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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arthritis Rheum. Author manuscript; available in PMC 2013 December 19.
Published in final edited form as:
PMCID: PMC3867978

HLA–B51/B5 and the Risk of Behçet’s Disease: A Systematic Review and Meta-Analysis of Case–Control Genetic Association Studies



To quantify by meta-analysis the genetic effect of the HLA–B5 or HLA–B51 (HLA–B51/B5) allele on the risk of developing Behçet’s disease (BD) and to look for potential effect modifiers.


Relevant studies were identified using the PubMed Medline database and manual searches of the literature. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by using the random-effects model. Subgroup meta-analyses and meta-regression analyses were undertaken to investigate the effects of selected study-level parameters on the pooled OR. Heterogeneity was assessed using the I2 statistic. Pooled results were used to calculate population-attributable risks (PAR) for BD in relationship to HLA–B51/B5.


A total of 4,800 patients with BD and 16,289 controls from 78 independent studies (published 1975–2007) were selected. The pooled OR of HLA–B51/B5 allele carriers to develop BD compared with noncarriers was 5.78 (95% CI 5.00–6.67), with moderate between-study heterogeneity (I2 = 61%). The subgroup analyses stratifying studies by geographic locations (Eastern Asia, Middle East/North Africa, Southern Europe, Northern/Eastern Europe) yielded consistent OR ranges (5.31–7.20), with I2 ranges of 52–70%. Univariate random-effects meta-regression indicated the percentage of male BD cases (P = 0.008) as a source of heterogeneity. The PAR within the various geographic areas were estimated at 32–52%.


The strength of the association between BD and HLA–B51/B5, and its consistency across populations of various ethnicities, lends further support to this allele being a primary and causal risk determinant for BD. Variations according to sex support an interaction of this allele with BD characteristics.


Behçet’s disease (BD) is a chronic vasculitis of arteries and veins of all sizes characterized by recurrent oral ulcers, genital ulcers, ocular and skin involvement, and other multisystemic features. Despite a worldwide distribution, BD clusters in an area that extends from far Eastern Asia to the Mediterranean basin (1,2).

Several lines of evidence suggest that host genetic factors play a pivotal role in determining susceptibility to BD. In particular, it has long been known that BD is associated with the major histocompatibility complex HLA–B5 allele (3) and, more specifically, with HLA–B51 (4), the predominant split of the HLA–B5 broad antigen (57). While the overrepresentation of HLA–B5 or HLA–B51 (HLA–B51/B5) among individuals with BD has been abundantly replicated, substantial between-study differences were found in the strengths of this genetic association with reported risk increases that ranged between 1.3 and 16 (2,8). It is likely that such disparities result from small sample sizes, but a true variability of the relationship between BD and HLA–B51/B5 might also exist across populations of different ethnicities or clinical subtypes of BD (2,9).

We undertook a systemic literature review and meta-analysis of genetic association case–control studies with the aim of estimating the true risk increase for BD development associated with HLA–B51/B5 carriage and identifying clinical or methodologic factors potentially influencing the effect size of this genetic association.


Identification and selection of studies

Case–control studies in which the HLA class I genotypes had been linked with BD were identified by electronic searches of the PubMed Medline database between January 1, 1973 and December 31, 2007. Terms used for the search contained combinations of the medical subject heading terms “Behçet’s syndrome” and “HLA antigens” (or alternatively “histocompatibility”), or several combinations of text search terms including “Behçet’s disease” (or “Behçet’s syndrome”) with “HLA–B5” (or “HLA–B51”) and with “genetic association” (or “case–control study”). Studies were also manually searched in the reference lists of retrieved articles, in review articles on BD, in textbooks and conference proceedings, by communication with experts, and through additional Internet searches. Full publications and abstracts were allowed and no language restriction was imposed.

To be included in the meta-analysis, a study had to be designed as a case–control study and had to provide sufficient information to construct a 2 × 2 contingency table for the frequencies of HLA–B51/B5 genotypes in BD cases and controls. Anticipating the potential issue that several studies include to some extent the same cases and/or controls, we paid close attention to authors, study subjects’ geographic locations, and numbers of study subjects. Unless these precisions were unequivocally stated in the cross-references of the publications, for multiple studies stemming from the same research teams, we contacted the authors asking them to notify us of such an overlap between cases and/or controls among their studies. With multiple overlapping publications, we generally selected the publication that contained the most BD cases.

Data extraction

Using a study-specific questionnaire, 2 investigators (MdM and AM) independently extracted data from the primary studies. For articles written in languages not spoken by either of these 2 investigators, data were extracted with the help of native or fluent speakers of the respective languages. The following data were collected: authors, publication year, journal, publication type and language, study population location, genotyping method, allele genotyped (HLA–B5 and/or HLA–B51), numbers of cases and controls, definitions or classification criteria used for BD, BD sample description, control sample description, and numbers and/or percentages of HLA–B51/B5–positive cases and controls. Results were compared, and disagreements were resolved by discussion and consensus. The primary author of one study was contacted for clarification and provided additional data on the number of investigated subjects.

Statistical analysis

For each study, we computed odds ratios (ORs) and 95% confidence intervals (95% CIs) using normal approximation to the log10 of the OR. Data from the entire study populations were pooled to compare HLA–B51/B5 frequencies between BD patients and control subjects. Pooled ORs and 95% CIs were calculated using random-effects inverse-variance models (10). Between-study heterogeneity was assessed using the DerSimonian–Laird chi-square–based Q statistics (11) and quantified using the I2 statistic (12). Wald’s chi-square tests were performed to assess between-subgroup differences of pooled ORs.

Random-effects normal-logistic models were used to calculate pooled estimates for the frequency of the HLA–B51/B5 allele in BD cases and control populations. This approach was recently used to calculate the prevalence of rare adverse events in colorectal cancer screening studies (13).

