NEW YORK – Using data for millions of individuals from a range of human populations, an international team has narrowed in on pathogenic contributors in pathways involved in gout, a chronic condition characterized by higher-than-usual blood uric acid levels and monosodium urate crystal deposits that affect the joints, combined with recurrent inflammatory arthritis flare-ups.
"Previous GWAS in gout had largely identified only genes involved in urate control, which is an essential prerequisite for gout," corresponding author Tony Merriman, a clinical immunology and rheumatology researcher affiliated with the University of Alabama at Birmingham, Qingdao University, and the University of Otago, said in an email. "Owing to the size of our study, we were able to identify many more genes, including those involved in the inflammatory aspect of gout."
As they reported in Nature Genetics on Tuesday, Merriman and colleagues from the US, New Zealand, and other international sites started with a genome-wide association study that included some 2.6 million participants of European, Latinx, East Asian, or African ancestry. The group encompassed 120,295 individuals with prevalent gout, they explained, noting that nearly three-quarters of the broader participant group were enrolled through 23andMe.
In a trans-ancestry meta-analysis, the team unearthed 295 loci with genome-wide significant ties to gout, while single-ancestry and sex-specific GWAS analyses led to additional gout-associated loci, bringing the tally to 410 variants at 377 gout-linked loci.
In particular, the investigators highlighted the apparent importance of innate immune response-related genes such as the interleukin-1 (IL-1) receptor 1 and IL-1 receptor agonist genes IL1R1 and IL1RN, along with genes from epigenetic remodeling, NLRP3 inflammasome, and cell osmolarity pathways that appeared to contribute to gout inflammatory features.
Merriman explained that gout-related genes from epigenetic regulation pathways may bump up innate immune cell responses to monosodium urate crystal deposits at joints in affected individuals, for example, while other gout features stem from cytokine activity such as the NLRP3 inflammasome regulation of the cytokine interleukin-1b.
In an association analysis focused on 630,117 participants, meanwhile, the team also tracked down 65 urate-linked loci that did not coincide with gout risk — a pattern suspected of stemming from pleiotropic effects for some of the urate level-linked variants identified.
Still, when the researchers went on to search for candidate genes and genetically correlated phenotypes through a series of fine-mapping, functional, and Mendelian randomization analyses, they uncovered genetic overlap between gout and other conditions such as cardiovascular disease or blood cell features that largely resembled genetic correlations found in urate-focused analyses.
Along with clues to processes underlying gout, the findings pointed to the possibility of tapping into treatment options already approved for targeting candidate genes suggested by loci found in the study. Among 108 genes prioritized in their analysis, the researchers found four genes targeted by existing therapies, including an interleukin-6 receptor targeting drug used to treat rheumatoid arthritis and other immune conditions.
"One of the treatment gaps in gout is preventing flares in people prone to flares, and in treating flares," Merriman explained, noting that current treatment options are toxic with prolonged use, or are expensive and difficult to access.