Functional Evaluation of Established Sjogren's Syndrome Immune Response Loci
? DESCRIPTION (provided by applicant): Sjogrens syndrome (SS) is a chronic, progressive autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands. Clinical manifestations may involve virtually any organ system, with severe oral and ocular dryness as a unifying feature. The etiology of SS is poorly understood, but clearly involves a complex genetic architecture influenced by environmental factors that lead to abnormal cellular and humoral immune responses. Difficulty in correctly diagnosing SS combined with the scarcity of effective therapeutic options often results in significant morbidity and irreversible damage to the exocrine glands. To determine genetic risk variants for SS, we have recently completed the first unbiased screen of the human genome using the genome-wide association (GWA) approach and have successfully established (Pmeta<5x10-8) IRF5, STAT4, IL12A, BLK, CXCR5, TNIP1 and variants in the HLA region as SS disease loci. Interestingly, IL12 signaling was central pathway implicated by these results. Of the SS risk loci identified, IL12A encodes the p35 subunit of IL12, IRF5 functions as a transcription factor for IL12B, IL12 signaling is mediated through STAT4, and IL12 is a cytokine involved in transcription of CXCR5. Recent studies published by ENCODE have revealed that ~80% of the human genome is biologically active but only 2-5% of the human genome encodes protein coding loci. The vast majority of non-protein coding sequences generate regulatory RNAs, many of which are expected to grant sequence specific addresses to transcription factors and other proteins and have potential to be responsible for most genetic associations with disease. We now seek to leverage our extensive infrastructure, sample and clinical data resources, experience in autoimmune disease genetics, and the wealth of new publicly available data defining functional genomic elements to identify precise causal variants and their disease mechanisms that underlie the statistical associations of risk loci in SS. The specific aims of this project are to use transracial and fine mapping in 600 Hispanic SS cases and 2000 healthy controls as well as 1000 European SS cases and 1000 healthy controls to refine association signals by leveraging the differing LD structure. We then seek to define the functional mechanisms of causal variants and haplotypes in two SS risk genes, IL12A and CXCR5 using molecular techniques coupled with cutting-edge sequencing technology. These studies are likely to facilitate development of a coherent view of the SS genetic architecture and importantly, provide fundamental new knowledge that will translate into novel diagnostic approaches and application of biological therapies currently being developed for other diseases that target IL12.