Stratified analysis by subgroup was performed to search for modifiers possibly affecting the observed genetic effect and to investigate the reasons for heterogeneity among studies. The 7 prespecified categorical study-level characteristics for assessment of sources of inter-study heterogeneity were: geographic area (classified into 5 regions: Eastern Asia, Middle East/North Africa, Southern Europe, Northern/Eastern Europe, and North America); allele genotyped (HLA–B5 or HLA–B51); serologic (i.e., complement-dependent microlymphocytoxicity assays) and molecular genotyping techniques (i.e., sequence-specific oligonucleotide or primer polymerase chain reaction); classification criteria used to define BD; publication type (defined as peer-reviewed journal versus publication in conference proceedings or books); publication language (defined as English versus non-English); and ethnic matching of controls to cases (defined as specifically mentioned versus not mentioned).

To further explore heterogeneity in study findings, we used univariate random-effects inverse-variance meta-regression analyses (10). The prespecified explanatory variables included the same 7 categorical covariates used for subgroup analyses (see above), plus the following 7 prespecified continuous covariates: mean or median age at disease onset or diagnosis for BD cases; mean or median age at study time for BD cases; percentage of BD cases in men, and with ocular, large-vessel, or central nervous system disease; and year of publication.

Funnel plot analysis and the arcsine test for binary outcomes (14) were used to detect publication bias. In addition, we also assessed publication bias with the Egger’s regression asymmetry test, the Begg-Mazumdar adjusted rank correlation test, and the test proposed by Peters et al (1517). To further examine the possibility of “small study effects,” we conducted 3 sensitivity analyses restricted to the studies that included ≥30 BD cases, ≥50 BD cases, and ≥100 subjects (cases plus controls) in total.

To assess the contribution of HLA–B51/B5 to BD development in the overall population, we calculated specific population-attributable risks (PAR) for HLA–B51/B5 carriage using the following standard formula:

PAR=p×[(relative risk1)relative risk)]

where p is the percentage of HLA–B51/B5 allele-carrying BD cases (18). Relative risk in this formula was approximated by the OR.

All statistics were computed with SAS software, version 9.1 (SAS Institute, Cary, NC). All statistical tests were 2-tailed and P values less than 0.05 were considered statistically significant, except publication bias tests, for which P values less than 0.10 were considered statistically significant.


Eligible studies

Figure 1 shows the flow chart of publications identified by the literature search to those finally retained. A total of 149 publications met the eligibility criteria for inclusion in the meta-analysis. Among those, 71 publications were subsequently excluded because they were considered to contain duplicate information or overlaps in case and/or control samples. Overlapping was primarily verified on the basis of cross-references and through the information provided by the contacted authors. In some instances, these decisions were made based on the concordances of authors, study areas, years of publication, and numbers of study subjects.

Figure 1
Flow chart of studies identified through the systematic review of the literature. BD = Behçet’s disease.

Eventually, we retained 78 independent, nonoverlapping studies meeting the selection criteria (4,1995). These studies were published between 1975 and 2007, and included 1 electronic publication (print version became available in 2008) (26) and 19 publications written in non-English languages (20,30,34,36,38,4042,46,49,60,65,70,77,81,82,88,89,95). The relevant data in 2 articles were based on 2 distinct geographic sites and ethnic populations (19,53), each of which was included as a separate population in the meta-analysis. Consequently, the 78 selected studies contributed to 80 distinct study populations.

The final data set included a total of 4,800 cases and 16,289 controls. The case number did not include a subgroup of immigrant patients with BD analyzed in one study because no ethnically representative control group had been considered (40). From another study that used the 1974 Japanese BD Research Committee (JBDRC) criteria to define BD (96), we did not use the subsets of cases with “possible” and “probable” BD because we considered the diagnostic specificity of these subgroups to be too low (84). From another study that contained several familial cases, we retained only the data for the unrelated subjects with BD (31).

Study characteristics

The principal study characteristics are shown in Figure 2. The geographic areas from which the 80 study populations had been recruited are further summarized in Table 1. For rare studies reporting results for both HLA–B5 and HLA–B51 genotypes (4,25,42,80,93), only the latter data were used for all analyses. The classification criteria used were: the International Study Group for Behçet’s Disease (97), n = 36; (1922,26, 28,32,34,43,44,48,5055,57,63,64,67,68,72,7476,78,81, 8789,91,92,95); 1974/1987 revised JBDRC (96,98), n = 16 (4,24,29,31,33,45,47,6062,70,71,79,84,85,94); O’Duffy (99), n = 6 (25,27,40,66,69,93); Mason and Barnes (100), n = 4 (23,39,42,56); Cheng and Zhang (101), n = 1 (82); and multiple sets, n = 5 (30,38,46,58,73). For 12 study populations, no statements were made with respect to the criteria used to define BD cases (3537,49,59,65,77,80,83,86,90). Matching criteria for controls were cited for 52 study populations and included ethnicity (n = 50), age (n = 7), and/or sex (n = 6).

Figure 2
Forest plot of results of published studies on the association between HLA–B51/B5 and Behçet’s disease (BD) (listed chronologically). Odds ratios (ORs) for the risk of HLA–B51/B5 allele carriers to develop BD compared with ...
Table 1
Geographic locations of the study populations (n = 80)

Aggregate information for one or several demographic and clinical characteristics of the BD cases (and which were given for the exact number of genotyped individuals) could be retrieved from 49 studies. These included information on mean/median age at disease onset/diagnosis (range 28–34 years) in 5 studies (28,30,32,51,54); mean/median age at study time (range 27–49.5 years) in 20 studies (22,27,39,44,46,47,51,54,55,57,58,68,69,72,81,86,88,91,93,94); percentages of males (range 28.6–90.5%) in 44 studies (22,2628,3033,36,39,41,4347,51,52,5458,6062,65,66,6871,75,8183,85,86,88,9195); and percentages of cases with ocular involvement (range 20–100%) in 32 studies (22,24,27,2931,33,35,39,41,4548,51,52,5557,65,66,68,7073,75,82,83,88,93,94), with central nervous system involvement (range 2.8–50%) in 16 studies (22,24, 30,31,39,4648,51,5557,72,73,75,94) and with large-vessel involvement (range 5.6–35.7%) in 16 studies (22,24,27,30, 31,39,41,47,51,56,57,66,72,73,75,94).

