Behçet's Disease Susceptibility Research Articles

The correlation of endoplasmic reticulum aminopeptidase 1 polymorphisms with Behçet's disease: a meta-analysis.

Substantial evidence has highlighted the mediation of endoplasmic reticulum aminopeptidase 1 (ERAP1) in the onset of Behçet's disease (BD), which can be differentially converted by ERAP1 variants. To comprehensively elaborate this issue, we undertook the meta-analysis to estimate the liaison of ERAP1 polymorphisms with BD risk. Literatures were retrieved in a standardised fashion and data underwent multi-perspective analyses utilizing STATA Statistical Software. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) of manifold comparisons between BD sufferers and healthy masses were exploited to evaluate the extent of relevance. Overall analyses suggested that the meanings of ERAP1 polymorphisms in BD susceptibility varied among plentiful variations, where rs10050860, rs17482078, rs2287987, rs1065407 and rs72773968 presented pathogenic influence and rs26618 acted out beneficial function, while rs27044, rs26653, rs27895 and rs3734016 had no pronounced biological significance. Additionally, the effect of rs30187 is not yet determined. Moreover, race appeared a crucial ingredient as Mongolian were more susceptible to suffering from BD than Caucasian, while the diagnostic criteria of BD exerted a relative inconspicuous role, where the International Study Group criteria slightly attenuated the pathogenicity of ERAP1 polymorphisms compared with the International Criteria for Behçet's Disease. Finally, an exceeding importance was attached to the proceeding analysis based on disparities in BD symptoms, ERAP1 haplotypes and HLA-B*51 in computing the hazard zonation of ERAP1 polymorphisms on BD tendency. The present meta-analysis prompted the heterogeneous influences of ERAP1 polymorphisms on BD development, which were malleable under the discrepancies in genetic grounds and disease diagnoses.

Associations between circulating interleukin-17 levels and Behcet's disease and between IL-17 gene polymorphisms and disease susceptibility: a meta-analysis.

To systematically investigate the relationship between circulating interleukin-17 (IL-17) levels and Behçet's disease (BD) and the associations between polymorphisms in IL17 genes and BD susceptibility. We searched the Medline, Embase, and Cochrane databases for relevant articles. We performed a meta-analysis of serum/plasma IL-17 levels in BD patients and controls and evaluated the associations between IL17A rs4711998, rs8193036, and rs2275913 and IL17F rs763780 and rs2397084 polymorphisms and the risk of BD. Twelve studies, involving 901 patients with BD and 1,131 controls, were included. Our meta-analysis revealed that circulating IL-17 levels were significantly higher in the BD group than in the control group (SMD = 1.422, 95% confidence interval [CI] = 0.689-2.155, p<0.001). Subgroup analysis by data type indicated higher IL-17 levels in the BD group in both the original and calculated data populations. Stratification by publication year revealed significantly lower vitamin D levels in the SSc group in both recent and older publication years. No significant differences in IL-17 levels were observed between the active and inactive disease groups. We found no evidence of associations between BD and IL17A rs2275913, L17F rs763780, or rs2397084 polymorphisms. However, a significant association was found between BD and IL17A rs4711998 and rs8193036 polymorphisms in the pooled cohort of affected individuals compared to that in pooled controls (odds ratio [OR] = 1.347, 95% CI = 1.043-1.741, p<0.001; OR = 0.691, 95% CI = 0.542-0.880, p=0.003). This meta-analysis revealed significantly higher circulating IL-17 levels in BD patients and showed evidence of associations between IL17A rs4711998 and rs8193036 polymorphisms and BD.

Protein Z (rs3024735; G79A and rs3024719; G-103A) gene polymorphisms in Behçet’s disease patients

