia was studied in 79 sib pair families with linkage in the MHC region and in 128 trio families using the transmission disequilibrium test (TDT). RESULTS Weak association of the common G allele was detected for TNFalpha -G308A in both samples independently with borderline significance in the sib pair families (0.064) and with a nominally significant value of P=0.022 in the trio families. Combining both samples produced P=0.003, while LTalpha+A252G, located approximately 2-3 kb distally, revealed P=0.03 and the two locus haplotype yielded a P value of 0.001. CONCLUSION Our data suggests association of the common G allele of the -G308A TNFalpha gene polymorphism with schizophrenia in a sample of 207 families. However, linkage disequilibrium with a different allele of the TNFalpha gene or another gene in the MHC region cannot be excluded.
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Affiliation(s)
- Sibylle G Schwab
- Department of Psychiatry, University of Bonn, Wilhelmstr. 31, D-53111 Bonn, Germany
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Um JY, Park JH, Kim HM. Gene polymorphisms in tumor necrosis factor locus and waist–hip ratio in obese Koreans. Clin Chim Acta 2003; 338:117-22. [PMID: 14637275 DOI: 10.1016/j.cccn.2003.08.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND The study was designed to investigate the association among tumor necrosis factor-beta (TNFbeta)+252A/G, TNF-alpha (TNFalpha)-308G/A polymorphisms and anthropometric parameters related to obesity in Korean obese subjects. METHODS The study included 152 obese healthy subjects (BMI>or=25 kg/m(2), range 25.0-40.4, age range 15-40 years) and 82 non-obese controls (BMI<25 kg/m(2), age range 15-40 years). Total fat mass and percent body fat were determined by dual-energy X-ray absorptiometry (DEXA). Genomic DNA was extracted and used for NcoI restriction fragment length polymorphism (RFLP)-based genotyping of TNF. RESULTS No differences were observed for allelic and genotype frequencies between obese and non-obese subjects. Also, no association of TNF polymorphisms was observed with body mass index (BMI) for genotype in obese subjects. In addition, age, percent body fat, BMI and cholesterol concentrations did not differ from TNF genotypes. However, waist-to-hip ratio (WHR) was significantly decreased in subjects with TNFalpha A/TNFbeta G haplotype compared with other haplotypes carriers (0.92+/-0.03 vs. 0.94+/-0.06, P=0.005). CONCLUSIONS These results suggest that TNF polymorphisms at position -308 and +252 are not a significant factor for BMI, but affect the WHR in obese Koreans.
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Affiliation(s)
- Jae-Young Um
- Department of Pharmacology, College of Oriental Medicine, Kyung Hee University, 1 Hoegi-Dong, Dongdaemun-Gu, 130-701, Seoul, South Korea
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Morris AM, Heilbronn LK, Noakes M, Kind KL, Clifton PM. -308 Nco I polymorphism of tumour necrosis factor alpha in overweight Caucasians. Diabetes Res Clin Pract 2003; 62:197-201. [PMID: 14625134 DOI: 10.1016/j.diabres.2003.08.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
We investigated whether a polymorphism in the promoter region of the TNFalpha gene (-308 A/G) is associated with reduced weight loss in obese Australian subjects on an energy restricted diet. 189 healthy subjects and 91 subjects with type II diabetes were genotyped for the -308 Nco I polymorphism using PCR-RFLP techniques. A subset of these subjects (211 females and 45 males), were placed on a 30% energy restricted diet (6200 kJ) for 12 weeks. Subjects were assessed every 2 weeks and changes in body weight, waist circumference and BMI were used as determinants of weight loss. Fasting plasma was analysed for glucose, insulin, lipids and free fatty acids. 64% of subjects were GG homozygotes, 31% were AG heterozygotes and 5% were AA homozygotes. There was no significant difference between the allele frequency in healthy subjects (0.21) and type 2 diabetic patients (0.24). The presence of the -308 A/G polymorphism did not significantly influence initial BMI, the amount of weight lost (GG, 8.1+/-0.65 kg, AG, 6.9+/-0.77 kg, AA, 7.6+/-0.12 kg), waist circumference or any metabolic variable. The AA variant at position -308 in the promoter region of the TNFalpha gene does not influence the amount of weight lost in overweight and obese men and women on a 30% energy restricted diet.