Quantitative data synthesis

The ORs for BD susceptibility associated with HLA–B51/B5 carriage are shown in Figure 2. Results are shown for all 80 separate case–control data sets, and the pooled result across all the data sets. The ORs for HLA–B51/B5 carriers to develop BD across the primary data sets were all >1, with values ranging from 1.18 (69) to 34.62 (75). For 2 studies with no controls having positive findings for HLA–B51/B5 (52,75), a single positive control was added to allow OR and 95% CI computations.

The pooled OR for BD susceptibility was 5.78 (95% CI 5.00–6.67). Pooled ORs within predefined subgroups consistently yielded positive ORs with overlapping 95% CIs (Table 2). For the overall estimate (I2 = 61%), and within most of the subgroups (I2 = 38–78%), analyses showed moderate heterogeneity.

Table 2
Pooled estimates for overall and subgroup meta-analyses for HLA–B51/B5 carriage and its association with BD risk*

The random-effects pooled prevalence for HLA–B51/B5 in BD cases and control populations were 57.2% (95% CI 53.4–60.9%) and 18.1% (95% CI 16.1–20.3%), respectively (Table 2). Compared with case and control populations from Eastern Asia, the Middle East/North Africa, and Southern Europe, the pooled percentages of HLA–B51/B5 carriage were 1.4–1.9-fold lower for cases and controls from Northern/Eastern Europe.

Bias and heterogeneity diagnostics

Weights attributed to the 80 individual data sets ranged from 0.15–4.87%, suggesting that none of the individual case–control populations had an unduly large effect on the pooled OR (Figure 2).

The results of the meta-regression analyses assessing the impact of the selected categorical and continuous covariates on the genetic association are shown in Tables 2 and and3,3, respectively. These analyses identified only the percentages of male BD cases as significantly affecting the genetic effect (Pcovariate = 0.008). However, compared with the unadjusted model (i.e., the model that did not include any covariate), adjustment for sex did not markedly lower heterogeneity in the model (detailed result not shown).

Table 3
Univariate random-effects meta-regression assessing potential effects of selected continuous covariates in the observed pooled effect of HLA–B51/B5 on the risk of developing BD*

The funnel plot distribution had a slightly asymmetric shape (Figure 3), and the tests proposed by Egger (P = 0.02) and Begg-Mazumadar (P = 0.10) were statistically significant, raising the possibility of a publication bias. However, the arcsine test (P = 0.13) and the test proposed by Peters (P = 0.12) did not reach statistical significance. In addition, the sensitivity analyses based only on the studies that included ≥30 BD cases, ≥50 BD cases, or a total sample size of ≥100 cases and controls, showed only a minor reduction of the pooled OR at 5.53 (95% CI 4.73– 6.48; 54 comparisons), 5.38 (95% CI 4.56–6.35; 39 comparisons), and 5.71 (95% CI 4.94–6.60; 66 comparisons), respectively.

Figure 3
Funnel plot for publication bias. The dashed vertical line indicates the pooled estimate. Precision was assessed by the inverse variance method.

PAR of HLA-B51/B5 for BD

PAR were calculated using the pooled OR obtained for the entire sample. Owing to the geographic variations of the percentages of BD cases carrying the HLA–B51/B5 allele, PAR were computed for geographic strata. The resulting PAR were 44.4% for Eastern Asia, 49.4% for Middle East/North Africa, 52.2% for Southern Europe, and 31.7% for Northern/Eastern Europe.


The pooled estimates of this meta-analysis of 4,800 cases and 16,289 controls indicat that the risk (“odds”) of HLA–B51/B5 carriers developing BD is increased by a factor of 5.78, and by a factor of 5.90 when considering only the split antigen HLA–B51. In agreement with previous observations about meta-analyses on a variety of genetic associations (102), we found that the pooled rates of HLA–B51/B5–positive BD cases varied across geographic locations, but the relative risk increases associated with this allele appeared to be fairly even for different ethnic populations. An additional important finding concerns the moderate heterogeneity, which we were able to partly explain by variations of sex distributions in the studied BD populations.

This meta-analysis was undertaken to gain further insight into the long known relationship between BD and the HLA–B51/B5 allele. The considerable range of the reported effect sizes, which became even more obvious during this investigation, has prevented accurate appraisal of the true impact this allele exerts on BD susceptibility. Another area of uncertainty was highlighted by the suggestion that this genetic association might hold true only for areas of high BD prevalence (2). Hence, the critical question persisted whether HLA–B51/B5 represented the disease-causing factor or simply reflected linkage disequilibrium with a nearby and truly causal BD gene (8,9,103,104).

Evaluation of our meta-analysis findings against the strength and consistency criteria for causal inference for gene–disease associations (105,106) adds epidemiologic support to the concept that HLA–B51/B5 itself is the BD-susceptibility allele. The likelihood that a given genetic association takes account of confounding (e.g., by linkage disequilibrium) diminishes with the increasing strengths of the association, and an unbiased OR of at least 3 to 5 was advanced as being indicative of causality (106). In addition, all 80 analyzed study populations consistently produced ORs >1, and our finding of a lack of a significant modifying effect of the ethnic background further weakens the hypothesis of linkage disequilibrium. Another criterion to infer a causal role of HLA–B51/B5 in BD is based on biologic plausibility. HLA class I molecules play a central role in the immune system and, despite the lack of direct experimental evidence for this theory, it is hypothesized that HLA–B51/B5 triggers BD by means of selective binding of pathogenic peptides (8,9,103,104).

To assess the absolute impact the HLA–B51/B5 allele might have on BD development, we calculated the PAR. This computed percentage suggested that the HLA–B51/B5 allele accounts for 32–52% of BD cases within various geographic subgroups. These values are substantially higher than a previous estimate derived from a family-based genetic association study, which indicated that 19% of the genetic susceptibility to BD would be explained by this allele (107).

As is common to meta-analyses of genetic association studies, statistical heterogeneity was found (108). Consequently, all our risk estimates were calculated using random-effects models. Although random-effects models generate confidence intervals with wider boundaries, the lower 95% confidence limits still largely supported positive odds of BD susceptibility for the HLA–B51/B5 carriers for the entire sample and within the analyzed subgroups (Table 2). Therefore, we think that the underlying heterogeneity should not have major repercussions on the interpretation of the overall findings of our meta-analysis, but this situation strongly highlights the influence of modifiers on the association of BD with HLA–B51/B5.

