Genomics and Viruses in Sjögren’s Syndrome

Abstract

Contributions from both genetic and environmental factors to the etiology of Sjogren's syndrome (SS) are being discovered, though their roles in disease pathogenesis remain obscure. An important key to fully understand how genetic variation leads to disease is to comprehensively test all potential variation for association. Extraordinary developments in our understanding of the inherent variation present in the human genome and rapid advances in the technical capacity to evaluate this variation are moving us closer to understanding the genetic etiology for numerous complex diseases. In particular, major shifts in the past few years from small candidate gene studies to large genome-wide screens for association of human variation with disease have been remarkably successful. Dozens of new disease associations previously thought intractable to discovery have now been identified in complex diseases. Although the genetics of SS remains vastly unexplored, rapid advances in our understanding of related autoimmune diseases illustrate the potential complexity of the expected genetic landscape for SS with several emerging themes. First, multiple genes contribute to increasing disease risk. Second, many genes have now been associated with multiple autoimmune disorders. Third, the frequencies of some disease-associated variants are relatively common while others are rare within populations. In addition, the frequency of any given disease risk allele often varies between different racial groups. Fourth, certain disease variants are more strongly associated with clinically recognizable disease subgroups or manifestations as opposed to more general susceptibility risk to disease. Overall, studies in autoimmune diseases related to SS provide an encouraging glimpse into the potential for success in establishing the genetic basis for SS. We discuss how genetics is transforming our understanding of autoimmunity with relevance to SS and review evidence suggesting how environmental influences on susceptible genetic backgrounds may conspire to generate disease. We also discuss recent advances in transcriptional profiling and proteomic studies, which are beginning to provide global views of gene or protein expression profiles. Collectively, the broad views offered by these powerful and complementary approaches are revealing important disease-associated pathways and enhancing our understanding of the etiological mechanisms in SS.