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Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of a number of diseases, including oncological and autoimmune diseases. The –308(g/a)TNF and –238(G/A)TNF polymorphisms are included in the extended ancestral haplotypes covering the whole complex of HLA genes. We assumed that the previously found effect of these polymorphisms on the overall survival (OS) of breast cancer (BC) patients may be a consequence of cooperation with the genomic environment, namely, with the AH8.1 and B57 haplotypes associated with autoimmune conditions. The archival collection of DNA from 442 primary BC patients and 327 women from the control group with known –308(g/a)TNF and –238(G/A)TNF genotypes was used in the work. Four hundred and twelve BC patients were tested for AH8.1 and B57 markers. During the study, the association of –308a and –238A alleles of the TNF gene with haplotypes AH8.1 and B57, respectively, was confirmed. Analysis of the results of the study demonstrated that TNF gene polymorphisms do not affect the predisposition to BC disease, but significantly decrease the OS of BC patients; moreover, the final effect of the TNF gene polymorphisms on the disease prognosis depends on genomic context. At stage II of the disease, the carriers of the –308ag/–238GG genotype in the presence of marker AH8.1 alleles and the –308gg/–238GG carriers, regardless of AH8.1 markers, had a 10-year OS above 80%, while a 10-year OS was lower than 50% in the –308ag/–238GG carriers in the absence of AH8.1 markers and in the –308gg/–238AG genotype carriers (p = 0.0076). The mechanisms of action of –308(g/a)TNF and ‒238(G/A)TNF differ, and a decrease in OS in the carriers of minor –238A allele is mediated by its association with HLA-B*57, while a decrease in OS in the carriers of –308a, on the contrary, is not associated with the ancestral AH8.1 haplotype. Thus, two genetically determined BC patient groups that have an unfavorable prognosis in conditions of standard BC therapy were detected. [ABSTRACT FROM AUTHOR]

Longitudinal studies aimed at evaluating patients clinical response to specific therapeutic treatments are frequently summarized in incomplete datasets due to missing data. Multivariate statistical procedures use only complete cases, deleting any case with missing data. MI and MIANALYZE procedures of the SAS software perform multiple imputations based on the Markov Chain Monte Carlo method to replace each missing value with a plausible value and to evaluate the efficiency of such missing data treatment. The objective of this work was to compare the evaluation of differences in the increase of serum TNF concentrations depending on the ­308 TNF promoter genotype of rheumatoid arthritis (RA) patients receiving anti-TNF therapy with and without multiple imputations of missing data based on mixed models for repeated measures. Our results indicate that the relative efficiency of our multiple imputation model is greater than 98% and that the related inference was significant (p-value < 0.001). We established that under both approaches serum TNF levels in RA patients bearing the G/A ­308 TNF promoter genotype displayed a significantly (p-value < 0.0001) increased ability to produce TNF over time than the G/G patient group, as they received successively doses of anti-TNF therapy.

Abstract: Introduction: The etiology of multisomatoform disorder (MSD) is still largely unknown, but genetic factors seem to have an influence on pathogenesis. Pain is a major symptom of MSD and polymorphisms of different proinflammatory cytokines have been found associated with pain in former studies. Therefore, we presumed that cytokine polymorphisms could also be associated with MSD. Patients and methods: Groups of 148 MSD patients with pain as the leading clinical symptom and 149 age and gender matched healthy controls participated in this study. Nine cytokine polymorphisms were genotyped and statistically analyzed for associations with MSD. Results: Allelic and genotypic associations were found for rs16944 (interleukin 1β), rs1800629 (tumor necrosis factor) and rs909253 (lymphotoxin α). After correcting for multiple testing, the association of rs1800629 with MSD remained significant. The rare A-allele was correlated with MSD (p =0.007). Discussion: Since the common G-allele of rs1800629 (TNFα) occurs much more often in the control group than in the MSD group it is assumed to be protective. Being carrier of the A-allele seems to be a risk factor for MSD. [Copyright &y& Elsevier]