Pertinently, our meta-regression analyses pinpointed the differing sex distributions as a significant source of between-study heterogeneity, although this result has to be interpreted keeping in mind the possibility of spurious statistical significance due to testing of multiple hypotheses. Nevertheless, this finding agrees with reports of HLA–B51/B5 carriage predominantly in male BD cases (32,52,88,95), and might reflect either a sex-specific genetic effect or confounding, since both male sex and HLA–B51/B5 carriage may be markers of more severe BD (1,2). In contrast, despite the reports that HLA–B51/B5 positivity determines the propensity for developing such manifestations (2,9), variations of percentages of BD cases with eye, central nervous system, or large-vessel disease did not appear to be statistically significant sources of heterogeneity. However, these calculations might have been under-powered in our analyses. The observed trend toward a significant variation according to genotyping technique is counterintuitive in light of the relatively small misassignment rates reported for HLA class 1 typing with serologic compared with molecular techniques (109,110).

The unresolved heterogeneity could also reflect biases in the reported strengths of the association between HLA–B51/B5 and BD. Indeed, graphic (Figure 3) and statistical methods indicated the possibility of a publication bias, even though sensitivity analyses suggested that the impact of “small study effects” on our overall results was not very strong. Alternatively, it can be hypothesized that the heterogeneity derives from epistatic or environmental risk determinants on the contribution of HLA–B51/B5 to BD development distributed unequally across BD populations. However, such an interaction with HLA–B51/B5 has not yet been identified for any of the other potential genetic or environmental BD-susceptibility factors (8,9, 103,104).

Our study has limitations. The allowance for inclusion of studies investigating the association of BD with HLA–B5 is arguable because this allelic group also recognizes the HLA–B52 split, which is not linked to BD (8,103). Hence, as suggested by the results of the subgroup meta-analysis for the individual effects of HLA–B5 and HLA–B51, our overall pooled result likely represents an underestimation, albeit small, of the true susceptibility associated with this genetic factor. The claim of consistency of the HLA–B51/B5 effect on BD risk across ethnic groups needs to be understood in the context that this effect remains to be demonstrated for the North American continent—there were only 2 eligible studies on ethnically diverse populations from the US and Mestizo Mexicans—and for other continents for which no such data have yet become available. Furthermore, because the analyzed studies were reported over a period of over 3 decades, they could not be evaluated for their compliances with current quality standards for genetic case–control association studies (e.g., control for population stratification) (111). To address this possible shortcoming, we used publication type, publication language, and year of publication as possible surrogate indices of study quality, and we conducted a subgroup meta-analysis separating publications according to whether or not they mentioned ethnic matching of case and control samples.

This comprehensive analysis of the effect of the HLA–B51/B5 allele on the risk of developing BD further illustrates this disease–gene association as one of the tightest known for a complex human trait. Future research should be directed toward unravelling the potential interactions of this allele with other genetic and nongenetic risk factors of BD and with BD phenotype.


We are indebted to the following physicians and researchers for their help in identification and selection of relevant studies: M. Accorinti, MD (Rome, Italy); Z. Alekberova, MD (Moscow, Russia); G. Azizlerli, MD (Istanbul, Turkey); T. Chajek-Shaul, MD (Jerusalem, Israel); M. Chen (Beijing, China); J. A. Correia, MD (Porto, Portugal); J. Crespo, MD (Coimbra, Portugal); F. Davatchi, MD (Tehran, Iran); M. F. Gonzalez-Escribano, PhD (Sevilla, Spain); J. Graña (Coruñ, Spain); A. Gül, MD, PhD (Istanbul, Turkey); H. Houman, MD (Tunis, Tunisia); S. K. Kim, MD (Daegu, South Korea); S. Kobayashi, MD (Tokyo, Japan); T. Lehner, MD (London, UK); W. Madanat, MD (Amman, Jordan); S. Ohno, MD, PhD (Sapporo, Japan); G. Palimeris, MD (Athens, Greece); S. Perrone, MD (Padua, Italy); P. Pivetti-Pezzi, MD (Rome, Italy); C. Salvarani (Reggio Emilia, Italy); J. Vaz-Patto, MD (Lisbon, Portugal); G. Wallace, MD (Birmingham, UK); H. Yazici, MD (Istanbul, Turkey); C. C. Zouboulis, MD (Dessau, Germany). We are also grateful to Drs. R. Seror, L. Teixeira, K. Yasuda, and Y. Zhang for their help in the translation of articles, and to Ms Janet Jacobson and Dr. Andrew Wang for editorial assistance.

Dr. LaValley’s work was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases Multidisciplinary Clinical Research Center (grant P60-AR047785). Dr. Mahr’s work was supported in part by a grant from the Société Nationale Française de Médecine Interne.


AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Mahr had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. De Menthon, Mahr.

Acquisition of data. De Menthon, Maldini, Mahr.

Analysis and interpretation of data. De Menthon, LaValley, Guillevin, Mahr.


