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A meta-analysis suggests an association between certain TNF promoter polymorphisms and Behçet's disease.

Lorena Baccaglini DDS, DDS, MS, PhD .


Systematic Review Conclusion

Behçet's disease is associated with -1031C, -238A and -857T polymorphisms in ethnic groups along the Silk Road.

Critical Summary Assessment

Meta-analyses of case-control studies suggest a modest link between certain TNF gene polymorphisms and Behçet's disease in some populations.

Evidence Quality Rating

Limited Evidence

Structured Abstract

Clinical Questions:

Are specific polymorphisms of the TNF gene associated with Behcet's disease in various ethnic groups?

Review Methods:

The authors searched for genetic studies of Behçet's disease (BD) published in 1950-2009 using three databases, without language or geographic restrictions. They contacted study authors when essential information was missing. The meta-analysis included original studies of BD cases and unrelated controls that allowed calculation of pooled odds ratios (OR). Two to three reviewers screened the studies and assessed eligibility. Two independent reviewers extracted the data, resolving discrepancies by consensus. Study quality and publication bias were not assessed. The main exposure was presence of one of five single nucleotide TNF polymorphisms (-1031C, -238A, -857T, -308A or -863A) and the outcome of interest was BD. The authors assessed statistical heterogeneity using Cochran's Q statistic and I2 values, and calculated pooled OR with 95% confidence intervals (CI) from individual allelic analyses using random effect models.

Main Results:

Of 65 initial studies, 10 met the inclusion criteria (three to seven case-control studies per polymorphism). A total of 413-802 cases and 548-997 controls were analyzed per TNF polymorphism. Of the five polymorphisms, three were associated with BD. The pooled OR (95% CI) were 1.35 (1.09-1.68) for -1031C, 0.76 (0.58-0.98) for -857T and 1.51 (1.12-2.04) for -238A. Samples were racially heterogeneous, although some statistical heterogeneity (I2=25%) in the association was present only in one analysis (-1031C). In general, studies tended to agree on the reported frequency of each polymorphism, except for the study by Alayli (2007), which reported a frequency of -238A several fold higher compared to other studies.


This meta-analysis of TNF polymorphisms showed a significant association between three polymorphisms (-1031C, -238A and -857T) and BD, whereas -863A and -308A polymorphisms were not associated with BD. Larger studies of the association between -308A polymorphism and BD would be helpful.

Source of Funding:

Lebanese National Council for Scientific Research (LCNRS); Chronic Care Center.


Importance and Context:

Behçet's disease (BD) is a rare multisystem disease associated with significant morbidity and potential mortality. The presence of recurrent oral ulcerations is a major diagnostic criterion and can be the first sign of BD. Dentists may participate in the differential diagnosis and management of these ulcers. The etiology of BD is unclear, although a genetic predisposition has been suggested. Identification of susceptibility genes could facilitate earlier diagnosis and therapeutic improvements. Some genetic studies have focused on tumor necrosis factor (TNF) promoter region polymorphisms because of reports of therapeutic effects of TNF-alpha inhibitors.

Strengths and Weaknesses of the Systematic Review:

This meta-analysis included a comprehensive search strategy and standardized study selection. In general, the authors included most items from the meta-analysis of observational studies in epidemiology checklist (MOOSE; Stroup DF et al., 2000), although this technique was not explicitly mentioned by the authors. However, a key element missing from the meta-analysis was a standardized assessment of individual study quality. The authors assessed statistical heterogeneity but did not determine publication bias. They did not conduct a sensitivity analysis, which would have tested the robustness of the evidence by examining summary estimates of only high quality studies. Lastly, only results from allelic analyses were pooled. The review provided no information on genotype or haplotype analyses.

Strengths and Weaknesses of the Evidence:

The total number of studies per polymorphism was small (three to seven). The number of cases and controls for each analysis varied from approximately 400 to almost 1,000 per group. An influential study by Alayli et al. had an abnormally high frequency of -238A in both cases and controls, which is inconsistent with other studies or published databases (e.g., the single nucleotide polymorphism database or dbSNP) and cannot be explained by racial heterogeneity. Therefore, pooled results for -238A could be highly biased. Results also may be dependent on the races included. For example, the OR for -238A was above 1 in the two Korean samples but below 1 (protective) in the three non-Asian samples, excluding the Alayli study. Although some results were statistically significant, their clinical relevance may be more limited because the association was not strong, (pooled ORs about 1.3-1.5 with lower limits of the 95% CI close to the null value). Thus, results should be interpreted with caution.

Implications for Dental Practice:

Prompt diagnosis and treatment of BD may help minimize the sequelae associated with this disease, such as blindness and organ involvement. Dentists may be the first health professionals to suspect this disease in patients with recurrent oral ulcers. The development of diagnostic tests based on genetic studies of BD could accelerate the time to final diagnosis and treatment initiation for suspected cases. However, the results of this meta-analysis provide only limited evidence of an association between the TNF polymorphisms investigated and BD, primarily because of the clinical heterogeneity, small number and unknown quality of the studies included.

Critical Summary Publication Date:


These summaries are not intended to, and do not, express, imply, or summarize standards of care, but rather provide a concise reference for dentists to aid in understanding and applying evidence from the referenced systematic review in making clinically sound decisions as guided by their clinical judgment and by patient needs. American Dental Association © 2019