The etiology of systemic lupus erythematosus (SLE) includes poorly understood genetic, environmental and sex-hormone factors acting on the immune system. The long term goal of this application is to identify genes involved in the etiopathogenesis of human SLE and to characterize the mechanisms by which these genes influence disease development. This application will also serve as a follow-up study of the initial linkage analyses performed in mouse models and in multiplex families. For this stage of mapping, the investigators propose to rely on association (linkage disequilibrium) studies in nuclear families as they will be able to collect a much larger study population than if they relied on the affected sib-pair pedigree approach. Childhood-onset SLE represents a potentially unique subgroup of patients because its early disease onset may be an indicator of increased genetic predisposition and penetrance, and because childhood-onset disease is more severe than adult-onset involving many organs and carrying a worse prognosis. The investigators therefore propose to study nuclear families of childhood-onset SLE subjects. Given that probands will be children, they anticipate that their parents and siblings will be available and strongly motivated to participate.
The specific aims are as follow. 1) Recruitment and blood and DNA collection from 850 nuclear families containing at least one subject with childhood-onset SLE. They will classify all subjects for clinical and laboratory evidence of SLE, its organ involvement, severity of disease and complications. This will be accomplished using four recruitment study sites, which will provide large pediatric lupus populations. 2) Testing for association with specific candidate genes suggested by linkage, synteny and functional relevance using the family-controlled generalized transmission disequilibrium test (TDT) approach. 3) Exploring candidate regions of about 5 cM suggested by linkage and synteny for patterns of linkage disequilibrium by testing for marker associations and haplotype sharing. Initially, they will use markers spaced roughly 0.5 cM apart in each region, with promising leads followed up at a 0.05 cM marker spacing. The investigators point out that this application integrates the talent of a multidisciplinary team, combining clinical expertise with highly qualified basic scientists and with genetic, epidemiological, molecular biological and genetic analytic expertise. They further state that this is a multi-center application from some of the largest pediatric lupus clinics in the country and, therefore, represents a major and unique resource for the study of the genetics of childhood-onset SLE.
| Ramos, Paula S; Oates, James C; Kamen, Diane L et al. (2013) Variable association of reactive intermediate genes with systemic lupus erythematosus in populations with different African ancestry. J Rheumatol 40:842-9 |
| Ramos, Paula S; Williams, Adrienne H; Ziegler, Julie T et al. (2011) Genetic analyses of interferon pathway-related genes reveal multiple new loci associated with systemic lupus erythematosus. Arthritis Rheum 63:2049-57 |
| Armstrong, D L; Reiff, A; Myones, B L et al. (2009) Identification of new SLE-associated genes with a two-step Bayesian study design. Genes Immun 10:446-56 |
