behet 's disease ( bd ) is an immune - mediated , systemic vasculitis , in which blood vessels of all sizes ( small , medium , and large ) in both the venous and arterial circulation can be affected . clinically it is characterised by recurrent aphthous ulcers of the mouth and/or genitals in combination with other systemic manifestations involving the skin , eyes , joints , vessels , gastrointestinal tract , or central nervous system . it lies at the crossroad between autoimmune and autoinflammatory disorders , may be triggered by infectious agents , and is characterised by a number of immunological aberrations , such as neutrophil hyperactivity ( reviewed in [ 3 , 4 ] ) . bd is most frequently observed in populations around the mediterranean basin , the middle east , and the far east , and the clustering of bd in populations along the ancient silk route suggests that an inherited tendency to bd was spread by travellers along these trading routes . multiple studies , in multiple populations , have confirmed a strong association between hla - b51 and bd , but other genes are also likely to be involved . copy number variation ( cnv ) is departure from the normal diploid number of genes ( n = 2 ) which may arise from gene duplication and deletion events and which may contribute substantially to quantitative variation in expression . an increasing number of cnvs have been characterised in the human genome with implications for both evolution and disease susceptibility . this cluster carries 5 highly homologous genes that encode for low affinity receptors for igg - complexed antigens , which are expressed widely throughout the haematopoietic system . these low affinity fc - gamma receptors are involved in the regulation of a multitude of innate and adaptive immune responses , with implications for both response to infection and susceptibility to autoimmunity . fcgr3b is expressed almost exclusively on neutrophils , and there is a clear correlation between gene copy number and fcgr3b cell surface expression , neutrophil adherence to igg - coated surfaces , and immune complex uptake . further , multiple studies have identified low fcgr3b cn ( i.e. , < 2 copies ) as a risk factor for systemic autoimmune diseases , such as systemic lupus erythematosus [ 810 ] , rheumatoid arthritis [ 11 , 12 ] , and primary sjgren 's syndrome [ 9 , 10 ] . we therefore examined the association between fcgr3b cnv and bd , in a cohort of iranian patients . ethics approval was obtained from the rheumatology research centre 's ethics committee of tehran university of medical sciences . 187 iranian bd patients were recruited from the behet 's clinic at shariati hospital , tehran , from early 2005 until late 2006 . 178 ethnically - matched , unrelated healthy volunteers were also recruited as normal controls between 2005 and 2007 . all the bd patients recruited for this study met the international study group ( isg ) criteria for bd . information was obtained regarding their age , gender , ethnicity , clinical features , and family history . serotyping for hla - b51 status was carried out in selected general immunologic laboratories within iran using routine commercial kits . genomic fcgr3b cn was determined using a quantitative real - time pcr method , as previously described . briefly , a duplex taqman copy number assay was performed , using fcgr3b specific primers ( applied biosystems , hs04211858 , fam - mgb dual labeled probe ) and rnase p ( applied biosystems , product 4403326 , vic - tamra dual - labeled probe ) as the reference assay . the assay was performed according to the manufacturer 's instructions and pcr reactions were run on an applied biosystems 7300 real - time pcr machine . copy number was determined using copy caller software ( v.1.0 , applied biosystems , usa ) , and results were accepted only when calling confidence was > 80% , and cq standard deviation between replicates was < 0.20 . analysis of fcgr3b cn in bd patients compared to controls , and with clinical manifestations within bd patients , was performed using logistic regression . 187 bd patients were included in the study ( mean age 32.7  8.2 , 48% female ) . baseline characteristics are summarised in table 1 . of those who were tested for hla status , 51% ( 89 of 175 ) were hla b5 positive and 51% ( 41 of 80 ) were hla b51 positive . the frequency of fcgr3b cn variants in both bd patients and controls is presented in table 2 . copy numbers ranged from 1 to 4 , and no null genotypes were observed in this cohort . the odds ratio for low copy number ( < 2 cn ) was 0.6 ( 95% ci 0.30 , 1.21 , p = 0.16 ) and the odds ratio for high copy number ( > 2 cn ) was 0.75 ( 96% ci 0.33 , 1.73 , p = 0.50 ) . therefore there was no evidence that either low or high fcgr3b was associated with bd , and in fact , both low cn and high cn were slightly decreased in bd patients relative to controls . further , there was no evidence of associations between fcgr3b cn variants and clinical manifestations within bd patients as shown in table 3 . this is the first study to examine the relationship between fcgr3b cn variants and behet 's disease , and we report no evidence of an association in terms of either disease susceptibility or clinical manifestations in this cohort of patients from iran . however , a previous study of turkish bd patients has reported associations between fcgr2a , fcgr3a , and fcgr3b snps and bd , in terms of both disease susceptibility and clinical manifestations , but this remains unconfirmed . other studies have reported intriguing but conflicting relationships between fcgr3b cn and vasculitis in the context of different diseases . for example , fcgr3b low cn ( < 2 ) is associated with granulomatosis with polyangiitis ( wegener 's granulomatosis ) and microscopic polyangiitis ( antineutrophil cytoplasmic antibody - associated systemic vasculitidies ) in one study , and high fcgr3b cn ( > 2 ) in another , and no association has been observed with vasculitis in conjunction with systemic lupus erythematosus . further , similar to bd , susceptibility to other systemic vasculitidies including giant cell arteritis and kawasaki 's disease has also been linked to snps within the fcgr gene cluster [ 16 , 17 ] . the fcgr gene cluster is a complex genomic region , with both snp and cnv polymorphism . while we were unable to demonstrate an association between fcgr3b cn and bd in this study , there are undoubted links to polymorphism in this region with vasculitic conditions . in future , the challenge will be to integrate cnv and snp data into haplotypes in order to systematically evaluate and contrast associations with different vasculitidies .
behet 's disease ( bd ) is an immune - mediated systemic vasculitis associated with hlab51 . 
 other gene associations are likely and may provide further insight into the pathogenesis of this disease . 
 fc - gamma receptors play an important role in regulating immune function . 
 copy number variation ( cnv ) of the fc - gamma receptor 3b ( fcgr3b ) gene is associated with other inflammatory conditions and may also play a role in bd . 
 the aim of this study was to determine whether cnv of the fcgr3b gene is associated with bd or its clinical features . 
 fcgr3b copy number was determined for 187 iranian patients and 178 ethnicity - matched controls using quantitative real - time pcr . 
 the genotype frequencies were comparable in both bd patients and controls . 
 the odds ratio for low copy number ( < 2cn ) was 0.6 ( p = 0.16 ) and the odds ratio for high copy number ( > 2cn ) was 0.75 ( p = 0.50 ) . 
 there was no association found between high or low cn of the fcgr3b gene and bd or its clinical features in this iranian population . 
 we are the first to report this finding which , when looked at in the context of other genetic studies , gives us further insight into the complex pathogenesis of bd .