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Affiliation(s)
- Alison M Morris
- Department of Physiology, Adelaide University, Adelaide, SA 5000, Australia.
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Moukoko CE, El Wali N, Saeed OK, Mohamed-Ali Q, Gaudart J, Dessein AJ, Chevillard C. No evidence for a major effect of tumor necrosis factor alpha gene polymorphisms in periportal fibrosis caused by Schistosoma mansoni infection. Infect Immun 2003; 71:5456-60. [PMID: 14500462 PMCID: PMC201038 DOI: 10.1128/iai.71.10.5456-5460.2003] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Hepatic periportal fibrosis (PPF), associated with portal hypertension, is a major pathological consequence of infections with Schistosoma mansoni and Schistosoma japonicum. Indeed, affected subjects may die from portal hypertension. Previous studies have indicated that tumor necrosis factor alpha (TNF-alpha) may aggravate fibrosis. We therefore investigated whether PPF was associated with certain polymorphisms of the TNF-alpha gene. Four polymorphisms (TNF-alpha -376 G/A, -308 G/A, -238 G/A, and +488 G/A) were investigated in two Sudanese populations living in an area in which S. mansoni is endemic. These polymorphisms were analyzed for 105 Sudanese subjects with various grades of PPF, from mild to advanced; all subjects were from two neighboring villages (Taweela and Umzukra). They were then analyzed for 70 subjects with advanced liver disease and for 345 matched controls from the Gezira region. We found no evidence of associations between these four polymorphisms and PPF in both of these studies. Thus, these four polymorphisms, two of which (TNF-alpha -376 and -308) were found to increase TNF-alpha gene transcription, are unlikely to have a major effect on PPF progression in these populations. However, this result does not exclude the possibility that these polymorphisms have a minor effect on PPF development.
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Affiliation(s)
- Carole Eboumbou Moukoko
- Immunologie et Génétique des Maladies Parasitaires, Institut National de la Santé et de la Recherche Médicale, INSERM U399, Laboratoire de Parasitologie-Mycologie, Faculté de Médecine, Marseille, France
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Bown MJ, Horsburgh T, Nicholson ML, Bell PRF, Sayers RD. Cytokine gene polymorphisms and the inflammatory response to abdominal aortic aneurysm repair. Br J Surg 2003; 90:1085-92. [PMID: 12945076 DOI: 10.1002/bjs.4176] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Cytokines are key mediators of the inflammatory response to surgery and polymorphic sites in their genes have been shown to affect cytokine production in vitro. The aim of this study was to determine whether cytokine gene polymorphisms affect cytokine production in vivo in patients undergoing abdominal aortic aneurysm (AAA) repair. METHODS One hundred patients admitted for elective AAA repair had plasma levels of interleukin (IL) 1beta, IL-6, IL-10 and tumour necrosis factor (TNF) alpha measured at induction of anaesthesia and 24 h after operation. Genotypes for each patient were determined using induced heteroduplex genotyping for the following loci: IL-1beta + 3953, IL-6 - 174, IL-10 - 1082/-592 and TNF-alpha - 308. RESULTS Patients with an IL-10 - 1082 A allele had a significantly higher IL-10 response to surgery than those without an A allele (P = 0.030) and there was also a significant difference in IL-10 response between patients with IL-10 - 1082 AA genotypes and those with GG genotypes (P = 0.030). CONCLUSION Elective AAA repair results in a measurable cytokine response. In this study the magnitude of this response was not affected by the individual patient's cytokine gene polymorphisms.
