Gout is a chronic disease that is caused by an innate immune response to deposited monosodium urate crystals in the setting of hyperuricemia. Here, we provide insights into the molecular mechanism of the poorly understood inflammatory component of gout from a genome-wide association study (GWAS) of 2.6 million people, including 120,295 people with prevalent gout. We detected 377 loci and 410 genetically independent signals (149 previously unreported loci in urate and gout). An additional 65 loci with signals in urate (from a GWAS of 630,117 individuals) but not gout were identified. A prioritization scheme identified candidate genes in the inflammatory process of gout, including genes involved in epigenetic remodeling, cell osmolarity and regulation of NOD-like receptor protein 3 (NLRP3) inflammasome activity. Mendelian randomization analysis provided evidence for a causal role of clonal hematopoiesis of indeterminate potential in gout. Our study identifies candidate genes and molecular processes in the inflammatory pathogenesis of gout suitable for follow-up studies.
- MeSH
- celogenomová asociační studie * MeSH
- dna (nemoc) * genetika MeSH
- genetická predispozice k nemoci * MeSH
- hyperurikemie genetika MeSH
- jednonukleotidový polymorfismus * MeSH
- kyselina močová * MeSH
- lidé MeSH
- mendelovská randomizace MeSH
- protein NLRP3 genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVE: To determine whether a gout polygenic risk score (PRS) is associated with age at gout onset and tophaceous disease in European, East Polynesian, and West Polynesian men and women with gout. METHODS: A 19-variant gout PRS was produced in 7 European gout cohorts (N = 4,016), 2 East Polynesian gout cohorts (N = 682), and 1 West Polynesian gout cohort (N = 490). Sex-stratified regression models were used to estimate the relationship between the PRS and age at gout onset and tophaceous disease. RESULTS: The PRS was associated with earlier age at gout onset in men (β = -3.61 in years per unit PRS [95% confidence interval (95% CI) -4.32, -2.90] in European men; β = -6.35 [95% CI -8.91, -3.80] in East Polynesian men; β = -3.51 [95% CI -5.46, -1.57] in West Polynesian men) but not in women (β = 0.07 [95% CI -2.32, 2.45] in European women; β = 0.20 [95% CI -7.21, 7.62] in East Polynesian women; β -3.33 [95% CI -9.28, 2.62] in West Polynesian women). The PRS showed a positive association with tophaceous disease in men (odds ratio [OR] for the association 1.15 [95% CI 1.00, 1.31] in European men; OR 2.60 [95% CI 1.66, 4.06] in East Polynesian men; OR 1.53 [95% CI 1.07, 2.19] in West Polynesian men) but not in women (OR for the association 0.68 [95% CI 0.42, 1.10] in European women; OR 1.45 [95% CI 0.39, 5.36] in East Polynesian women). The PRS association with age at gout onset was robust to the removal of ABCG2 variants from the PRS in European and East Polynesian men (β = -2.42 [95% CI -3.37, -1.46] and β = -6.80 [95% CI -10.06, -3.55], respectively) but not in West Polynesian men (β = -1.79 [95% CI -4.74, 1.16]). CONCLUSION: Genetic risk variants for gout also harbor risk for earlier age at gout onset and tophaceous disease in European and Polynesian men. Our findings suggest that earlier gout onset involves the accumulation of gout risk alleles in men but perhaps not in women, and that this genetic risk is shared across multiple ancestral groups.
