My work in the Center for Autoimmune Genomics and Etiology is focused on identifying the molecular mechanisms that drive genetic associations with lupus and other autoimmune diseases. Genome-wide association studies have identified over 93 published genetic loci that affect lupus risk, but these studies do not reveal mechanistic information. In fine-mapping studies of IRF5/TNPO3, STAT4/STAT1, ETS1, and IRF7, I have used high-density genotyping data from over 20,000 subjects to develop the most likely statistical models that explain lupus risk at each locus. These models allow us to identify the variants most likely to be causal at which time we can turn to biological assays to identify allelic differences in transcription factor binding, epigenetic regulation, and mRNA and protein expression. We have also taken a systems-biology approach to these analyses, as we use the type-1 Interferon pathway (which includes over half of the genes in lupus-risk loci) to understand the role of single genetic variants in modulating this inflammatory pathway.
Over the past three years, I have led a genome-wide association study for eosinophilic esophagitis (EoE). Through this study, we have made substantial progress in answering a long-standing question in the field of allergic inflammation, namely the explanation for the tissue specific nature of allergic responses. We started by interrogating >2.5 million genetic variants in EoE cases (collected locally for the Discovery cohort) and through CoFAR (for the replication cohort) with local and out-of-study control subjects. We identified four novel susceptibility loci for EoE with the strongest association at the CAPN14 gene. This GWAS has greatly enhanced our understanding of the genetic etiology of EoE. In fact, the results elucidate the tissue-specific nature of EoE. One of the most significantly associated loci, CAPN14 is specifically expressed in the esophagus; dynamically upregulated as a function of disease activity and genetic haplotype and after exposure of epithelial cells to IL-13; and located in an epigenetic hotspot modified by IL-13. Furthermore, by computationally clustering EoE cases and controls based upon the esophageal expression of genes nearby variants associated a p<0.0001 (not just genome-wide significant loci), we were able to perfectly segregate cases and controls.