Genetic Linkage in Lupus

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Project Abstract There are 124 publications that establish 185 disease risk loci for the genetics of systemic lupus erythematosus (SLE) with robust supporting data. This is a completely different situation than when AI0274717 started 33 years ago as a search for genetic linkage. Now, in addition to the 185 risk loci we have strong circumstantial evidence for an etiologic role for Epstein-Barr virus (EBV) at the origin of SLE, especially considering the recently published powerful association between the location in the genome of transcription complexes containing the Latency III gene product, Epstein Barr Nuclear Antigen 2 (EBNA2) and the genetic risk loci of SLE. This association has been confirmed and extended to the at present known SLE risk loci. In addition, new data show that EBNA3C and EBNALP, both also EBV Latency III gene products, are also powerfully concentrated at the SLE risk loci, all three, EBNA2, -3C, & -LP, clustering together and in aggregate binding indirectly to more than half the known SLE risk loci. A set of human transcription factors and co-factors (TFs) tend to bind DNA at these same SLE risk loci. Our hypothesis is that many genetic mechanisms that cause SLE operate in the EBV transformed B cell, because of the EBV Latency III gene expression. Since ~90% of the plausibly causal variants in the 185 risk loci are in genomic regions, predicted to have regulatory function; therefore, the role of TFs promises to be important in the genetic mechanisms of SLE. What is missing, a serious gap in our knowledge, is the identify of the Target genes regulated by these risk variants. Given the unexpected, but dominating influence of the Latency III gene products in associations with the SLE risk loci, we conclude that the cell type in which to begin the systematic search for the disease relevant Target genes is the EBV-infected and transformed B cell. In Aim 1 we will focus on identifying Target genes in these cells for as many of the 185 SLE risk loci as possible with special attention focused on the involvement of EBNA2. In Aim 2 we will concentrate on the allelic differences in Target gene expression induced by the risk and non-risk alleles of SLE risk locus variants, again with special attention to the possible role of EBNA2. We have preliminary data that support our technical capacity to perform the experiments proposed and have constructed many of the reagents needed to perform the proposed experiments, which have been initiated. We will adapt high throughput systems biology methods to screen and explore the gene regulation of the 185 loci to build a foundation to evaluate the role EBNA2 has in SLE etiology relevant regulation. Extraordinary new commercially available methods will make the screening procedures proposed practical, feasible and affordable. If our hypothesis is correct and we demonstrate EBNA2-dependent mechanisms of gene regulation at the risk loci, then these would be nominated as potential causal mechanisms for the genesis of SLE. These results will lay the foundation for the important next step, to perturb the identified mechanism in ways that change the risk of developing SLE or that change the capacity of the illness to persist.