Aim of the workTo investigate protein Z (PZ) gene polymorphic variations; PZ G79A (rs3024735) and PZ G-103A (rs3024719) in Behçet's disease (BD) patients and their possible relation with disease manifestations, activity and damage. Patients and methodsThis study included 100 BD patients and 100 controls. BD current activity form (BDCAF) and the BD damage index (BDI) were assessed. Genomic DNA analysis of PZ G79A (rs3024735) and PZ G-103A (rs3024719) single nucleotide polymorphisms, was assessed by Real-time PCR-TaqMan SNP genotyping assay. ResultsThe mean age of patients was 33.4 ± 6.8 years and median disease duration was 9 years. AA and GA genotypes of PZ G79A polymorphism were significantly higher in patients than controls (p = 0.003 and p = 0.004 respectively). The frequency of A allele was significantly higher in patients than controls (p < 0.001). There was no difference between patients and controls regarding AA and GA genotypes of PZ G-103A polymorphism (p = 0.5 and p = 0.2 respectively). There was a significant association between AA and GA genotypes of PZ G79A polymorphism with retinal vascular occlusion (RVO) (p < 0.001) and deep vein thrombosis (DVT) (p = 0.003), neutrophil–lymphocyte ratio (p < 0.001) and BDI (p < 0.001). There was no association between PZ G79A genotypes and BDCAF (p = 0.8). A allele of PZ G79A polymorphism was associated with increased BD susceptibility (p < 0.001), RVO (p = 0.001) and DVT (p = 0.01). ConclusionPZ G79A (rs3024735) polymorphism A allele was associated with increased susceptibility to BD with increased risk of developing RVO, DVT and damage, while AA and GA genotypes of PZ G-103A polymorphism were not significantly increased in BD patients.

Diverse selection pressures shaping the genetic architecture of behçet disease susceptibility.

Behçet disease (BD) is a polygenic, multifactorial, multisystem inflammatory condition with unknown etiology. Global distribution of BD is geographically structured, highest prevalence observed among East Asian, Middle Eastern, and Mediterranean populations. Although adaptive selection on a few BD susceptibility loci is speculated, a thorough evolutionary analysis on the genetic architecture of BD is lacking. We aimed to understand whether increased BD risk in the human populations with high prevalence is due to past selection on BD associated genes. We performed population genetics analyses with East Asian (high BD prevalence), European (low/very low BD prevalence), and African (very low/no BD prevalence) populations. Comparison of ancestral and derived alleles’ frequencies versus their reported susceptible or protective effect on BD showed both derived and ancestral alleles are associated with increased BD risk. Variants showing higher risk to and more significant association with BD had smaller allele frequency differences, and showed less population differentiation compared to variants that showed smaller risk and less significant association with BD. Results suggest BD alleles are not unique to East Asians but are also found in other world populations at appreciable frequencies, and argue against selection favoring these variants only in populations with high BD prevalence. BD associated gene analyses showed similar evolutionary histories driven by neutral processes for many genes or balancing selection for HLA (Human Leukocyte Antigen) genes in all three populations studied. However, nucleotide diversity in several HLA region genes was much higher in East Asians suggesting selection for high nucleotide and haplotype diversity in East Asians. Recent selective sweep for genes involved in antigen recognition, peptide processing, immune and cellular differentiation regulation was observed only in East Asians. We conclude that the evolutionary processes shaping the genetic diversity in BD risk genes are diverse, and elucidating the underlying specific selection mechanisms is complex. Several of the genes examined in this study are risk factors (such as ERAP1, IL23R, HLA-G) for other inflammatory diseases. Thus, our conclusions are not only limited to BD but may have broader implications for other inflammatory diseases.

Interleukin-27 gene variant rs153109 is associated with enhanced cytokine serum levels and susceptibility to Behçet's disease in the Iranian population.

Behcet's disease (BD) is a systemic vasculitis, characterized by recurrent oral aphthous, genital ulcers, ocular lesions, and other organ involvement. Interleukin (IL)-27 with its pro- and anti-inflammatory effects might be an important effective cytokine in this disease. The aim of this study was to investigate the association of IL-27 serum concentration and a single-nucleotide polymorphism (SNP) rs153109 (-964 A > G) with the risk and clinical features of the patients with BD. IL-27 Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the IL-27 serum levels were measured using enzyme-linked immunosorbent assay (ELISA). It is shown that AG, GG, and AG + GG genotypes, as well as G allele of rs153109, can significantly increase the risk of BD in total and in male individuals. Significantly higher frequencies of AG and GG genotypes and G allele were observed in total and male patients with an active form of BD. AG and GG genotypes were associated with joint (p = 0.046) and vascular (p = 0.02) involvement. The frequency of the G allele was higher in all patients, as well as in female patients with vascular involvement (p = 0.02). Serum cytokine analysis indicated an increased level of IL-27 in BD patients compared to healthy subjects (p = 0.038). Additionally, a higher level of IL-27 was detected in patients carrying the rs153109 GG genotype (p = 0.04) and those with renal (p = 0.009) and skin (p = 0.05) involvement. In conclusion, this study underscores the involvement of IL-27 rs153109 variants and increased serum level in BD susceptibility and pathogenesis.