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Affiliation(s)
- M J Bown
- Department of Surgery, University of Leicester, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK. matthew@
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Handoko HY, Nancarrow DJ, Hayward NK, Ohaeri JU, Aghanwa H, McGrath JJ, Levinson DF, Johns C, Walters MK, Nertney DA, Srinivasan TN, Thara R, Mowry BJ. Tumor necrosis factor haplotype analysis amongst schizophrenia probands from four distinct populations in the Asia-Pacific region. Am J Med Genet B Neuropsychiatr Genet 2003; 121B:1-6. [PMID: 12898567 DOI: 10.1002/ajmg.b.20059] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
A single nucleotide polymorphism (TNF(-308A)) within the promoter region of the gene encoding tumor necrosis factor (TNF), has been significantly associated with schizophrenia in a study of Italian patients and control subjects Boin et al. [2001: Mol Psychiatry 6:79-82]. We have applied case-control analyses to examine TNF promoter haplotypes (containing TNF(-308) and two additional promoter variants: TNF(-376) and TNF(-238)) in four schizophrenia cohorts drawn from Australian, Indian Fijian, Indigenous Fijian, and Brahmin populations. In addition, we have applied the sibling transmission disequilibrium (STD) test to promoter haplotypes within 81 trios drawn from Australian Caucasian pedigrees with multiple schizophrenia cases, and 86 trios drawn from the Brahmin population of Tamil Nadu province in Southern India. Within each of these cohorts, we found no evidence of recombination between these tightly linked promoter variants, supporting previous studies which demonstrated that only a subset of the eight possible haplotypes exist. Of the four observed haplotypes, we and others have observed only one carries the TNF(-308A) variant allele. We report no significant differences in TNF promoter haplotype frequencies between the patient and control groups within each population, although the Indian Fijian cohort showed a trend towards reduced TNF(-308A) alleles amongst schizophrenia cases (P = 0.07). We found no evidence of bias in TNF promoter haplotype transmission to schizophrenia probands. Very similar results were obtained when only the TNF(-308) polymorphism was considered. Taken together, these data provide no support for the involvement of TNF promoter variants TNF(-308), TNF(-376), and TNF(-238) in schizophrenia susceptibility within four ethnically distinct cohorts.
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Affiliation(s)
- Herlina Y Handoko
- Queensland Centre for Schizophrenia Research, The Park, Centre for Mental Health, Wacol, Queensland, Australia
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Abstract
Insulin resistance is increasingly recognized as a chronic, low-level, inflammatory state. Hyperinsulinemia and insulin action were initially proposed as the common preceding factors of hypertension, low high-density lipoprotein cholesterol, hypertriglyceridemia, abdominal obesity, and altered glucose tolerance, linking all these abnormalities to the development of coronary heart disease. The similarities of insulin resistance with another inflammatory state, atherosclerosis, have been described only in the last few decades. Atherosclerosis and insulin resistance share similar pathophysiological mechanisms, mainly due to the actions of the two major proinflammatory cytokines, TNF-alpha and IL-6. Genetic predisposition to increased transcription rates of these cytokines is associated with metabolic derangement and simultaneously with coronary heart disease. Dysregulation of the inflammatory axis predicts the development of insulin resistance and type 2 diabetes mellitus. The knowledge of how interactions between metabolic and inflammatory pathways occur will be useful in future therapeutic strategies. The effective administration of antiinflammatory agents in the treatment of insulin resistance and atherosclerosis is only the beginning of a promising approach in the management of these syndromes.
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Affiliation(s)
- José Manuel Fernández-Real
- Section of Diabetes, Endocrinology and Nutrition, University Hospital of Girona Dr. Josep Trueta, 17007 Girona, Spain.
