Whole-genome screening for susceptibility genes in multicase families with Behçet's disease

Abstract

Objective: Behçet's disease is generally considered to be a multifactorial disease with important genetic and environmental components. A strong association between an HLA class I antigen, HLA-B51, and Behçet's disease has long been known. However, analysis of multicase families has suggested a substantial contribution of non-HLA loci. The aim of this study was to perform a whole-genome linkage analysis for identification of other susceptibility loci for Behçet's disease in multicase families.

Methods: The study group comprised a total of 193 individuals (90 male, 103 female) from 28 multicase families of Turkish origin; 83 of the subjects (50 males, 33 females) fulfilled the International Study Group criteria for Behçet's disease. Three hundred ninety-five highly informative microsatellite markers spanning the genome were genotyped using fluorescent polymerase chain reaction primers and a fully automated electrophoresis platform. After the first analysis, 33 additional markers that were located close to the peak linkage areas were genotyped in all individuals. Nonparametric multipoint linkage analysis was carried out using GeneHunter version 2.1 software.

Results: Evidence for linkage (P < or = 0.05) was obtained in 16 chromosome regions: 1p36, 4p15, 5q12, 5q23, 6p22-24, 6q16, 6q25-26, 7p21, 10q24, 12p12-13, 12q13, 16q12, 16q21-23, 17p13, 20q12-13, and Xq26-28. After the addition of further markers, the maximum nonparametric linkage score increased from 3.5 to 3.94 at 12p12-13 (D12S77; P = 0.0002) and from 3.07 to 3.70 at 6p22-24 (D6S285; P = 0.0005).

Conclusion: This study is the first systematic genome screen in Behçet's disease and provides evidence of linkage to several non-HLA susceptibility loci in a cohort of Turkish multicase families. This represents the first step toward the identification of novel Behçet's disease susceptibility genes.