Association between Interleukin-10 Gene Polymorphisms and Behcet's Disease Susceptibility: Evidence from a Meta-Analysis.

Epidemiological studies have demonstrated that interleukin-10 (IL-10) polymorphisms may be associated with the development of Behcet's disease (BD). However, the published results were inconsistent. Therefore, this meta-analysis was conducted to derive a more precise relationship between IL-10 polymorphisms and BD susceptibility. Online databases (PubMed, Embase, Science Citation Index (SCI), CNKI, and WanFang) were searched to identify eligible studies. Odds ratio (OR) and a 95% confidence interval (CI) were applied to assess the relationship strength between IL-10 -1082A>G (rs1800896), -819T>C (rs1800871), and -592A>C (rs1800872) polymorphisms and BD susceptibility. Publication bias, sensitivity, and cumulative analyses were conducted to measure the robustness of our findings. Finally, fifteen articles (36 independent case-control studies) involving 5,971 patients and 8,913 controls were included. Overall, significant associations between -819T>C polymorphisms and BD risk were observed in the total population (C vs. T: OR = 0.72, 95%CI = 0.67‐0.77, P < 0.01, I2 = 36.6%; TC vs. TT: OR = 0.73, 95%CI = 0.66‐0.80, P < 0.01, I2 = 23.0%; CC vs. TT: OR = 0.52, 95%CI = 0.39‐0.70, P < 0.01, I2 = 53.7%; TC+CC vs. TT: OR = 0.67, 95%CI = 0.61‐0.71, P < 0.01, I2 = 22.1%; and CC vs. TT+TC: OR = 0.66, 95%CI = 0.53‐0.82, P < 0.01, I2 = 57.8%). Moreover, the IL-10 -592 A>C polymorphism and the ACC haplotype exhibited a significant, protective effect against BD susceptibility. In summary, our meta-analysis suggested that IL-10 gene polymorphisms may play a salient role for BD development.

ERAP1 polymorphisms interactions and their association with Behçet's disease susceptibly: Application of Model-Based Multifactor Dimension Reduction Algorithm (MB-MDR).

Behçet's disease (BD) is a chronic multi-systemic vasculitis with a considerable prevalence in Asian countries. There are many genes associated with a higher risk of developing BD, one of which is endoplasmic reticulum aminopeptidase-1 (ERAP1). In this study, we aimed to investigate the interactions of ERAP1 single nucleotide polymorphisms (SNPs) using a novel data mining method called Model-based multifactor dimensionality reduction (MB-MDR). We have included 748 BD patients and 776 healthy controls. A peripheral blood sample was collected, and eleven SNPs were assessed. Furthermore, we have applied the MB-MDR method to evaluate the interactions of ERAP1 gene polymorphisms. The TT genotype of rs1065407 had a synergistic effect on BD susceptibility, considering the significant main effect. In the second order of interactions, CC genotype of rs2287987 and GG genotype of rs1065407 had the most prominent synergistic effect (β = 12.74). The mentioned genotypes also had significant interactions with CC genotype of rs26653 and TT genotype of rs30187 in the third-order (β = 12.74 and β = 12.73, respectively). To the best of our knowledge, this is the first study investigating the interaction of a particular gene's SNPs in BD patients by applying a novel data mining method. However, future studies investigating the interactions of various genes could clarify this issue.

Fas and microRNAs Variations as a Possible Risk for Behçet Disease.

