Ongoing studies at the OMRF have recruited and genotyped over 160 families multiplex for systemic lupus erythernatosus (SLE). Subgroup analysis of those families containing at least one SLE patient with age of onset less than 16 has revealed a putative susceptibility gene for early onset lupus with a lod score of 3.0 at 17p13. Independent analysis of affected relative pairs in the 160 family collection, using a principal component approach, confirms that age of onset is a major covariate, producing a lod of 4.4 at the same site, D17s1298. We have designated this putative susceptibility gene SLE pediatric 1 (SLEP1), and the goal of this application is to find and characterize this gene. First, we expect that an additional 30-45 families containing at least one member with pediatric onset SLE will become available from ongoing efforts to recruit multiplex pedigrees at OMRF, and we will seek to confirm the effect at D17s1298 in a second cohort. If successful, we will use fine mapping techniques, first with additional microsatellite markers and later with SNPs, to narrow the region of interest to 2-3 cM. Next, we will evaluate potential candidate genes in the narrowed susceptibility region by genotyping at SNP markers in known genes in the region and analyzing these by linkage disequilibrium methods. At this stage, priority will be given to any genes in the region with a plausible role in autoimmune pathogenesis. Finally, if the SNP selected to identify the gene through linkage disequilibrium to SLE does not prove to be the causative mutation, we will sequence the putative susceptibility gene and attempt to discover the functional mutations leading to SLEP1. This project is proposed in support of a K08 Mentored Clinical Scientist Development Award. It is relevant to the career goals of the principal investigator, both as a pediatric rheurnatologist and as a new scientific investigator. This project has the potential to increase our understanding of the genetic factors contributing to the pathogenesis of early onset SLE, as well as lupus in general. It will allow the principal investigator to interact with a number of collaborators and to become more familiar with the state of the art genotyping and biostatistical analysis techniques currently used in the OMRF lupus genetics project. In addition, this project has the potential to generate related projects in molecular biology that would allow the principal investigator to become fully independent.
| Sestak, A L; Nath, S K; Kelly, J A et al. (2008) Patients with familial and sporadic onset SLE have similar clinical profiles but vary profoundly by race. Lupus 17:1004-9 |
| Sestak, Al; O'Neil, K M (2007) Familial lupus and antiphospholipid syndrome. Lupus 16:556-63 |
| Sestak, Andrea L; Nath, Swapan K; Sawalha, Amr H et al. (2007) Current status of lupus genetics. Arthritis Res Ther 9:210 |
| Lee, Young Ho; Witte, Torsten; Momot, Tanja et al. (2005) The mannose-binding lectin gene polymorphisms and systemic lupus erythematosus: two case-control studies and a meta-analysis. Arthritis Rheum 52:3966-74 |
| Sestak, Andrea L; Nath, Swapan K; Harley, John B (2005) Genetics of systemic lupus erythematosus: how far have we come? Rheum Dis Clin North Am 31:223-44, v |
