Angiotensin-converting enzyme gene polymorphism in Behçet’s disease in Iranian population

Behçet’s disease (BD) is a chronic inflammatory disease with undefined etiopathogenesis. However, it is believed that it is multisystemic disease with spontaneous remissions and relapses similar to various autoimmune diseases (1). BD can also affect vasculitis, endothelial cells dysfunction and neurological systems as well as ocular and arthritis (2). BD Patients with ocular manifestation show relapsing-remitting uveitis and retinal vasculitis (3). The prevalence of Behçet’s disease is high in the “old silk route” which includes Turkey, Iran, China, England and Japan (1). The local renin-angiotensin system (RAS) in the vessel wall plays a crucial role in vascular endothelial control, contributing to the flow of inflammatory mediators (3). Angiotensin-converting enzyme (ACE) is the regulatory component of the RAS which converts angiotensin I to active angiotensin II and thereby inactivating bradykinin. The polymorphism of ACE is defined by the presence (I) or absence (D) of 287 bp Alu repetitive sequence in intron 16. Individuals with I/I genotype have the lowest level of enzyme activity, whereas those with I/D and D/D genotypes have the intermediate and the highest level of enzyme activity, respectively (4). In the present study, the possible association of ACE gene polymorphism with Behçet’s disease with or without ocular manifestation has been investigated. This case-control study has been approved by ethical committee of ophthalmic research center, Shahid Beheshti University of Medical Sciences (IR.SBMU.ORC.REC.1396.14). Total of 211 individuals including; 51 BD patients (37 males and 14 females) with posterior uveitis manifestation (optic neuritis or atrophy, retinal vasculitis, retinitis, vitritis), 84 non-ocular BD patients (49 males and 35 females) and 76 sex-ethnically matched healthy control group (43 males and 33 women) without any history of inflammatory disease referred by Labbafinejad medical center (Tehran), were genotyped for Insertion/ Deletion polymorphism of ACE gene as described previously (5). The Statistical Package for Social Sciences (SPSS), and Chi-square test (X test) was performed to analysis data. The mean age for 135 BD patients was 36 ± 9 years. There was no significant difference in the frequencies of genotypes and alleles (p > .05) between BD patients and control group (Table 1). The frequencies of genotypes and alleles between three groups (ocular BD patients, non-ocular BD patients, healthy group) showed no significant difference (Table 1). Behçet’s disease is a multifactorial disease in which genetic factors along with environmental factors and infectious agents are involved (6). Genetic studies have shown associations of several different genes with Behçet’s disease including Human Leukocyte antigen (HLA-A, HLA-B), Toll-like receptor (TLR) and Fucosyltransferase 2 (FUT2) (7), Interleukins (IL-10, IL1β, IL-17, IL23R, IL12RB2, IL-27,IL37), Endothelial nitric oxide synthase (eNOS) and Tumor necrosis factor (TNF-α) genes (8–14). Vasculitis and hypercoagulability are the main features of BD which could be caused by activated endothelial cells and platelets (15). To the best of our knowledge, this is the first study to investigate the prevalence of ACE gene polymorphism (Insertion/Deletion) among BD patients (with or without ocular manifestation) in an Iranian population. We found no significant difference between BD group and healthy controls. In subgroup analysis (ocular-BD and non-ocular BD) no significant difference was observed between these groups and controls. Similar to our results, studies of Ozturk et al. (the sample size was 120 individuals including 90 BD patients and 30 healthy controls) and Dursun et al. (the sample size was 163 individuals including 73 BD patients and 90 healthy controls) in a Turkish population indicated that ACE gene I/D polymorphism does not play an important role in the development of BD (4,16). However, two other studies performed on the same population reported the association of ACE gene I/D polymorphism with Behçet’s disease (P < .001, P = .044). The sample size in these two studies were 566 individuals (266 BD patients and 300 healthy controls) and 185 individuals (35 BD patients and 150 healthy controls) respectively (8,15). On the base of a meta-analysis performed by Mandal RK et al. on these four studies and one extra study from Korean population it was concluded that individuals carrying D/D genotype have 1.5-fold risk of developing BD disease (17). In this metaanalysis, authors suggested that in order to validate the results, larger studies with stratified case-control population and biological characterization were needed. Conflicting results observed among several studies could be due to sample sizes, different genetic backgrounds and/or ethnicity differences.