Behçet disease (BD) belongs to a disease family that has a transparent borderline between autoinflammatory and autoimmune disorders. Fas and some miRNAs have revealed to display remarkable roles in both autoimmune and autoinflammatory processes, and they can play important roles in defective apoptosis in BD. We investigated the association of the susceptibility of BD with Fas, miRNA variations, and their both single and combined presence in a Turkish population as a case-control study. The distributions of FAS-670 A>G rs1800682, mir146a rs2910164, and mir196a rs11614913 polymorphisms are analyzed with the polymerase chain reaction-restriction fragment length polymorphism method in 115 BD patients and 220 controls in 6-month period. Statistical analysis indicates that in the case of Fas-670 A/G rs1800682, AA genotype and A allele have a protective role in BD (p = 0.0004 and p = 0.0009, respectively). The dominant model (AA + AG/GG) also displays a protective effect on BD unlike the recessive model (p = 0.03). In addition, both homozygous genotype (CC) of rs2910164 of mir-146a (p = 0.04) and the dominant model (CC + CG vs. GG) have protective effects on BD unlike the recessive model (p < 0.0001). Both mir-196a2 rs1800682 polymorphism and combined genotype analysis of rs1800682-rs2910164 and rs1800682-rs11614913 gave no statistically significant differences within the groups for genotypes and either of the alleles (p > 0.05). These findings indicate that both Fas rs1800682 and mir-146a rs2910164 variants might be important factors participating in the protection against BD in the Turkish population.

Meta-analysis of associations between interleukin-10 polymorphisms and susceptibility to Behcet's disease.

The aim of this study was to determine whether interleukin-10 (IL-10) polymorphisms are associated with susceptibility to Behcet's disease (BD). A meta-analysis was conducted, examining the associations between the IL-10 - 1082 G/A, - 819 C/T, and - 592 C/A polymorphisms and BD in various ethnic groups. Fourteen studies involving 5992 patients and 8966 controls were considered in the meta-analysis. Meta-analysis of the IL-10 - 1082 G/A polymorphism showed no association between BD and the - 1082 G allele (odds ratio (OR) = 0.951, 95% confidence interval (CI) = 0.790-1.146, p = 0.601). Meta-analysis of the IL-10 - 819 C/T polymorphism revealed a significant association between BD and the - 819 C allele (OR = 0.751, 95% CI = 0.684-0.825, p < 0.001) in all study subjects. Stratification by ethnicity indicated a significant association between the - 819 C allele and BD in Turkish (OR = 0.779, 95% CI = 0.709-0.856, p < 0.001) and Asian (OR = 0.676, 95% CI = 0.631-0.725, p < 0.001), but not in Middle Eastern populations. Meta-analysis of the - 592 C allele showed an association with BD in all study subjects (OR = 0.792, 95% CI = 0.662-0.948, p = 0.011) Stratification by ethnicity indicated a significant association between the - 592 C allele and BD in Asian populations (OR = 0.656, 95% CI = 0.512-0.841, p = 0.001). This meta-analysis showed that the IL-10 - 819 C/T and - 592 C/A polymorphisms are associated with BD susceptibility, especially in Asian population.

Associations of Mitochondrial Deoxyribonucleic Acid Polymorphisms With Behçet's Disease in the Korean Population.

This study aims to examine the possible associations of mitochondrial single nucleotide polymorphisms (SNPs) and Behçet's disease (BD) in a larger patient group. Whole blood or buffy coat was collected from 98 BD patients (31 males, 67 females; mean age 48±2.8 years; range 20 to 60 years) from four university hospitals located in the Chung-Cheong district of the Republic of Korea, and 196 age- and sex-matched healthy controls (HCs) (62 males, 134 females; mean age 46.91±12.90 years; range 20 to 68 years) from Konyang University Hospital. Twenty targeted mitochondrial deoxyribonucleic acids (DNAs) were genotyped and compared using the revised Cambridge Reference Sequence. Chi square and Fisher's exact tests were used to analyze association of mitochondrial DNA SNPs with BD susceptibility and its clinical characteristics. There were no differences for m.248A>G, m.304C>A, m.709G>A, m.3010G>A, m.3970C>T, m.4883C>T, m.5178C>A, m.6392T>C, m.6962G>A, m.10310G>A, m.10609T>C, m.12406G>A, m.12882C>T, m.13928G>C, m.14668C>T, m.16129G>A, and m16304T> between patient and HC groups. However, m.16182A>C and m.16183A>C were more frequently observed in the patient group than the HC group (22 [22.4%] vs. 24 [12.2%], p=0.061 and 32 [32.7%] vs. 42 [21.4%], p=0.092) but without statistical significance. m.4883C>T and m.5178C>A were associated with posterior location of oral ulcers (p=0.025 for each) and m.16183A>C was associated with deep oral ulcers (p=0.001), while m.16189T>C was associated with deep oral ulcers and thrombosis (p=0.042, 0.048, respectively). m.16182A>C and m.16183A>C may be associated with BD in the Korean population.

