Large genome-wide study finds ‘dozens’ of new causal genes, pathways in gout
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PHILADELPHIA — Researchers have identified “dozens” of new causal genes and pathways responsible for disease activity in patients with gout, according to a presenter at ACR Convergence 2022.
“We have had urate genome-wide association studies revealing over 200 loci controlling serum urate levels and these are dominated by molecular control of renal and gut excretion of urate,” Tony Merriman, PhD, of the University of Alabama at Birmingham, told attendees. “Our hypothesis goes that there are unidentified genes in the human genome that are involved in inflammation and gout.”
Merriman and colleagues endeavored to produce a genome-wide association study that was larger than previous efforts, with the current analysis including nearly 10 times more patients with gout than previous genome studies, he said. Researchers included participants from 13 cohorts across four distinct ancestral groups, including African, East Asian, European and Latin populations.
Genes that are potentially involved with gout were identified by way of the Gene and Tissue Expression dataset or through having the “candidate gene missense a causal variant,” Merriman said. Researchers conducted pathway analyses and drug repositioning analysis.
The analysis included a total of 120,282 individuals with gout. According to the researchers, the study yielded 339 gout-associated loci, including 515 “independently associated” variants, Merriman said. A total of 123 loci did not demonstrate any overlap with any previously reported loci involved with urate or gout. The analysis revealed the clonal hematopoiesis indeterminate pathway in addition to pathways regulating insulin and purine and glutamine metabolizing processes. Finally, the analysis reveals the prostate’s potential role in urate production and regulation.
“We have implicated new processes and dozens of new genes in gout inflammation, and these are candidate genes and pathways for future translational research,” Merriman said. “There was no obvious NLRP3 inflammasome components, but we did see genes known to be involved in regulation.”
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Merriman T. Abstract 1678. Presented at: ACR Convergence 2022; Nov. 11-14, 2022; Philadelphia (hybrid meeting).
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