1. Kaklamani VG, Vaiopoulos G, Kaklamanis PG. Behçet’s disease. Semin Arthritis Rheum. 1998;27:197–217. [PubMed]
2. Sakane T, Takeno M, Suzuki N, Inaba G. Behçet’s disease. N Engl J Med. 1999;341:1284–91. [PubMed]
3. Ono S, Aoki K, Sugiura S, Nakayama E, Itakura K. HL-A5 and Behçet’s disease [letter] Lancet. 1973;2:1383–4. [PubMed]
4. Ohno S, Ohguchi M, Hirose S, Matsuda H, Wakisaka A, Aizawa M. Close association of HLA-Bw51 with Behçet’s disease. Arch Ophthalmol. 1982;100:1455–8. [PubMed]
5. Du KM, Ji Y, Xie JH, Fu M, Sun Y, Jin Y, et al. HLA-A, -B, -DR haplotype frequencies from DNA typing data of 26,266 Chinese bone marrow donors. Hum Immunol. 2007;68:854–66. [PubMed]
6. Mori M, Beatty PG, Graves M, Boucher KM, Milford EL. HLA gene and haplotype frequencies in the North American population: the National Marrow Donor Program Donor Registry. Transplantation. 1997;64:1017–27. [PubMed]
7. Valluei V, Mustafa M, Santhosh A, Middleton D, Alvales M, el Haj E, et al. Frequencies of HLA-A, HLA-B, HLA-DR, and HLA-DQ phenotypes in the United Arab Emirates population. Tissue Antigens. 2005;66:107–13. [PubMed]
8. Verity DH, Marr JE, Ohno S, Wallace GR, Stanford MR. Behçet’s disease, the Silk Road and HLA-B51: historical and geographical perspectives. Tissue Antigens. 1999;54:213–20. [PubMed]
9. Fietta P. Behçet’s disease: familial clustering and immunogenetics. Clin Exp Rheumatol. 2005;23:S96–105. [PubMed]
10. Van Houwelingen HC, Arends LR, Stijnen T. Advanced methods in meta-analysis: multivariate approach and meta-regression. Stat Med. 2002;21:589–624. [PubMed]
11. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88. [PubMed]
12. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58. [PubMed]
13. Whitlock EP, Lin JS, Liles E, Beil TL, Fu R. Screening for colorectal cancer: a targeted, updated systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;149:638–58. [PubMed]
14. Rucker G, Schwarzer G, Carpenter J. Arcsine test for publication bias in meta-analyses with binary outcomes. Stat Med. 2008;27:746–63. [PubMed]
15. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101. [PubMed]
16. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34. [PMC free article] [PubMed]
17. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295:676–80. [PubMed]
18. Hennekens CH, Buring JE, Mayrent SL. Epidemiology in medicine. Little Brown; Boston (MA): 1987.
19. Ahmad T, Zhang L, Gogus F, Verity D, Wallace G, Madanat W, et al. CARD15 polymorphisms in Behçet’s disease. Scand J Rheumatol. 2005;34:233–7. [PubMed]
20. Alekberova ZS, Madanat V, Polianskaia IS, Prokaeva TB. The HLA-B5 immunogenetic marker in Behçet’s disease. Ter Arkh. 1993;65:12–4. In Russian. [PubMed]
21. Al-Joofy I, Muslih RK, Mousawy KM, Al-Waiz MM. HLA typing for class I and class H antigens in Iraqi patients with Behçet’s disease (sporadic and familial cases) Adv Exp Med Biol. 2003;528:217–20. [PubMed]
22. Alpsoy E, Yilmaz E, Coskun M, Savas A, Yegin O. HLA antigens and linkage disequilibrium patterns in Turkish Behçet’s patients. J Dermatol. 1998;25:158–62. [PubMed]
23. Al-Rawi ZS, Sharquie KE, Khalifa SJ, Al-Hadithi FM, Munir JJ. Behçet’s disease in Iraqi patients. Ann Rheum Dis. 1986;45:987–90. [PMC free article] [PubMed]
24. Arber N, Klein T, Meiner Z, Pras E, Weinberger A. Close association of HLA-B51 and B52 in Israeli patients with Behçet’s syndrome. Ann Rheum Dis. 1991;50:351–3. [PMC free article] [PubMed]
25. Assaad-Khalil SH. Clinical, genetic, immunological, and biochemical features of 180 Egyptian patients with Behçet’s disease. In: O’Duffy JD, Kokmen E, editors. Behçet’s disease: basic and clinical aspects. Marcel Dekker; New York: 1991. pp. 269–77.
26. Atalay A, Yildiz-Demirtepe S, Tatlipinar S, Sanli-Erdogan B, Cobankara V, Yildirim C, et al. HLA-B51 gene and its expression in association with Behçet’s disease in Denizli Province of Turkey. Mol Biol Rep. 2008;35:345–9. [PubMed]
27. Azizleri G, Aksungur VL, Sarica R, Akyol E, Ovul C. The association of HLA-B5 antigen with specific manifestations of Behçet’s disease. Dermatology. 1994;188:293–5. [PubMed]
28. Ba’Arah B, Hadid A. Association of HLA-B5, B27 and B12 with specific manifestations of Behçet’s disease in Jordanian patients. J Bahrain Med Soc. 2002;14:79–84.
29. Balboni A, Pivetti-Pezzi P, Orlando P, Rubini M, Selvatici R, Accorinti M, et al. Serological and molecular HLA typing in Italian Behçet’s patients: significant association to B51-DR5-DQw3 haplotype. Tissue Antigens. 1992;39:141–3. [PubMed]
30. Castillo Palma MJ, Sanchez Roman J, Ocana Medina C, Gonzalez Escribano MF, Nunez Roldan A, Lopez-Checa F. Serologic and molecular HLA typing in patients from Andalucia with Behçet’s disease: genetic and clinical correlations. Med Clin (Barc) 1996;106:121–5. In Spanish. [PubMed]
31. Chajek-Shaul T, Pisanty S, Knobler H, Matzner Y, Glick M, Ron N, et al. HLA-B51 may serve as an immunogenetic marker for a subgroup of patients with Behçet’s syndrome. Am J Med. 1987;83:666–72. [PubMed]