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Shbaklo H, Azar ST, Terwedow H, Halaby G, Naja RP, Zalloua PA. No association between the -1031 polymorphism in the TNF-alpha promoter region and type 1 diabetes. Hum Immunol 2003; 64:633-8. [PMID: 12770796 DOI: 10.1016/s0198-8859(03)00053-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Tumor necrosis factor alpha (TNF-alpha) is an important immunomodulator and is believed to be involved in the development or progression of type 1 diabetes. In the following study, we evaluated TNF-alpha promoter polymorphisms at positions -863 and -1031 and their association with type 1 diabetes in a group of 210 diabetic patients from Lebanon. Our results show that in our population, the C allele is predominant at position -863, whereas the A allele is very rare (2%). At position -1031, however, the C and T allele distribution was similar in both the patient (17.8% vs 82.2%, respectively) and the control (21.4% vs 79.6%) groups. No association of TNF-alpha genotype at position 1031 with type 1 diabetes was found as demonstrated by the family-based association test and the transmission disequilibrium test. However, when patient genotypes were compared, the recessive CC genotype was only found in type 1 diabetic males but not in type 1 diabetic females. This observation, however, requires further investigation in a larger sample before conclusive association to gender is suggested. In conclusion, our results demonstrate that no association between TNF-alpha polymorphism and type 1 diabetes seems to exist in our population.
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Affiliation(s)
- Hadia Shbaklo
- Genetics Research Laboratory, Chronic Care Center, Beirut, Lebanon
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Ko GTC, Lee SC, Pu YB, Ng MCY, So WY, Thomas N, Chan WB, Cockram CS, Chan JCN. Tumour necrosis factor-alpha promoter gene polymorphism at - 308 (genotype AA) in Chinese subjects with Type 2 diabetes. Diabet Med 2003; 20:167-8. [PMID: 12581271 DOI: 10.1046/j.1464-5491.2003.00829_1.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Baena A, Leung JY, Sullivan AD, Landires I, Vasquez-Luna N, Quiñones-Berrocal J, Fraser PA, Uko GP, Delgado JC, Clavijo OP, Thim S, Meshnick SR, Nyirenda T, Yunis EJ, Goldfeld AE. TNF-alpha promoter single nucleotide polymorphisms are markers of human ancestry. Genes Immun 2002; 3:482-7. [PMID: 12486607 DOI: 10.1038/sj.gene.6363898] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
We present a map of single nucleotide polymorphisms (SNPs) in the human tumor necrosis factor (TNF)-alpha promoter based upon exploratory sequencing of 333 human TNF-alpha gene promoters from individuals of distinct ancestral backgrounds. We detect 10 TNF-alpha promoter SNPs that occur with distinct frequencies in populations of different ancestry. Consistent with these findings, we show that two TNF-alpha SNPs, the -243 SNP and the -856 SNP, are the first SNP markers of a sub-Saharan African-derived extended haplotype and an Amerindian HLA haplotype, respectively. Comparisons of TNF-alpha promoter SNP allele frequencies can thus help elucidate variation of HLA haplotypes and their distribution among existing ethnic groups and shed light into the history of human populations.
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Affiliation(s)
- A Baena
- Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA
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Küçükaycan M, Van Krugten M, Pennings HJ, Huizinga TWJ, Buurman WA, Dentener MA, Wouters EFM. Tumor necrosis factor-alpha +489G/A gene polymorphism is associated with chronic obstructive pulmonary disease. Respir Res 2002; 3:29. [PMID: 12537602 PMCID: PMC150514 DOI: 10.1186/rr194] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2001] [Revised: 07/22/2002] [Accepted: 08/13/2002] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Chronic obstructive pulmonary disease (COPD) is characterized by a chronic inflammatory process, in which the pro-inflammatory cytokine Tumor Necrosis Factor (TNF)-alpha is considered to play a role. In the present study the putative involvement of TNF-alpha gene polymorphisms in pathogenesis of COPD was studied by analysis of four TNF-alpha gene polymorphisms in a Caucasian COPD population. METHODS TNF-alpha gene polymorphisms at positions -376G/A, -308G/A, -238G/A, and +489G/A were examined in 169 Dutch COPD patients, who had a mean forced expiratory volume in one second (FEV1) of 37 +/- 13%, and compared with a Dutch population control group of 358 subjects. RESULTS The data showed that the TNF-alpha +489G/A genotype frequency tended to be different in COPD patients as compared to population controls, which was due to an enhanced frequency of the GA genotype. In line herewith, carriership of the minor allele was associated with enhanced risk of development of COPD (odds ratio = 1.9, p = 0.009). The other TNF-alpha gene polymorphisms studied revealed no discrimination between patients and controls. No differences in the examined four TNF-alpha polymorphisms were found between subtypes of COPD, which were stratified for the presence of radiological emphysema. However, comparison of the COPD subtypes with controls showed a significant difference in the TNF-alpha +489G/A genotype in patients without radiological emphysema (chi2-test: p < 0.025 [Bonferroni adjusted]), while no differences between COPD patients with radiological emphysema and controls were observed. CONCLUSION Based on the reported data, it is concluded that COPD, and especially a subgroup of COPD patients without radiological emphysema, is associated with TNF-alpha +489G/A gene polymorphism.
