Background Signal Transduction and Activation of Transcription (STAT) transcription factors are evolutionarily ancient, mediating signals from the cytoplasm to the nucleus in eukaryotic life for the past 400 million years. The STAT protein sits quiescent in the cytoplasm until phosphorylated whereupon it dimerizes with another STAT protein. The phosphorylated STAT dimer is then transported to the nucleus and becomes a transcription factor activating or suppressing gene expression. The STAT1–STAT4 locus has powerful common variant associations with SLE risk with odds ratio = 1.5 and p < 10–20 in all human ancestries and also has an association, though not necessarily identical to SLE, with rheumatoid arthritis, primary biliary cirrhosis, Behcet’s Disease, Sjögren’s syndrome, progressive systemic sclerosis, and type I diabetes.
Methods Genome wide association studies of SLE, Bayesian and frequentist fine mapping methods, DNA affinity purification assays, and electrophoretic mobility shift assays.
Results We are attempting to identify the causal variants and determine the mechanism for SLE disease risk at this locus. Our data suggest that the risk haplotype alters the expression of mRNA from both STAT1 and STAT4. Application of frequentist and Bayesian methods restrict the plausibly causal variants to four possibilities in introns 4 and 5 of STAT4 under the assumption that the association observed across human ancestries is being driven by the same causal variants. Three of these four polymorphisms are predicted to alter the binding of a specific transcription factor, leading to the hypothesis that the same transcription factor is operating at multiple sites in a risk haplotype. We have data suggesting differential and allele preferential binding of the transcription factor at one variant with evaluation of the others in process. This may possibly be the first discovered example of the phenomenon of multiple transcription factor binding on multiple variants of a risk haplotype.
Conclusion In general, genome wide association studies (GWASs) provide powerful evidence of the presence of a genetic variation altering phenotype risk without revealing what the specific responsible variant is among those in a statistical dead heat for causation, in which cell type(s) or stage(s) of differentiation in which the risk difference is relevant, or what the molecular mechanism might be. We have work underway to reveal these details for lupus loci, initially concentrating on IRF5, STAT1-STAT4, and ETS1. The STAT1-STAT4 association with SLE can be isolated to involve only a few variants, which are predicted to have curiously similar transcription factor binding behaviour.
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