1. ¹Steno Diabetes Center, Gentofte, Denmark
2. ²Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
3. ³Department of Medicine, University of Minnesota School of Medicine, SE Minneapolis, MN, USA
4. ⁴Department of Molecular Medicine, The Rolf Luft Center for Diabetes Research, Karolinska Institute, Stockholm, Sweden

Correspondence: Dr T Mandrup-Poulsen, Steno Diabetes Center, Niels Steensensvej 2, DK-2820 Gentofte, Denmark. E-mail: tmpo@steno.dk

⁵These authors contributed equally to the study

Received 24 January 2005; Revised 15 July 2005; Accepted 18 July 2005; Published online 15 September 2005.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by production of autoantibodies against intracellular antigens and tissue injury. Defective apoptosis of activated immune cells leads to the development of autoantibodies in SLE. FasL initiated apoptosis is central for peripheral tolerance. Fas deficiencies in humans and mice predispose toward systemic autoimmunity. SLE is conferred by many genes. The genetic effects may be concentrated by familial clustering or by stratifying of subphenotypes. We have tested polymorphisms and haplotypes in FAS and FASL for association to SLE or subphenotypes in 126 multiplex American SLE pedigrees and found association of the FAS codon214 AC^C/T as well as the FAS-670G>A'-codon214 AC^C/T' haplotype to thrombocytopenia in SLE. Furthermore we have functionally characterized the FAS/FASL promoter polymorphisms associated with SLE in other populations and demonstrate that the activity depends on the allelic variants as well as on the haplotype. The presence of FAS-670G, which affects STAT1 binding, leads to the highest activity. FASL-844C activity is modified by the cis acting -478A and, hence, the haplotype and not the individual variant, determines the promoter activity. We conclude that the FAS/FASL promoter haplotypes are functional and that polymorphisms in FAS may contribute to thrombocytopenia in SLE.