Abstracts

Identifying genes that influence the development of seizures in complex genetic medical disorders may provide valuable insights into mechanisms of epileptogenesis. Neurological involvement is a major manifestation of systemic lupus erythematosus (SLE), an autoimmune disorder with multiple genetic and environmental determinants. The objective of this study was to identify genetic loci influencing the expression of seizures in the setting of SLE. SLE families with two or more affected individuals were ascertained for linkage. Following informed consent data collection and genotyping was performed using standard research protocols. All individuals affected with SLE met American College of Rheumatology revised criteria for SLE. Non-parametric genome-wide linkage analysis was performed using 318 microsatellite markers. The linkage model allowed the inclusion of clinical covariates as a method of accounting for genetic locus heterogeneity. Two clinical covariates were analyzed, one representing a history of seizures in a SLE-affected individual, and the other representing the number of family members affected with seizures. A total of 117 African-American (AA) and 228 European-American (EA) affected-relative-pairs in 340 pedigrees were analyzed. The study sample consisted of 769 individuals affected with SLE, of which 106 had seizures, a rate of 14%. Using the seizure covariate we found linkage to two chromosomal regions in the AA population, 16p13-p12 and 17q21, not detected using the baseline model without covariates (maximum multipoint lod scores of 2.54 and 2.1, respectively). Similarly in the EA population, use of the clinical seizure covariate produced linkage to two regions not detected with the baseline model, 3p25 and 14q13 (maximum multipoint lod scores of 2.28 and 2.53, respectively). These results suggest important genetic effects related to the development of seizures in SLE. Identifying such genetic determinants may shed light on epileptogenic pathways, as well as provide useful indicators of seizure susceptibility in SLE patients. These results also demonstrate the power of the covariate method to detect linkage in the setting of locus heterogeneity in complex genetic disease. (Supported by NIH)