The introduction of antitumor necrosis factor (TNF) agents has improved the outcome for many patients with rheumatoid arthritis (RA). To date, the only replicated genetic predictor of anti-TNF response is the −308 G > A single-nucleotide polymorphism in the TNF promoter region. The presence of the −308 TNF G/G genotype appears to be a marker of good response to anti-TNF treatment. Anti-citrullinated protein antibodies (ACPA) have been linked with erosive disease, and have been established as the single most reliable prognostic factor in clinical practice. To test the hypothesis that the ACPA status may affect the −308 G/G patients rate of response to TNF blockade, we prospectively investigated a group of 52 RA patients with the −308 G/G genotype who were ACPA (+) or ACPA (−). All patients were treated with adalimumab, and the clinical response was studied using the Disease Activity Score in 28 joints (DAS28) at 24 weeks of treatment. Over 85% of patients were DAS28 responders in both groups. No significant differences were found between patients from both groups, according to the DAS28 criteria of response at week 24 ( p = 0.79). In conclusion, our findings suggest that the ACPA status does not affect the clinical response to anti-TNF therapy in −308 TNF G/G patients. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor alpha (TNF-α) gene is located within the class III region of the major histocompatibility complex (MHC) on the short arm of the human sixth chromosome. Two polymorphisms in the promoter region of the TNF-α gene (-308 and -238) have been associated with the genetic susceptibility to develop ulcerative colitis in both Caucasian and Asian populations.The aim of this study was to determine the role of TNF-α gene polymorphisms and those from the HLA-DRB1 locus in the susceptibility to develop ulcerative colitis (UC).Eighty Mexican mestizo patients suffering from UC and 99 ethnically matched unrelated healthy controls were genotyped for two TNF-α polymorphisms located in the promoter region (positions -308, -238) by polymerase chain reaction (PCR) and amplification refractory mutation system (ARMS) as well as high resolution DNA typing for HLA-DRB1 alleles were performed.The frequency of individuals positive for allele 2 of the TNF-308 polymorphism was significantly higher in UC patients than healthy controls (23.7% versus 3%, pC = 0.00002; OR = 10.1; CI 95% = 2.69–26.8). No statistically significant deviation from normality was found between TNF*A (-238) and UC Mexican patients. Clinical manifestations such as pancolitis, extraintestinal manifestations and colectomy were not associated with any of the TNF promoter region polymorphisms. However, HLA-DRB1*15 was found to be associated with pancolitis and HLA-DRB1*0103 with the need of proctocolectomy.In conclusion, this clinical differential pattern of association distinguished in two neighboring loci within the MHC region suggest an independent role of the TNF locus in the genetic susceptibility to develop UC. [Copyright &y& Elsevier]

Crohn’s disease (CD) appears in forms so diverse that it has been hypothesized CD might be a syndrome, with different pathogenic mechanisms leading to the various clinical phenotypes. This may plausibly explain the conflicting and inconclusive results with regard to HLA associations in unselected groups of patients. The power of these association studies may increase when disease heterogeneity is taken into account. As fistulising CD has been proposed as a separate subgroup of patients with CD, we studied the carrier frequencies (CF) of the DRB1 alleles in 35 unrelated Caucasian Dutch CD patients with proven peri-anal fistulas. A striking decrease in the frequency of the DRB1 * 03 allele was found in those patients with peri-anal fistulas when compared with a panel of 2400 healthy controls (HC) (3% vs 25%; P = 0.005; Odds Ratio [OR] = 0.09). The DRB1 * 03 allele is in strong linkage disequilibrium with a polymorphism at position –308 in the promoter region of the gene encoding TNFα ( TNFA-308 * 2). We investigated whether this allele frequency was decreased as well. Surprisingly, the CF of TNFA-308 * 2 was 29%, not different from the CF of 98 HC (34%; P = 0.7; OR = 0.8). This study is the first showing a significant negative association between DRB1 * 03 and a particular subgroup of CD patients. Thus, patient selection may largely determine the outcome of genetic association studies in CD, as we previously observed no association with this allele in an unselected population of CD patients. As DRB1 * 03 frequency, but not the closely linked TNFA-308 * 2, was decreased, this suggests recombination between the DRB1 and TNFA loci in this group of patients, and may help to define the biological basis of fistula formation. [ABSTRACT FROM AUTHOR]

Abstract: One third of Trypanosoma cruzi-infected individuals develop chronic Chagas disease cardiomyopathy (CCC) while the majority remains asymptomatic (ASY). About 30% of CCC patients develop heart failure due to end-stage inflammatory dilated cardiomyopathy. Increased production of tumor necrosis factor (TNF)-α has been described in all clinical forms of Chagas disease, and the highest levels are detected in CCC patients with severe ventricular dysfunction. Genetic susceptibility may play a role in the clinical outcome of Chagas disease. We investigated TNF as a candidate gene for susceptibility to development and/or progression of CCC. We analyzed the TNFa microsatellite and the −308 TNF promoter polymorphisms, in 166 CCC compared to 80 ASY geographically and age-matched patients in an association study. To analyze the association of TNF polymorphisms with progression of the cardiomyopathy, CCC patients were also grouped in three categories according to degree of left ventricular (LV) dysfunction into severe (n =57), mild to moderate (n =21) and absent (n =88). Our results show no significant differences either between CCC and ASY patients, or among CCC patients according to severity of cardiomyopathy with respect to TNFa or −308 TNF promoter polymorphisms. These results indicate that TNF polymorphisms are associated neither to CCC development nor to progression to more severe forms of cardiomyopathy in Brazilian Chagas disease patients. [Copyright &y& Elsevier]

Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine mainly secreted by macrophages and T-cells that play a key role in the pathogenesis of many infectious and inflammatory diseases. The TNF gene cluster is located within the class-III region of the highly polymorphic major histocompatibility complex on human chromosome 6p21. A cluster of six multiallelic microsatellites has been identified in the TNF region, named TNF a–e. TNFb, TNFc, TNFd, and TNFe are (GA)n repeats, whereas TNFa and TNFf are (GT)n and (CA)n repeats, respectively. The TNFd microsatellite locus maps 8–10 kb centromeric to the TNF-α gene, downstream to the TNF-β gene. [ABSTRACT FROM AUTHOR]