32. Choukri F, Chakib A, Himmich H, Hue S, Caillat-Zucman S. HLA-B*51 and B*15 alleles confer predisposition to Behçet’s disease in Moroccan patients. Hum Immunol. 2001;62:180–5. [PubMed]
33. Chung YM, Tsai ST, Liao F, Liu JH. A genetic study of Behçet’s disease in Taiwan Chinese. Tissue Antigens. 1987;30:68–72. [PubMed]
34. Crespo J. for the Grupo Nacional para o Estudo da Doença de Behçet. Behçet’s disease: a national casuistic. Med Interna. 1997;4:225–32. In Portugese.
35. Crews SJ, Mackintosh P, Barry DR, Willshaw HE. HLA antigens and certain types of uveitis. Trans Ophthalmol Soc U K. 1979;99:156–9. [PubMed]
36. Djawari D, Lang B, Hornstein OP. HLA typing in patients of German origin with recurrent benign aphthosis and Behçet’s disease. Z Hautkr. 1984;59:1005–9. In German. [PubMed]
37. Ersoy F, Berkel I, Firat T, Kazokoglu H. HLA antigens associated with Behçet’s disease. Arch Dermatol. 1977;113:1720–1. [PubMed]
38. Fernandez Miranda C, Palacio Perez-Medel A, Martinez-Martin P, Montalban Pallares MA, Dominguez Ortega L, Ramirez Diaz-Bernando J. Enfermedad de Behçet: presentación de 22 casos. Rev Esp Reumatol. 1983;10:37–43. In Spanish.
39. Gemignani G, Berrettini S, Bruschini P, Sellari-Franceschini S, Fusari P, Piragine F, et al. Hearing and vestibular disturbances in Behçet’s syndrome. Ann Otol Rhinol Laryngol. 1991;100:459–63. [PubMed]
40. Godeau P, Torre D, Campinchi R, Bloch-Michel E, Schmid M, Nunez-Roldan A, et al. HL-A and Behçet’s disease. Rev Fr Transfus Immunohematol. 1977;20:43–6. In French. [PubMed]
41. Golousenko I. The relationship of the HLA antigen system to Behçet’s disease. Vestn Dermatol Venerol. 1990;5:55–7. In Russian. [PubMed]
42. Grana J, Sanchez Burson J, Atanes A, Montoya A, Alonso C, Galdo F. Enfermedad de Behçet y HLA en Galicia. Rev Esp Reumatol. 1987;14:214–7. In Spanish.
43. Gul A, Uyar FA, Inanc M, Ocal L, Barrett JH, Aral O, et al. A weak association of HLA-B*2702 with Behçet’s disease. Genes Immun. 2002;3:368–72. [PubMed]
44. Gunesacar R, Erken E, Bozkurt B, Ozer HT, Dinkci S, Erken EG, et al. Analysis of CD28 and CTLA-4 gene polymorphisms in Turkish patients with Behçet’s disease. Int J Immunogenet. 2007;34:45–9. [PubMed]
45. Haim S, Gideoni O, Barzilai A. The histocompatibility antigens in patients with Behçet’s disease. Acta Derm Venereol. 1977;57:243–5. [PubMed]
46. Hamza M, Ayed K, Eleuch M, Ayed HB. HLA antigens in Behçet’s disease. Sem Hop. 1986;62:1314–6. In French.
47. Hong C. HLA antigens in Korean patients with Behçet’s disease. 25th International Congress of Ophthalmology; Rome (Italy). Kugler & Ghedini; 1987. pp. 1694–700.
48. Houman MH, Neffati H, Braham A, Harzallah O, Khanfir M, Miled M, et al. Behçet’s disease in Tunisia: demographic, clinical and genetic aspects in 260 patients. Clin Exp Rheumatol. 2007;25:S58–64. [PubMed]
49. Ito K, Nakagawa J, Ikehara Y, Uyama M. HL-A antigens in Behçet’s disease. In: Shimizu T, editor. Studies on etiology, treatment and prevention of Behçet’s disease: Behçet’s Disease Research Committee of Japan. Ministry of Welfare; Tokyo: 1975. pp. 198–200. In Japanese.
50. Itoh Y, Inoko H, Kulski JK, Sasaki S, Meguro A, Takiyama N, et al. Four-digit allele genotyping of the HLA-A and HLA-B genes in Japanese patients with Behçet’s disease by a PCR-SSOP-Luminex method. Tissue Antigens. 2006;67:390–4. [PubMed]
51. Jang WC, Park SB, Nam YH, Lee SS, Kim JW, Chang IS, et al. Interleukin-18 gene polymorphisms in Korean patients with Behçet’s disease. Clin Exp Rheumatol. 2005;23:S59–63. [PubMed]
52. Kilmartin DJ, Finch A, Acheson RW. Primary association of HLA-B51 with Behçet’s disease in Ireland. Br J Ophthalmol. 1997;81:649–53. [PMC free article] [PubMed]
53. Kotter I, Gunaydin I, Stubiger N, Yazici H, Fresko I, Zouboulis CC, et al. Comparative analysis of the association of HLA-B*51 suballeles with Behçet’s disease in patients of German and Turkish origin. Tissue Antigens. 2001;58:166–70. [PubMed]
54. Koumantaki Y, Stavropoulos C, Spyropoulou M, Messini H, Papademetropoulos M, Giziaki E, et al. HLA-B*5101 in Greek patients with Behçet’s disease. Hum Immunol. 1998;59:250–5. [PubMed]
55. Kulahli I, Balci K, Koseoglu E, Yuce I, Cagli S, Senturk M. Audio-vestibular disturbances in Behçet’s patients: report of 62 cases. Hear Res. 2005;203:28–31. [PubMed]
56. Lavalle C, Alarcon-Segovia D, del Giudice-Knipping JA, Fraga A. Association of Behçet’s syndrome with HLA-B5 in the Mexican mestizo population. J Rheumatol. 1981;8:325–7. [PubMed]
57. Lee EB, Kim JY, Lee YJ, Park MH, Song YW. TNF and TNF receptor polymorphisms in Korean Behçet’s disease patients. Hum Immunol. 2003;64:614–20. [PubMed]
58. Lee S, Koh YJ, Kim DH, Bang D, Nam IW, Lee KH, et al. A study of HLA antigens in Behçet’s syndrome. Yonsei Med J. 1988;29:259–62. [PubMed]
59. Lehner T, Welsh KI, Batchelor JR. The relationship of HLA-B and DR phenotypes to Behçet’s syndrome, recurrent oral ulceration and the class of immune complexes. Immunology. 1982;47:581–7. [PubMed]
