Takayasu arteritis is a systemic inflammatory disease of the large arteries and their major branches. The etiology and pathogenesis of Takayasu arteritis are poorly understood, however, a genetic contribution to the disease has been suggested by the established genetic association with HLA-B*52. Our recent work identified and confirmed multiple genetic susceptibility loci for Takayasu arteritis outside of the HLA region. These include a genetic risk locus on the leukocyte receptor complex (LRC) region on chromosome 19q13.4. We localized the genetic signal in this region to RPS9/LILRB3, and the causal variant(s) in this locus is tagged by the SNP rs11666543 which influences the expression levels of multiple transcripts within this region suggesting that the causal variant is located within a regulatory genetic element. Indeed, rs11666543 is located within an active enhancer region in primary monocytes, and the disease risk variant is associated with significant reduction of LILRB3 mRNA expression. LILRB3 is an inhibitory immunoregulatory receptor expressed on antigen presenting cells, and its deficiency has been linked to monocyte/macrophage activation. We propose to use innovative state-of-the-art genomic and epigenomic approaches, followed by functional studies to identify and characterize the causal genetic variants in this locus, and their functional pathogenic effect upon disease susceptibility.
Takayasu arteritis is a chronic debilitating inflammatory disease of unknown etiology. This grant proposal aims to functionally characterize a novel genetic susceptibility locus we recently discovered for this disease located on the leukocyte receptor complex (LRC) gene-rich region on chromosome 19. Integrating genomic, epigenomic, and transcriptomic data, followed by targeted functional genomic studies, we will comprehensively understand the pathological consequences of this genetic risk locus, and thereby identify novel pathways for disease pathogenesis that can be targeted for therapy.
| Coit, Patrick; Direskeneli, Haner; Sawalha, Amr H (2018) An update on the role of epigenetics in systemic vasculitis. Curr Opin Rheumatol 30:4-15 |
| Gensterblum-Miller, Elizabeth; Wu, Weisheng; Sawalha, Amr H (2018) Novel Transcriptional Activity and Extensive Allelic Imbalance in the Human MHC Region. J Immunol 200:1496-1503 |
| Ortiz-Fernández, Lourdes; Carmona, Francisco David; López-Mejías, Raquel et al. (2018) Cross-phenotype analysis of Immunochip data identifies KDM4C as a relevant locus for the development of systemic vasculitis. Ann Rheum Dis 77:589-595 |
| Alperin, Jessie M; Ortiz-Fernández, Lourdes; Sawalha, Amr H (2018) Monogenic Lupus: A Developing Paradigm of Disease. Front Immunol 9:2496 |
| Renauer, Paul; Sawalha, Amr H (2017) The genetics of Takayasu arteritis. Presse Med 46:e179-e187 |
