“We know that it’s in the non-coding variants where we need to be looking for disease mechanism,” Dr. Nigrovic says.
With successful new ways of identify noncoding variants in the human genome, Dr. Nigrovic says we can begin to see how genes known to be associated with rheumatic diseases work. This insight will uncover new pathways that may lead to transformative new perspectives on rheumatic disease activity.
“Much like doctors treating cancer no longer think of disease solely in terms of anatomical location, such as lung or ovary, we are uncovering new ways to see rheumatic diseases beyond disease classification as RA or a subtype of JIA—instead we can think more about how a rheumatic disease is driven by a gene pathway,” Dr. Nigrovic explains.
Implications for Care
Although this current understanding of genetic activity for rheumatic diseases is far from immediate therapeutic application, developing an understanding of genome-associated disease mechanisms may provide a road map for future therapeutics, including repurposing an already developed drug.
Example: One of the proteins Dr. Nigrovic’s team identified in a prior study of the RA-associated gene CCR6 is a protein being targeted to treat ovarian cancer.3
“If we can identify a cellular pathway that is engaged or suppressed, it’s possible that we can screen existing compounds to target the same pathway that genetic investigation is telling us is connected to rheumatic disease,” he suggests.
Specific to JIA, Dr. Nigrovic says pediatric manifestations of rheumatic disease may provide a rich area to investigate disease biology due to the stronger genetic burden often observed with early-onset disease. However, he says genetic disease pathways in adults are also similar biologically. His lab has recently received funding to explore the genetic underpinnings of some of this biology, and he is in the early stages of applying genetic investigation approaches to lupus.
Carina Stanton is a freelance science journalist in Denver.
References
- Li G, Martínez-Bonet M, Wu D, et al. High-throughput identification of noncoding functional SNPs via type II S enzyme restriction. Nat Genet. 2018 Aug;50(8):1180–1188.
- Westra H-J, Martínez-Bonet M, Onengut-Gumuscu S, et al. Fine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes. Nat Genet. 2018 Oct;50(10):1366–1374.
- Li G, Cunin P, Wu D, et al. The rheumatoid arthritis risk variant CCR6DNP regulates CCR6 via PARP-1. PLoS Genet. 2016 Sep; 12(9): e1006292.