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Affiliation(s)
- Mehmet Küçükaycan
- Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Department of Pulmonology, Maastricht University, Maastricht, The Netherlands
| | - Michiel Van Krugten
- Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands
| | | | - Tom WJ Huizinga
- Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Wim A Buurman
- Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Department of Surgery, Maastricht University, Maastricht, The Netherlands
| | - Mieke A Dentener
- Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Department of Pulmonology, Maastricht University, Maastricht, The Netherlands
| | - Emiel FM Wouters
- Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Department of Pulmonology, Maastricht University, Maastricht, The Netherlands
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Majetschak M, Obertacke U, Schade FU, Bardenheuer M, Voggenreiter G, Bloemeke B, Heesen M. Tumor necrosis factor gene polymorphisms, leukocyte function, and sepsis susceptibility in blunt trauma patients. CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY 2002; 9:1205-11. [PMID: 12414751 PMCID: PMC130126 DOI: 10.1128/cdli.9.6.1205-1211.2002] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The tumor necrosis factor alpha (TNF-alpha) -308 G/A and TNF-beta NcO1 polymorphisms have been described to be associated with an increased risk for sepsis in critically ill patients. Functional consequences associated with these polymorphisms remain unclear. We compared the genotype distribution of these TNF polymorphisms with susceptibility to severe sepsis and leukocyte function in blunt trauma patients (n = 70; mean injury severity score, 24 points [range, 4 to 57). Severe sepsis was defined according to the American College of Chest Physicians-Society of Critical Care Medicine consensus conference criteria. Genotyping for the NcO1 polymorphism (alleles TNFB1 and TNFB2) was performed by PCR and digestion of the products with NcO1, and that for the TNF-alpha -308 G/A polymorphism (alleles TNF1 and TNF2) was performed by real-time PCR. Leukocyte function was assessed by measurement of the production of endotoxin-induced cytokines (TNF-alpha, interleukin-6 [IL-6], and IL-8) in whole blood. TNF-alpha, IL-6, and IL-8 were determined by enzyme-linked immunosorbent assay. For the genotypes of the TNF-alpha -308 G/A polymorphism, differences in the frequency of development of severe sepsis were not detectable. Patients developing severe sepsis after trauma were significantly more likely to possess a homozygous genotype of the TNF-beta NcO1 polymorphism. Compared with heterozygotes, the odds ratio for the TNFB2/B2 genotype for the development of severe posttraumatic sepsis was 11 (P = 0.01), and that for the TNFB1/B1 genotype was 13 (P = 0.014). TNF-alpha -308:TNF-beta NcO1 haplotype analysis showed that the TNFB2:TNF2 haplotype is significantly negatively associated with development of severe sepsis. Patients homozygous for the TNFB1 or TNFB2 allele showed a persistently higher cytokine-producing capacity during at least 4 to 8 days after trauma than the heterozygotes. In patients homozygous for the TNF1 allele, a higher TNF-alpha- and IL-8-producing capacity was found only at day 1 after trauma. Although the TNF-beta NcO1 polymorphism appears to be less likely to be causative for development of severe sepsis after trauma, it is thus far the only genetic marker identified which can be used as a relevant risk estimate for severe sepsis in trauma patients immediately after the injury.