Association of Protein Z intronic G79A Polymorphism with susceptibility to deep vein thrombosis in Egyptian patients with Behcet's disease: A preliminary report

Behcet disease (BD) is a multi-systemic inflammatory disorder, which can affect all types of blood vessels. Thrombotic vasculopathy is one of the major causes complicating the clinical course of BD. This study aims to investigate potential associations between G79A polymorphisms of the protein Z (PZ) gene and venous thrombosis as well as other clinical manifestations in Egyptian patients with BD. Sixty patients who satisfied the International Study Group criteria for BD and sixty healthy age and sex- matched control subjects were genotyped for G79A polymorphisms of the PZ gene by restriction fragment length polymorphism PCR. Plasma levels of PZ were estimated using enzyme linked immunosorbent assay kit. Our preliminary data revealed that, compared to the GG genotype, the AA and AG PZ intron F genotypes were significantly associated with BD susceptibility and with reduced plasma PZ levels. The patients were then subgrouped according to Protein Z G79A genotypes to examine the G79A genotype frequencies according to the clinical characteristics, where there was a statistically significant association between AG and AA genotypes frequencies and deep venous thrombosis. In conclusion, our study nominates the minor A allele of the PZ G79A polymorphism as a discriminatory genetic marker for identification of BD patients at high risk for developing thrombotic events. However, large scaled studies are needed to verify these preliminary results.Key words: Behcet's disease; Protein Z; Deep vein thrombosis; intron F G79A polymorphism.

Behçet's disease: An immunogenetic perspective.

Behçet's disease (BD) is a chronic and rare multisystemic disorder defined byautoimmunity and inflammatory characteristics, manifested by ocular lesions, recurrent genital and oral ulcers, skin symptoms and arthritis as well as neurological, intestinal, and vascular involvement. Despite the unknown cause of BD, there issome strong documentationfor immunological, genetic, environmental, and infectious factors playing a role in the pathogenesis of BD. While the nature of the genetic variants remains unidentified, many genetic risk factors are considered to contribute to BD susceptibility. Along with human leukocyte antigen gene encoding B*51 (HLA-B*51) and areas including the major histocompatibility complex class I, genome-wide association studies have recognized numerous other BD susceptibility genes including those encoding interleukin (IL)-10, IL-12 receptor β 2 (IL-12RB2), IL-23 receptor (IL-23R), C-C chemokine receptor 1 gene, signal transducer and activator of transcription 4 (STAT4), endoplasmic reticulum aminopeptidase (ERAP1), and genes encoding killer cell lectin-like receptor family members (KLRC4-KLRK1). It is believed that BD could be considered as a disorder lyingin between autoimmune and autoinflammatory syndromes. The positive responses to classical immunosuppressive agents like azathioprine and cyclosporineand involvement of autoantigens in the initiation of the disorder are the main BD features that reflect the autoimmune nature of the disorder. In this review, we address recent findings on the role of common cytokines, antibodies and immunogenetic factors in BD.

Association of MICA Alleles and Human Leukocyte Antigen B in Turkish Patients Diagnosed With Behçet's Disease

