Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of auto-antibodies and a diverse array of clinical manifestations. Genetic predisposition clearly plays a role in the risk for developing SLE. In recent years, genome scans have identified several SLE susceptibility loci, including the chromosome 1q25-43 region, which is syntenic with a susceptibility interval identified in murine SLE models. In this study, we looked for associations between the observed genetic linkage of the chromosome 1q regions to SLE with clinical manifestations of SLE. By grouping families on the basis of common associated traits, it is thought that the sample heterogeneity is decreased while increasing the power to detect SLE susceptibility genes.
Methods We stratified a cohort of 125 multiplex families (60 Caucasian, 34 Asian, 19 Hispanic, 9 African, and 3 mixed) containing 152 SLE-affected sibpairs by the presence of a particular clinical feature of SLE in at least one family member, and compared the resulting linkage to SLE with the linkage signal derived from families lacking the clinical feature. Non-parametric multipoint linkage analysis was performed on 16 microsatellite markers spanning the 1q25-43 susceptibility region (75.46 cM) using GENEHUNTER, a program which allows complete multipoint analysis with a large number of highly polymorphic markers.
Results The strongest evidence for linkage was detected for two SLE-related traits: neuropsychiatric symptoms and anti-double-stranded DNA (anti-dsDNA) autoantibodies. The highest non-parametric linkage (NPL) score of 2.45 (p = 0.007) at D1S491 (228 cM) in 1q32.2 was obtained in families with at least one SLE-affected member positive for anti-dsDNA. In the subset of families with neuropsychiatric symptoms (seizures and/or psychosis), a NPL score of 2.34 (p = 0.01) was observed at D1S235 (255 cM) in 1q42.3.