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Affiliation(s)
- Matthias Majetschak
- Department of Trauma Surgery, University Hospital Mannheim, Ruprecht-Karls-University Heidelberg, 68167 Mannheim, The Netherlands.
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Heijmans BT, Westendorp RGJ, Droog S, Kluft C, Knook DL, Slagboom PE. Association of the tumour necrosis factor alpha -308G/A polymorphism with the risk of diabetes in an elderly population-based cohort. Genes Immun 2002; 3:225-8. [PMID: 12058258 DOI: 10.1038/sj.gene.6363859] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2001] [Revised: 01/18/2002] [Accepted: 01/23/2002] [Indexed: 11/09/2022]
Abstract
Ample evidence supports a role for tumour necrosis factor alpha (TNFalpha) in the development of type 2 diabetes and cardiovascular disease. TNFalpha expression was found to be influenced by a -308G/A polymorphism in the promoter of the gene encoding TNFalpha (TNF). We investigated the contribution of this polymorphism to diabetes and cardiovascular mortality in a population-based cohort of 664 subjects aged 85 years and over (Leiden 85-plus Study). The -308G/A TNF promoter polymorphism was associated with the prevalence of diabetes in old age (P = 0.006). The risk of diabetes among subjects homozygous for the A-allele was estimated to be 4.6-fold (95% CI, 1.6-13.3) higher than among subjects homozygous for the common G-allele. The promoter polymorphism did not, however, predict mortality from all causes, cardiovascular diseases, cancer or infectious diseases during a 10-year follow-up period. In addition to the promoter polymorphism, TNFa and TNFc microsatellite genotypes were determined but these polymorphisms were not associated with morbidity or mortality. In conclusion, the -308G/A polymorphism in the TNF promoter is strongly associated with the risk of diabetes but not cardiovascular mortality in old age.
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Affiliation(s)
- B T Heijmans
- Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands.
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Furuta M, Yano Y, Ito K, Gabazza EC, Katsuki A, Tanaka T, Ohtake K, Hirata N, Hori Y, Araki-Sasaki R, Sumida Y, Adachi Y. Relationship of the tumor necrosis factor-alpha -308 A/G promoter polymorphism with insulin sensitivity and abdominal fat distribution in Japanese patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2002; 56:141-5. [PMID: 11891022 DOI: 10.1016/s0168-8227(01)00358-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
We investigated the relationship of the A/G variant of the tumor necrosis factor-alpha (TNF-alpha) gene promoter at position -308 with insulin resistance and abdominal fat distribution in type 2 diabetic patients in the Japanese population. The TNF-alpha polymorphism was evaluated by polymerase chain reaction-restriction fragment length polymorphism in 142 healthy volunteers and 132 type 2 diabetic patients. Insulin sensitivity was assessed by homeostasis model assessment (HOMA) index in healthy subjects and hyperinsulinemic euglycemic clamp in type 2 diabetic patients. Abdominal fat distribution was evaluated by computed tomography (CT) scanning in diabetic patients. The TNF-alpha polymorphism was detected in three healthy volunteers and three type 2 diabetic patients, all of them being heterozygotes. There was no significant difference in allele frequencies of the -308 polymorphism between healthy subjects (0.0106) and type 2 diabetic patients (0.0114). HOMA index was no significant difference between healthy subjects with and without polymorphism (1.09 +/- 0.03 vs. 1.02 +/- 0.05). Glucose infusion rate (GIR), an index of insulin sensitivity, was not significantly different between diabetic patients with and without TNF-alpha polymorphism (40.4 +/- 4.1 vs. 45.0 +/- 1.8 micromol/kg per min). Moreover, no remarkable effect of TNF-alpha polymorphism on abdominal fat distribution was observed in diabetic patients. These results suggest that A/G heterozygotes of the TNF-alpha gene promoter at position -308 play no major role in the pathogenesis of insulin resistance or abdominal fat distribution in Japanese type 2 diabetic patients.