This study aims to investigate whether or not MHC class I polypeptide-related sequence A (MICA) polymorphisms are associated with the susceptibility to Behçet's disease (BD) in a Turkish population. The study included 38 Turkish BD patients (20 males, 18 females; mean age 34±10.9 years) and 51 ethnically matched healthy controls (30 males, 21 females; mean age 36±12.8 years). MICA and human leukocyte antigen B (HLA-B) alleles were determined in all subjects by using the Luminex technology. LABType sequence-specific oligonucleotide MICA test (One Lambda) and sequence-specific oligonucleotide B locus tests (Gene-Probe) were used for the typing studies. A total of 16 MICA alleles were found in BD patients as well as in control subjects. The gene frequency of MICA*006 was significantly higher in the BD patients compared to controls (14.5% vs. 0.9%; odds ratio [OR]: 17.092 95% confidence interval [CI] [2.155~135.554]; p<0.05). When haplotypes were evaluated, an association was found between the haplotypes HLA-B*51-MICA*006 (11.8% and 0.9%; OR: 13.567 95% CI [1.679~109.577]; p<0.001) and HLA-B*51-MICA*009 (27.6% and 13.7%; OR: 2.4 95% CI [1.127~5.109]; p<0.05). Frequencies of HLA-B*49-MICA*004 (0% and 6.8%) and HLA-B*52- MICA*009 (0% and 10.7%) were significantly higher in controls compared to BD patients (p<0.05). Our study shows that the MICA*006 (MICA-A6) and the MICA*009 alleles are associated with BD susceptibility in HLA-B*51 positive Turkish population, particularly in HLA-B*51 patients with MICA*006, which might be considered as a diagnostic biomarker for BD in the future.

Clinical significance of NCOA5 gene rs2903908 polymorphism in Behçet's disease.

Behçet's disease (BD) is an autoimmune multisystemic disease. The precise etiology of BD is not fully understood; however, it is thought that interactions between genetic and environmental factors play an essential role in its pathogenesis. The nuclear receptor coactivator-5 (NCOA5) gene encodes a coregulator for nuclear receptor subfamily 1 group D member 2 (NR1D2) and estrogen receptor 1 and 2 (ESR1 and ESR2). Also, the NCOA5 gene insufficiency leads to an elevated expression of IL-6, and increased levels of IL-6 were found to be related to the pathogenesis of BD. In this study, we aimed to clarify the impact of the NCOA5 rs2903908 polymorphism on susceptibility and clinical findings of BD. This study included 671 participants (300 BD patients and 371 healthy controls). The analyses of NCOA5 rs2903908 polymorphism was performed by using the TaqMan allelic discrimination assay. The frequency of TT genotype of the NCOA5 rs2903908 polymorphism was found significantly higher in BD patients compared to those in healthy controls (p=0.016, OR=1.46, 95 % CI=1.08-1.99). Also, the frequencies of CT genotype was observed significantly higher in BD patients with genital ulceration and uveitis than without genital ulceration and uveitis (p=0.002 and p=0.005, respectively). The most significant association was found between C allele frequencies of BD patients with and without uveitis (p=0.0001). Our study represents for the first time that the NCOA5 rs2903908 polymorphism seemed to be linked to BD susceptibility and clinical findings.

Genetic Analysis with the Immunochip Platform in Behçet Disease. Identification of Residues Associated in the HLA Class I Region and New Susceptibility Loci.

Behcet's disease (BD) is an immuno-mediated vasculitis in which knowledge of its etiology and genetic basis is limited. To improve the current knowledge, a genetic analysis performed with the Immunochip platform was carried out in a population from Spain. A discovery cohort comprising 278 BD cases and 1,517 unaffected controls were genotyped using the Immunochip platform. The validation step was performed on an independent replication cohort composed of 130 BD cases and 600 additional controls. The strongest association signals were observed in the HLA class I region, being HLA-B*51 the highest peak (overall P = 6.82E-32, OR = 3.82). A step-wise conditional logistic regression with classical alleles identified HLA-B*57 and HLA-A*03 as additional independent markers. The amino acid model that best explained the association, includes the position 97 of the HLA-B molecule and the position 66 of the HLA-A. Among the non-HLA loci, the most significant in the discovery analysis were: IL23R (rs10889664: P = 3.81E-12, OR = 2.00), the JRKL/CNTN5 region (rs2848479: P = 5.00E-08, OR = 1.68) and IL12A (rs1874886: P = 6.67E-08, OR = 1.72), which were confirmed in the validation phase (JRKL/CNTN5 rs2848479: P = 3.29E-10, OR = 1.66; IL12A rs1874886: P = 1.62E-08, OR = 1.61). Our results confirm HLA-B*51 as a primary-association marker in predisposition to BD and suggest additional independent signals within the class I region, specifically in the genes HLA-A and HLA-B. Regarding the non-HLA genes, in addition to IL-23R, previously reported in our population; IL12A, described in other populations, was found to be a BD susceptibility factor also in Spaniards; finally, a new associated locus was found in the JRKL/CNTN5 region.

