At his laboratory, Dr. Nigrovic and his colleagues recently developed a new method called SNP-seq (i.e., single nucleotide polymorphism-DNA sequencing) that, with support from the Rheumatology Research Foundation, was employed to screen 27 non-HLA loci in JIA to identify such regulatory variants, finding more than 100 candidate variants.9 They also developed a technique called Flanking Restriction Enhanced Pulldown (FREP) and used it to define two new associations between specific regulatory proteins and two JIA-associated SNPs that modulate expression of the T cell regulatory gene STAT4.10
“Arthritis transcends the pediatric–adult boundary. We need to unshackle ourselves from the current nomenclature and to unlock the potential of GWAS to reveal new mechanisms involved in this continuum,” he said.
Age of onset nevertheless remains informative, he said. “In most diseases, early onset means genetic loading, suggesting that pediatric-onset disease may be an especially rich area to seek genetically driven disease.” In a new review in Arthritis & Rheumatology, Dr. Nigrovic and his colleagues also explore the continuity of pediatric and adult arthritis from a genetics perspective.11
Genomics Clues Beyond Rheumatology
Rheumatologists can turn to precision medicine research advances in other diseases and outside sources to find methods and concepts that lead to personalized, effective treatment of rheumatic diseases. Cancer researchers pioneered efforts to find genes that contribute to disease risk.
“With few exceptions, it’s never a single penetrative allele or gene. We’re looking for many genes that may contribute to cancer,” said Josh Stuart, PhD, professor in the Biomedical Engineering Department and Baskin Engineering Endowed Chair at the University of California, Santa Cruz. “How we can use an integrative, pathway-level approach to not only classify phenotypes, but select treatments in a patient-specific way?”
Genomics research in a group of patients with the same type of tumor may not show many commonalities, so researchers drill down to the pathway level to find those links. An advanced prostate cancer patient may have various gene mutations, for example. When researchers group him with others who have similar disease, “we look for alterations in the genome, then look for alterations in the transcriptome. Think of the transcriptome as everything that’s different from a matched, normal sample,” said Dr. Stuart. “We’re hoping the genes that interlink the genomic variations to these more transcriptional phenotypic variations are somehow critical to the signaling of the tumor, and if we reverse them, it will somehow have an effect.” The patient’s pathway profile may suggest specific treatment options.