Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
A Polymorphic Microsatellite in the Fli1 Promoter Is Associated with Nephritis and Serositis in the Carolina Lupus (CLU) Cohort
Svenson, John L., Nietert, Paul, Gilkeson, GS, Nowling, Tamara K.
The Ets factor Fli1 is implicated as a key modulator of lupus disease expression. Over-expressing Fli1 in healthy mice, results in the development of an autoimmune kidney disease similar to that observed in lupus. Fli1 levels are elevated in lymphocytes from lupus mouse models and patients. Lowering the levels of Fli1 in two lupus mouse models significantly improved disease and prolonged survival. We identified a polymorphic GA microsatellite in the mouse Fli1 promoter that is shorter in lupus prone mouse strains compared to control mouse strains and demonstrated that the length is inversely proportional to expression in T cells. The microsatellite is conserved between mouse and human. To determine whether microsatellite length is associated with disease or disease characteristics in lupus patients and to analyze the role of the microsatellite in the human gene in T cells.
The promoter region containing the microsatellite was amplified from over 1100 patients and unaffected controls enrolled in the Carolina Lupus (CLU), SLE in Gullah Health (SLEIGH) and MUSC lupus clinic cohorts and genotyped. Fli1 message levels were measured by real-time RTPCR in 50 lupus patient RNA samples. The length of the microsatellite and message levels were analyzed for correlation/association with disease and disease characteristics. The promoter region of the human gene was cloned from four unaffected controls and role of the microsatellite analyzed by transient transfection in a T cell line.
We identified 23 alleles spanning 1339 repeats of the GA microsatellite. The length of the microsatellite was inversely correlated with activity of the human promoter in a T cell line. There was significant association of microsatellite length of 22 repeats with disease in the CLU cohort and specifically with nephritis in the CLU patients. A microsatellite length of 26 repeats was associated with serositis in the CLU patients and inversely associated with serositis in the SLEIGH patients. Interestingly, Fli1 message levels were significantly higher in patients with serositis.
Although there is a correlation between length of the Fli1 promoter GA microsatellite and Fli1 expression in a T cell line, a specific microsatellite length of 22 repeats was associated with disease, specifically with nephritis, in the CLU cohort. Additionally, a microsatellite length of 26 repeats was associated with serositis in the CLU patients whereas the same length appears to be protective in the SLEIGH patients and higher Fli1 transcript levels correlated with serositis. Together these results suggest that a specific lengths of the microsatellite may serve as markers for disease, specifically nephritis and serositis. It will be of interest to determine how the microsatellite functions in regulating Fli1 expression and how Fli1 levels specifically impact nephritis and serositis.
To cite this abstract, please use the following information:
Svenson, John L., Nietert, Paul, Gilkeson, GS, Nowling, Tamara K.; A Polymorphic Microsatellite in the Fli1 Promoter Is Associated with Nephritis and Serositis in the Carolina Lupus (CLU) Cohort [abstract]. Arthritis Rheum 2009;60 Suppl 10 :1744