A meta-analysis of the association between Behçet's disease and MICA-A6.

Behçet's disease (BD) is a multi-system inflammatory condition with unknown cause, characterized by a triple-symptom complex of recurrent oral aphthous ulcers, genital ulcers, and uveitis and skin lesions. It predominantly affects people living around the Mediterranean basin and in Japan. The effects of the major histocompatibility complex class I chain related gene A (MICA) A6 allele on susceptibility to Behçet's disease (BD) have been reported previously, however, their results have been unreliable. The present study aimed to determine whether an association between the MICA-A6 allele and BD susceptibility exists. A total of 12 case-control studies, examining the association between MICA-A6 and BD and involving 752 cases and 1,175 controls were included in the present meta-analysis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The results of meta-analysis revealed that the frequency of the MICA-A6 allele in the case group was significantly higher than those in the control groups (P<0.001, OR=2.43, 95% CI: 1.99-2.97). Sub-group analysis by ethnicity indicated that the association between of MICA-A6 gene to BD remained in Asian populations (5 cases and 731 controls) and Caucasian populations (242 cases and 444 controls) with OR=2.65, 95% CI: 2.07-3.38 and OR=2.23, 95% CI: 1.37-3.62, respectively. These findings demonstrate that MICA-A6 gene is associated with susceptibility to BD. The MICA-A6 gene may serve as an early diagnostic marker for BD in the future.

Association of cytokine gene polymorphisms (IL‑6, IL‑12B, IL‑18) with Behcet's disease : A meta-analysis.

This study aims to investigate the association of cytokine gene polymorphisms with the risk of Behcet's disease (BD) via comprehensive meta-analysis. The Embase and PubMed databases covering the period from the earliest possible year to May2015 were searched. A total of 13eligible articles including 2,065BD patients and 1,559controls were recruited. Odds ratios (ORs) and 95 % confidence intervals (CIs) were used to assess the strength of the associations. Potential publication bias was evaluated using Egger's linear regression test. Meta-analysis indicated associations between IL‑6 rs1800795, IL‑12B rs3212227, and IL‑18 rs1946518 in all study subjects: IL‑18 rs1946518 in the dominant model (IL‑18 rs1946518: OR= 0.48, 95 % CI:0.34-0.70, P = 0.000) and the homozygote model (IL‑18 rs1946518: OR= 0.40, 95 % CI:0.25-0.65, P = 0.000); and IL‑6 rs1800795 and IL‑12B rs3212227 in the dominant model (IL‑6 rs1800795: OR= 0.53, 95 % CI:0.39-0.72, P = 0.000; IL‑12B rs3212227: OR= 1.26, 95 % CI:1.06-1.48, P = 0.007; IL‑18 rs1946518: OR= 0.46, 95 % CI:0.33-0.65, P = 0.000). No significant evidence for associations of IL‑18 rs187238 polymorphisms with BD susceptibility was detected. In summary, this meta-analysis finds that IL‑6 rs1800795 and IL‑18 rs1946518 polymorphisms decrease the risk of BD. However, IL‑12B rs3212227 increases BD susceptibility. Further large-scale investigation of this association is necessary.

Association of ERAP1 Gene Polymorphisms With Behçet's Disease in Han Chinese.

Behçet's disease (BD) is a common uveitis entity in China. The endoplasmic reticulum aminopeptidase 1 (ERAP1), has a significant influence on the stability and immunological properties of MHC-I loaded peptides. In the present study, we investigated the association of ERAP1 gene polymorphisms with BD in a Chinese Han population. A two-stage case-control study was carried out in 930 BD patients and 1704 healthy controls. Seven single nucleotide polymorphisms (SNPs) of the ERAP1 gene were determined using a PCR restriction fragment length polymorphism (PCR-RFLP) assay and one SNP was genotyped by TaqMan SNP genotyping assay. Furthermore, ERAP1 expression in peripheral blood mononuclear cells (PBMCs) was examined in genotyped individuals by real-time PCR. The result demonstrated that the frequencies of the A allele of rs1065407 and C allele of rs10050860 were significantly decreased in BD patients (Pc = 8.5 × 10-8, OR = 0.51; Pc = 1.1 × 10-5, OR = 0.54, respectively). No significant association was observed for the other six SNPs. ERAP1 expression in AA carriers of rs1065407 and CC carriers of rs10050860 was higher than that observed in AC/CC carriers (P = 0.022) or CT/TT carriers (P = 0.018) by LPS-stimulated PBMCs, respectively. In addition, the expression of ERAP1 in active BD patients not receiving immunosuppression was significantly lower than that in healthy controls (P = 3.8 × 10-4). Our study showed that rs1065407 and rs10050860 of the ERAP1 gene may contribute to the genetic susceptibility of BD by modulating the expression of ERAP1.

