Functional Analysis of a Human Tumor Necrosis Factor α (TNF-α) Promoter Polymorphism Related to Joint Damage in Rheumatoid Arthritis

Kaijzel, Eric L.; Krugten, M V van; Brinkman, Brigitta M. N.; Huizinga, Tom W J; Straaten, Tahar van der; Hazes, J. M. W.; Hw, Ziegler-Heitbrock; Nedospasov, Sergei A.; Breedveld, Ferdinand C.; Verweij, Cornelis L.

doi:10.1007/bf03401767

Cited by 96 publications

(75 citation statements)

References 38 publications

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“…We have used various TNF À308G promoter constructs in transfection of the Raji B cell line and never found these to be resistant to induction. [189][190][191] Wilson et al were also unable to provide evidence of a major difference in affinity of DNA binding proteins in this study. Another group has published several studies 192,193 using À308 constructs and were unable to detect a difference in the activity of variants lacking the 3 0 UTR in contrast to Wilson et al, but did observe differences when the 3 0 UTR was present, in contrast to the study of Brinkman et al…”

Section: Ex Vivo Tnf Productioncontrasting

confidence: 57%

“…Studies in our laboratory showed that introduction of these constructs into cell lines produced no evidence that these polymorphisms had any influence on the activity of the promoter. 185,190 However, it remained possible that the relatively minor changes present in these promoter variants produce an effect that is too subtle to detect. We therefore decided to remove larger regions, consisting of 10 bp regions around the promoter polymorphisms, and replace them with an irrelevant sequence, reasoning that replacing a relatively large region of the promoter around a possible regulatory site would prevent any activator/inhibitor protein binding and therefore result in a measurable functional effect.…”

Section: Ex Vivo Tnf Productionmentioning

confidence: 99%

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Is there a future for TNF promoter polymorphisms?

2004

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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 À308G/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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Section: Ex Vivo Tnf Productioncontrasting

confidence: 57%

Section: Ex Vivo Tnf Productionmentioning

confidence: 99%

Is there a future for TNF promoter polymorphisms?

2004

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“…30 In vitro transfection assays indicate that TNF À238 A allele does not appear to have a direct effect on transcriptional activation of the TNF gene. 31 A study of subjects with chronic active hepatitis C, however, found that the frequency of the TNF À238 A allele was significantly higher in subjects than controls.…”

Section: Discussionmentioning

confidence: 99%

Genetic risk factors for infection in patients with early rheumatoid arthritis

et al. 2004

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We analyzed clinical and genetic factors contributing to infections in 457 subjects with early rheumatoid arthritis (RA) enrolled in a prospective, 1-year clinical trial of methotrexate and the TNF inhibitor etanercept. Subjects were genotyped for the following single nucleotide polymorphisms (SNPs): (TNF À308, À238, and þ 488); lymphotoxin-a (LTA) (LTA þ 249, þ 365, and þ 720); and Fc gamma receptors FCGR2A 131 H/R; FCGR3A 176 F/V; and FCGR3B NA 1/2 and genotypes were correlated with infections. At least one URI was noted in 52% of subjects (99/191) with the NA2/NA2 genotype of the neutrophil-specific FCGR3B gene, compared to 42% (77/181) of those with the NA1/NA2 genotype and 39% (23/59) of those with the NA1/NA1 genotype (P ¼ 0.038). Urinary tract infection (UTI) was associated with the TNF À238 A (odds ratio(OR) 2.56, 95% confidence interval (CI) 1.05-6.25) and LTA þ 365 C (OR 1.73, 95% CI 1.07-2.79) alleles, and marginally with the FCGR3A F allele (OR 1.72, 95% CI 0.99-3.00). There was a striking linear correlation between UTI and the number of risk alleles defined by these three SNPs (Po0.001), suggesting an additive effect on susceptibility. These findings have important implications for the role of genetics in susceptibility to bacterial and viral infections.

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“…31 There is, however, controversy regarding the functional significance of the TNFA -238 polymorphism. Studies have reported that the -238 A allele either increases, 32 decreases 33,34 or has no effect on TNFA transcription, 35,36 depending on the conditions of the experiment. Our findings suggest that the A allele of the -238 polymorphism may be responsive to dietary fatty acid intake, as has been shown for the -308 A allele.…”

Section: Discussionmentioning

confidence: 99%

The tumor necrosis factor-α gene -238 G>A polymorphism, dietary fat intake, obesity risk and serum lipid concentrations in black and white South African women

et al. 2012

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BACKGROUND/OBJECTIVES: This study explored interactions between dietary fat intake and the tumor necrosis factor-a gene (TNFA) -238 G4A polymorphism (rs361525) on adiposity and serum lipid concentrations in apparently healthy premenopausal black and white South African (SA) women. SUBJECTS/METHODS: Normal-weight (N ¼ 107) and obese (N ¼ 120) black, and normal-weight (N ¼ 89) and obese (N ¼ 62) white SA women underwent measurements of body composition, fasting lipids and dietary intake, and were genotyped for the -238 G4A polymorphism. RESULTS: Black women had a higher -238 GA genotype frequency than white women (Po0.001), but there were no differences between body mass index groups. Black women with the -238 A allele had a greater body fat % than those with the GG genotype (Po0.001). Further, in black women, with increasing polyunsaturated:saturated fat ratio and omega-6 (n-6):omega-3 (n-3) ratio, high-density lipoprotein-cholesterol (HDL-C) concentrations decreased, and total cholesterol (T-C):HDL-C ratio increased in those with the GA genotype but not the GG genotype. In addition, with increasing n-3 polyunsaturated fatty acid intake (percentage of total energy intake, %E), T-C:HDL-C ratio decreased in those with the GA genotype, but not in those with the GG genotype. In white SA women, with increasing eicosapentaenoic acid (%E) intake, low-density lipoprotein-cholesterol concentrations decreased in those with the GG genotype but not the GA genotype. CONCLUSIONS: The -238 G4A polymorphism was associated with body fatness in black women. Interactions between -238 G4A genotypes and dietary fat intake on serum lipids and adiposity differed depending on dietary fat intake, but those for serum lipids were not the same in black and white SA women.

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Functional Analysis of a Human Tumor Necrosis Factor α (TNF-α) Promoter Polymorphism Related to Joint Damage in Rheumatoid Arthritis

Cited by 96 publications

References 38 publications

Is there a future for TNF promoter polymorphisms?

Is there a future for TNF promoter polymorphisms?

Genetic risk factors for infection in patients with early rheumatoid arthritis

The tumor necrosis factor-α gene -238 G>A polymorphism, dietary fat intake, obesity risk and serum lipid concentrations in black and white South African women

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