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Affiliation(s)
- Masahiko Furuta
- Third Department of Internal Medicine, Mie University School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan
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Dalziel B, Gosby AK, Richman RM, Bryson JM, Caterson ID. Association of the TNF-alpha -308 G/A promoter polymorphism with insulin resistance in obesity. OBESITY RESEARCH 2002; 10:401-7. [PMID: 12006640 DOI: 10.1038/oby.2002.55] [Citation(s) in RCA: 108] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Obesity is a major risk factor for the development of type 2 diabetes. Tumor necrosis factor (TNF)-alpha is a candidate gene for the development of both obesity and insulin resistance. We investigated whether a common polymorphism in the promoter region (-308 G/A) of the TNF-alpha gene was associated with increased risk for the development of insulin resistance and cardiovascular disease in an obese Australian population. RESEARCH METHODS AND PROCEDURES Obese, non-diabetic subjects (146 women and 34 men) were genotyped with polymerase chain reaction-restriction fragment length polymorphism techniques, and anthropometric and biochemical measurements were analyzed. A homeostasis model assessment (HOMA) score was used to gauge the level of insulin resistance. RESULTS The frequencies of the G allele and the A allele were 0.759 and 0.241, respectively. Subjects homozygous for the A allele had higher fasting insulin levels (226 vs. 131 pM; p < 0.001), higher HOMA scores (10.2 vs. 5.3; p < 0.001), higher systolic blood pressure (143 vs. 129 mm Hg; p = 0.02), and lower high-density lipoprotein (HDL) cholesterol (1.13 vs. 1.25 mM; p = 0.04) than did subjects homozygous for the G allele. Whereas an association between insulin resistance and body mass index or waist circumference was seen in all subjects, a highly significant negative correlation of HDL cholesterol to HOMA scores (r = -0.710; p < 0.001) occurred in subjects with the A allele only. DISCUSSION The -308 G/A TNF-alpha gene variant conveys an increased risk for the development of insulin resistance in obese subjects. The presence of low HDL cholesterol levels further increases the risks associated with insulin resistance in carriers of the A allele.
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Affiliation(s)
- Bronwen Dalziel
- Human Nutrition Unit, Department of Biochemistry, University of Sydney, Australia.
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Nicaud V, Raoux S, Poirier O, Cambien F, O'Reilly DSJ, Tiret L. The TNF alpha/G-308A polymorphism influences insulin sensitivity in offspring of patients with coronary heart disease: the European Atherosclerosis Research Study II. Atherosclerosis 2002; 161:317-25. [PMID: 11888514 DOI: 10.1016/s0021-9150(01)00648-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
There is accumulating evidence for a role of tumor necrosis factor-alpha (TNF-alpha) in insulin resistance induced by obesity. The purpose of this study was to investigate whether the TNF alpha/G-308A polymorphism was associated with responses to oral glucose and fat tolerance tests in a case--control study comparing male offspring with a paternal history of premature myocardial infarction (cases, n=335) to age-matched controls (n=340) recruited from 14 European university populations. Genotype frequencies did not significantly differ between cases and controls. Among cases, those carrying the A allele exhibited a higher area under the curve for insulin (64.5 vs 55.9 mU h/l, P=0.009), a higher increment between baseline concentration and peak of insulin (63.1 vs 52.8 mU/l, P=0.005) and a greater decrease between peak and insulin at 120 min (49.1 vs 36.8 mU/l, P=0.003) than those with the GG genotype. No such effect was observed in control subjects. No association was observed with response to a fat tolerance test either in cases or in controls. The present results suggest that the TNF alpha/G-308A polymorphism might interact with other susceptibility factors to coronary heart disease to predispose to insulin resistance, and that the ability of TNF-alpha to induce insulin resistance may extend beyond obesity.
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Affiliation(s)
- V Nicaud
- Institut National de la Santé et de la Recherche Médicale, Unit 525, 91 Bd de l'Hôpital, 75634 Paris Cedex 13, France
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