Inflammation-related cytokine gene polymorphisms in Behçet's disease.

Behçet’s disease (BD) is a complex, multisystemic inflammatory disorder of unclear etiology. Single nucleotide polymorphisms in tumor necrosis factor (TNF) and interleukin (IL)-10 genes have been implicated in susceptibility to BD with inconsistent results in several ethnic populations. The aim of this case-control study was to evaluate the association of TNF-α (−308G/A), TNF-β (+252A/G), and IL-10 (−1082G/A, −819C/T, and −592 C/A) polymorphisms with susceptibility of BD in Saudi patients. Molecular genotyping of TNF-α, TNF-β, and IL-10 gene polymorphisms was performed to analyze the alleles and genotypes distribution in 272 Saudi subjects, including BD patients (61) and healthy controls (211). The frequencies of allele A and genotype GA of TNF-α (−308G/A) were significantly higher, whereas those of allele G and genotypes GG were significantly lower in BD patients than controls, indicating that A allele and GA genotype are susceptible, while G allele and GG genotype may be refractory to BD. The distribution of frequencies of alleles and genotype of TNF-β (+252A/G) promoter polymorphism was not significantly different between BD patients and healthy controls. Genotypes 1082GG, −819TT, and 592AA of IL-10 polymorphisms are significantly associated with susceptibility risk of BD, while genotypes 1082AA, 1082GA, 819CC, 819CT, 592CC, and 592CA are resistant to BD. This study indicates that TNF-α (−308G/A) and IL-10 (−1082G/A, −819C/T, and −592C/A) polymorphisms are associated with risk of BD susceptibility in Saudi patients. However, larger scale studies in Saudi population as well as in other ethnicities are needed to confirm this association.

Polymorphisms of the NOS3 gene in Tunisian patients with Behçet's disease

Behçet's disease (BD) is a multisystem inflammatory disease characterized by recurrent orogenital ulceration, ocular inflammation and skin lesions. Reduced plasma nitric oxide (NO) levels in patients with BD have been implicated in the development of the endothelial abnormalities and thrombotic complications occurring in these patients. Polymorphisms in the endothelial nitric oxide synthase gene (NOS3) have been inconsistently associated with BD. This inconsistency may derive from population stratification secondary to ethnic diversity, and consideration limited to only one rather than combinations of polymorphisms. We studied three genetic variations in the NOS3 gene: a single nucleotide polymorphism in the promoter region -786T>C, in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4 (4a4b) of the NOS3 gene in 100 unrelated Tunisian patients with BD and 148 healthy controls. In addition, we also examined the association of NOS3 gene haplotypes with BD. Analyses of the Glu298Asp, -786T>C and 4a4b polymorphisms were made by the polymerase chain reaction (PCR) restriction fragment length polymorphism technique and PCR genotyping, respectively. The distribution of the Glu298Asp genotype differed significantly between patients with BD and controls (P = 0.01). Allele Asp298 was significantly more frequent in patients with BD than in controls (P = 0.005, OR = 1.70, 95% CI 1.14-2.54). In contrast, distribution of alleles and genotypes of -786T>C and 4a4b polymorphisms was not different between the control and BD group. However, the frequency of Asp-T-4b haplotype was significantly higher in patients with BD than in healthy controls. By gender, the signification remained only for heterozygous men (P = 0.03) and homozygous women (P = 0.02). These results suggest that Glu298Asp polymorphism of the NOS3 gene is associated with BD susceptibility in Tunisian patients.