Genetic linkage of systemic lupus erythematosus to 13q32 in African American families with affected male members

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving genetic and environmental factors. Previously, our group showed that SLE females with affected male relatives have higher prevalence of renal disease than SLE females with no affected male relatives in a sample of 372 individuals from 159 families. By adding 392 individuals from 181 new families, we replicated this finding in the largest collection of families with affected males, confirming our hypothesis that multiplex SLE families with at least one affected male member ("male families") comprise a distinct subpopulation of SLE multiplex families. We studied 64 male families by a genome-wide scan for SLE and found the largest signal (lod=3.08) at 13q32 in 18 African American male families using an affected-relative-pair model-free linkage method. Closer examination of IBD sharing at this region suggested a dominant mode of inheritance. Multipoint model-based linkage analysis generated a lod score of 3.13 in the same chromosomal region with a low-disease allele frequency of 0.0004 and a disease penetrance of 0.5 for the 18 African American male families. We performed fine mapping in these and three additional African American male families and the SLE predisposing locus was localized to a region tightly linked to the marker D13S892. We have therefore confirmed the linkage of SLE to 13q32, which was reported previously, and suggested that an SLE susceptibility gene in this region is specific to predisposition of African Americans to a specific form of SLE, with males at high risk.