60. Matsuo Y, Fuchimoto S, Zaima T, Tanaka H, Sakagami K, Munimai T, et al. HL-A and Behçet’s syndrome. Igakunoayumi. 1975;94:192–3. In Japanese.
61. Mineshita S, Tian D, Wang LM, Jian XY, Li SY, Fang GZ, et al. Histocompatibility antigens associated with Behçet’s disease in northern Han Chinese. Intern Med. 1992;31:1073–5. [PubMed]
62. Mizoguchi M, Matsuki K, Mochizuki M, Watanabe R, Ogawa K, Harada S, et al. Human leukocyte antigen in Sweet’s syndrome and its relationship to Behçet’s disease. Arch Dermatol. 1988;124:1069–73. [PubMed]
63. Mizuki N, Meguro A, Tohnai I, Gul A, Ohno S, Mizuki N. Association of major histocompatibility complex class I chain-related gene A and HLA-B alleles with Behçet’s disease in Turkey. Jpn J Ophthalmol. 2007;51:431–6. [PubMed]
64. Mizuki N, Ota M, Katsuyama Y, Yabuki K, Ando H, Yoshida M, et al. HLA class I genotyping including HLA-B*51 allele typing in the Iranian patients with Behçet’s disease. Tissue Antigens. 2001;57:457–62. [PubMed]
65. Moriyama H, Mimura Y. Correlation between ocular manifestations of Behçet’s disease and HLA antigens. In: Shimizu T, editor. Studies on etiology, treatment and prevention of Behçet’s disease: Behçet’s Disease Research Committee of Japan. Ministry of Welfare; Tokyo: 1976. pp. 147–50. In Japanese.
66. Muftuoglu AU, Yazici H, Yurdakul S, Pazarli H, Ozyazgan Y, Tuzun Y, et al. Behçet’s disease: lack of correlation of clinical manifestations with HLA antigens. Tissue Antigens. 1981;17:226–30. [PubMed]
67. Munoz-Saa I, Cambra A, Pallares L, Espinosa G, Juan A, Pujalte F, et al. Allelic diversity and affinity variants of MICA are imbalanced in Spanish patients with Behçet’s disease. Scand J Immunol. 2006;64:77–82. [PubMed]
68. Nakao K, Isashiki Y, Sonoda S, Uchino E, Shimonagano Y, Sakamoto T. Nitric oxide synthase and superoxide dismutase gene polymorphisms in Behçet’s disease. Arch Ophthalmol. 2007;125:246–51. [PubMed]
69. O’Duffy JD, Taswell HF, Elveback LR. HL-A antigens in Behçet’s disease. J Rheumatol. 1976;3:1–3. [PubMed]
70. Okinami S, Hayashi M, Uyama M. HLA antigens in the patients with Behçet’s disease, sarcoid-uveitis, and endogeneous uveitis (author’s translation) Nippon Ganka Gakkai Zasshi. 1977;81:43–7. In Japanese. [PubMed]
71. Okuyama T, Kunikane H, Kasahara M, Ohno S, Aizawa M, Conighi C, et al. Behçet’s disease. In: Albert ED, Baur MP, Mayr WR, editors. Histocompatibility testing. Springer; Berlin: 1984. pp. 397–402.
72. Park SH, Park KS, Seo YI, Min DJ, Kim WU, Kim TG, et al. Association of MICA polymorphism with HLA-B51 and disease severity in Korean patients with Behçet’s disease. J Korean Med Sci. 2002;17:366–70. [PMC free article] [PubMed]
73. Picco P, Porfirio B, Gattorno M, Buoncompagni A, Falcini F, Cusano R, et al. MICA gene polymorphisms in an Italian paediatric series of juvenile Behçet’s disease. Int J Mol Med. 2002;10:575–8. [PubMed]
74. Pirim I, Atasoy M, Ikbal M, Erdem T, Aliagaoglu C. HLA class I and class II genotyping in patients with Behçet’s disease: a regional study of eastern part of Turkey. Tissue Antigens. 2004;64:293–7. [PubMed]
75. Pittoni V, Vaglio S, Magrini L, Accorinti M, Pivetti-Pezzi P, Girelli G, et al. Polymorphism of the Duffy erythrocyte chemokine receptor in Italian patients with Behçet’s disease. Rheumatol Int. 2003;23:116–20. [PubMed]
76. Prokaeva T, Alekberova Z, Madanat W, Jazdovskiy V, Ermakova N. Behçet’s disease in Russia. In: Hamza M, editor. Behçet’s disease. Pub Adhoua; Tunis: 1997. pp. 190–5.
77. Psilas K, Polymenidis Z, Georgiades G. Antigen HLA-B5 in Adamantiades-Behçet’s syndrome (author’s translation) J Fr Ophtalmol. 1979;2:701–4. In French. [PubMed]
78. Salvarani C, Boiardi L, Mantovani V, Olivieri I, Ciancio G, Cantini F, et al. Association of MICA alleles and HLA-B51 in Italian patients with Behçet’s disease. J Rheumatol. 2001;28:1867–70. [PubMed]
79. Sekido M, Ohtani T, Okuda K, Tadokoro I. Studies on HLA antigens in patients with Behçet’s syndrome. Yokohama Med Bull. 1976;27:1–4.
80. Shahram F, Davatchi F, Nadji A, Jamshidi A, Bahar K, Akbarian M, et al. HLA-B51 frequency in Iranian patients with Behçet’s disease. Adv Exp Med Biol. 2003;528:229–30. [PubMed]
81. Shang YB, Zhai N, Li JP, Han SX, Li XF, Zhang X, et al. Study on association between polymorphism of HLA class I and class II genes and Behçet’s disease. Chin J Microbiol Immunol. 2006;26:56–9. In Chinese.
82. Si CW, Wong JH, Xi HL. Association of HLA with Behçet’s disease and its significance. Zhonghua Nei Ke Za Zhi. 1988;27:363–5. 390–1. In Chinese. [PubMed]
83. Soylu M, Ersoz TR, Erken E. The association between HLA B5 and ocular involvement in Behçet’s disease in southern Turkey. Acta Ophthalmol (Copenh) 1992;70:786–9. [PubMed]
84. Takano M, Miyajima T, Kiuchi M, Ohmori K, Amemiya H. Behçet’s disease and the HLA system. Tissue Antigens. 1976;8:95–9. [PubMed]
