New Causal Genes, Pathways Implicated in Gout Pathogenesis

The Clonal Hematopoiesis of Indeterminate Potential (CHIP) pathway and new casual genes have been identified and implicated in gout pathogenesis, according to results presented at the American College of Rheumatology (ACR) Convergence 2022, held from November 10 to 14, in Philadelphia, Pennsylvania.

More than 2,622,830 individuals were enrolled in a genome-wide association study (GWAS) to identify casual genes and pathways associated with the progression of hyperuricemia to gout. Participants were identified from 13 cohorts and 4 ancestral groups.

• African: with gout (n=3052) vs without gout (n=77,891)
• East Asian: with gout (n=10,729) vs without gout (n=82,807)
• European: with gout (n=100,661) vs without gout (n=2,106,003)
• Hispanic: with gout (n=5840) vs without gout (n=235,847)

Candidate causal genes were identified via co-localization with expression quantitative trait loci (eQTL); interleukin (IL)-1β response QTL was identified using the 500FG cohort; and pathway analysis was completed using Kyoto Encyclopedia of Genes and Genomes (KEGG) database.

Researchers identified 339 loci associated with gout encompassing 515 independently-associated variants, of which 123 loci were not among any previously loci reported in urate or gout; 1657 cis- and 267 trans-eQTLs were identified for 252 of the 339 loci.

More than 93 genetic variants were identified in the 500FG cohort previously unassociated with urate that may be linked to gout inflammation. These variants had an amplified signal, whereas 317 genetic variants previously associated with urate did not exhibit an amplified signal. Notably, rs9973741, the top-associated variant unassociated with urate, was co-localized with genetic control of IL-1b production when stimulated, and IL1RN and IL38 expression, indicating that these genes are causal at this locus.

Co-localized eQTL genes identified to regulate NLRP3 inflammasome activation and activity included TMEM176B, SCAP, INSIG2, SREBF-AS1, FADS2, and NLRC3. Genes mutated in the CHIP pathway — a new pathway identified in the study including epigenome modification proteins — such as TET2, EZH2, IDH2, and RUNX1, were implicated in gout pathogenesis.

An associated signal was seen in xanthine dehydrogenase, but only among men and co-localized with XDH expression in the prostate. Regulation of urate by the prostate “potentially represents a novel risk factor for gout in men,” the researchers noted.

The researchers implicated new causal genes and pathways in gout, including genes that regulate urate, NLRP3 inflammasome activity and autophagy, and the identification of the CHIP pathway.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.