The aetiology of Behçet's disease is unknown. However, family studies indicate a strong genetic background for Behçet's disease with a complex inheritance model. The majority of patients with Behçet's disease are sporadic cases with asymptomatic parents. However, clustering of Behçet's disease in some families has long been observed. A positive family history was noted among 2-3% of the Japanese and 8-34% of the Turkish and Middle Eastern patients with Behçet's disease. Description of familial aggregation with the prevalence of familial cases in a group of patients open to many biases, and recurrence risk in relatives, especially in siblings (ls) is the preferred way to document the familial aggregation.
We aimed to investigate the sibling recurrence risk ratio (ls) in Behçet's disease for the estimation of the magnitude of genetic factors in the disease pathogenesis. The ls is defined as the ratio of risk of being affected among the siblings of patients and risk of being affected in the general population. A significant deviation from unity suggests familial aggregation, and it is a good way of quantifying the genetic effects without knowing the exact mode of inheritance of the disease studied.
We interviewed 170 consecutive unrelated patients with a detailed questionnaire, and ascertained their family trees as well as Behçet's disease related manifestations in their relatives. Then, to avoid an ascertainment bias, we selected the immediately older sibling, or if an older sibling was not available, the immediately younger sibling of the index cases for further evaluation. We contacted 166 siblings by telephone, and all 29 subjects with recurrent oral ulcers were invited for further examination. Seven of them were diagnosed as Behçet's disease fulfilling the International Study Group criteria. Sibling recurrence rate for Behçet's disease was found to be 4.2%, which gives a ls value of 11.4-52.5 by using the figures from the previous studies on the point prevalence of Behçet's disease in Turkey (8-37/10,000).
This considerably high ls value indicates a strong evidence for a hereditary background in Behçet's disease, and warrants more detailed molecular genetic studies for the identification of susceptibility loci.
Association of HLA-B51 with Behçet's disease is regarded as being the strongest evidence of genetic contribution described to date. This strong association has been confirmed in different ethnic groups, but genetic linkage of this region to Behçet's disease has not yet been documented. We have recently analyzed 12 multicase Behçet's disease families to ascertain whether there is genetic linkage between HLA-B and Behçet's disease using the transmission disequilibrium test (TDT) since it is a test for linkage in the presence of association and not sensitive to a stratified population. We used 5 polymorphic microsatellite markers (DQCAR, TNFd, TNFa, TNFb and MICA5) within the major histocompatibility complex (MHC) region as well as serologically determined HLA-B and HLA-A antigens for the analysis. Extended TDT and a Monte Carlo simulation with 1,000 replicates revealed evidence of linkage to Behçet's disease only for HLA-B. Chi-squared statistics of the individual alleles revealed a positive result only for HLA-B51.
We also estimated the contribution of HLA-B (lHLA-B) to the overall genetic susceptibility to Behçet's disease using identity by descent (IBD) sharing of HLA-B alleles in these families. Using the proportion of affected pairs sharing zero HLA-B alleles, we calculated lHLA-B to be 1.6, and hence the contribution of HLA-B to the overall genetic susceptibility to BD was estimated to be 12-19% with an assumption of a multiplicative interaction between disease susceptibility loci.
The contribution of the HLA-B locus to the overall genetic susceptibility to BD is relatively small, and further studies are needed to map other susceptibility genes for Behçet's disease using either a whole-genome-screening or a candidate gene approaches.
A novel susceptibility gene?
We have currently been investigating 28 multicase families of Behçet's disease, and our preliminary results of non-parametric linkage analysis in these families have revealed a novel susceptibility locus for Behçet's disease in a region about 17 cM to HLA-B locus (6p22-p23). This novel telomeric locus for Behçet's disease might be in linkage disequilibrium with HLA-B51, or alternatively there might be 2 loci for Behçet's disease on the 6p acting together. We hope that identification of this novel susceptibility gene could help to understand the pathogenesis of Behçet's disease further.