85. Takeno M, Kariyone A, Yamashita N, Takiguchi M, Mizushima Y, Kaneoka H, et al. Excessive function of peripheral blood neutrophils from patients with Behçet’s disease and from HLA–B51 transgenic mice. Arthritis Rheum. 1995;38:426–33. [PubMed]
86. Tanaka K, Kajiyama K, Imamura T, Jimi S, Watanabe T, Sato H, et al. Genetic and environmental factors in the development of Behçet’s disease. Tohoku J Exp Med. 1985;145:205–13. [PubMed]
87. Verity DH, Wallace GR, Vaughan RW, Kondeatis E, Madanat W, Zureikat H, et al. HLA and tumour necrosis factor (TNF) polymorphisms in ocular Behçet’s disease. Tissue Antigens. 1999;54:264–72. [PubMed]
88. Wang YS, Jiang LH, Shen H, Mu GY, Pan GJ, Qin TG, et al. Association of HLA-B51 and Behçet’s disease patients with uveitis. Chin J Ocul Fundus Dis. 2004;20:203–5. In Chinese.
89. Xu L, Lu Y, Fan L, Yang J, Yao F, Gu Y. Study on the association between the HLA-B*51 gene with Behçet’s disease in Shanghai area. Curr Immunol. 2005;25:141–4. In Chinese.
90. Yabuki K, Mizuki N, Ota M, Katsuyama Y, Palimeris G, Stavropoulos C, et al. Association of MICA gene and HLA-B*5101 with Behçet’s disease in Greece. Invest Ophthalmol Vis Sci. 1999;40:1921–6. [PubMed]
91. Yanagihori H, Oyama N, Nakamura K, Mizuki N, Oguma K, Kaneko F. Role of IL-12B promoter polymorphism in Adamantiades-Behçet’s disease susceptibility: an involvement of Th1 immunoreactivity against Streptococcus sanguinis antigen. J Invest Dermatol. 2006;126:1534–40. [PubMed]
92. Yasuoka H, Okazaki Y, Kawakami Y, Hirakata M, Inoko H, Ikeda Y, et al. Autoreactive CD8+ cytotoxic T lymphocytes to major histocompatibility complex class I chain–related gene A in patients with Behçet’s disease. Arthritis Rheum. 2004;50:3658–62. [PubMed]
93. Yazici H, Chamberlain MA, Schreuder I, D’Amaro J, Muftuoglu M. HLA antigens in Behçet’s disease: a reappraisal by a comparative study of Turkish and British patients. Ann Rheum Dis. 1980;39:344–8. [PMC free article] [PubMed]
94. Zervas J, Vayopoulos G, Sakellaropoulos N, Kaklamanis P, Fessas P. HLA antigens and Adamantiades-Behçet’s disease (A-BD) in Greeks. Clin Exp Rheumatol. 1988;6:277–80. [PubMed]
95. Zouboulis CC, Buttner P, Djawari D, Kirch W, Keitel W, Garbe C, et al. The HLA pattern in Adamantiades-Behçet’s disease in Germany: association of occurrence, clinical symptoms and follow-up in 39 patients. Hautarzt. 1993;44:81–5. In German. [PubMed]
96. Behçet’s Disease Research Committee of Japan Behçet’s disease: guide to diagnosis of Behçet’s disease. Jpn J Ophthalmol. 1974;18:291–4.
97. International Study Group for Behçet’s Disease Criteria for diagnosis of Behçet’s disease. Lancet. 1990;335:1078–80. [PubMed]
98. Mizushima Y. Recent research into Behçet’s disease in Japan. Int J Tissue React. 1988;10:59–65. [PubMed]
99. O’Duffy JD. Suggested criteria for diagnosis of Behçet’s disease [abstract] J Rheumatol. 1974;1(Suppl 1):18.
100. Mason RM, Barnes CG. Behçet’s syndrome with arthritis. Ann Rheum Dis. 1969;28:95–103. [PMC free article] [PubMed]
101. Cheng SP, Zhang XX. Some special clinical characteristics of Behçet’s disease: case-series report and literature review. Chin J Intern Med. 1980;19:15–20. In Chinese.
102. Ioannidis JP, Ntzani EE, Trikalinos TA. ’Racial’ differences in genetic effects for complex diseases. Nat Genet. 2004;36:1312–8. [PubMed]
103. Direskeneli H. Behçet’s disease: infectious aetiology, new autoantigens, and HLA-B51. Ann Rheum Dis. 2001;60:996–1002. [PMC free article] [PubMed]
104. Hirohata S, Kikuchi H. Behçet’s disease. Arthritis Res Ther. 2003;5:139–46. [PMC free article] [PubMed]
105. Weed DL. Interpreting epidemiological evidence: how meta-analysis and causal inference methods are related. Int J Epidemiol. 2000;29:387–90. [PubMed]
106. Campbell H, Rudan I. Interpretation of genetic association studies in complex disease. Pharmacogenomics J. 2002;2:349–60. [PubMed]
107. Gul A, Hajeer AH, Worthington J, Barrett JH, Ollier WE, Silman AJ. Evidence for linkage of the HLA–B locus in Behçet’s disease, obtained using the transmission disequilibrium test. Arthritis Rheum. 2001;44:239–40. [PubMed]
108. Ioannidis JP, Trikalinos TA, Ntzani EE, Contopoulos-Ioannidis DG. Genetic associations in large versus small studies: an empirical assessment. Lancet. 2003;361:567–71. [PubMed]
109. Gourley IS, Kearns J, McKeen M, Birkos S, Brown M, Kamoun M. HLA class I typing of volunteers for a bone marrow registry: QC analysis by DNA-based methodology identifies serological typing discrepancies in the assignment of HLA-A and B antigens. Tissue Antigens. 2002;59:211–5. [PubMed]
110. Usichenko T, Lattermann A, Mueller-Eckhardt G. Serology versus ARMS-PCR in prospective HLA-class I typing for bone marrow transplantation. Ann Hematol. 1998;77:97–100. [PubMed]
111. Huizinga TW, Pisetsky DS, Kimberly RP. Associations, populations, and the truth: recommendations for genetic association studies in Arthritis & Rheumatism. Arthritis Rheum. 2004;50:2066–71. [PubMed]