Abstract
Gout is a common arthritis resulting from increased serum urate, and many loci have been identified that are associated with serum urate and gout. However, their influence on the progression from elevated serum urate levels to gout is unclear. This study aims to explore systematically the effects of genetic variants on the pathogenesis in approximately 5,000 Chinese individuals. Six genes (PDZK1, GCKR, TRIM46, HNF4G, SLC17A1, LRRC16A) were determined to be associated with serum urate (PFDR < 0.05) in the Chinese population for the first time. ABCG2 and a novel gene, SLC17A4, contributed to the development of gout from hyperuricemia (OR = 1.56, PFDR = 3.68E-09; OR = 1.27, PFDR = 0.013, respectively). Also, HNF4G is a novel gene associated with susceptibility to gout (OR = 1.28, PFDR = 1.08E-03). In addition, A1CF and TRIM46 were identified as associated with gout in the Chinese population for the first time (PFDR < 0.05). The present study systematically determined genetic effects on the progression from elevated serum urate to gout and suggests that urate-associated genes functioning as urate transporters may play a specific role in the pathogenesis of gout. Furthermore, two novel gout-associated genes (HNF4G and SLC17A4) were identified.
Highlights
Gout is among the most common forms of inflammatory arthritis and affects approximately 1 to 6% of the population in various countries[1,2,3]
Thirteen loci in ten genes (TCF7L2, A1CF, PDZK1, GCKR, ABCG2, SLC2A9, TRIM46, HNF4G, SLC17A1 and ESR1) were determined to be associated with serum urate, with P values below 0.05 (Table 1)
HNF4G is a novel gout-associated gene associated with the pathogenesis of gout (OR = 1.28, PFDR = 1.08E-03), and two other genes, A1CF and TRIM46, were identified to be associated with susceptibility to gout in the Chinese population for the first time
Summary
Gout is among the most common forms of inflammatory arthritis and affects approximately 1 to 6% of the population in various countries[1,2,3]. A large meta-analysis of genome-wide association studies (GWAS) identified 28 loci associated with serum urate concentration[9]; this result only explained approximately 7% of the variance in serum urate concentrations, and only a portion of those loci were determined to be associated with the risk of gout[9,10]. It is necessary to systematically analyze genetic effects on the progression from elevated serum urate to gout and to further identify novel candidate loci that affect the risk of HUA and gout. Population groups have been reported to show common heterogeneity in the genetic contribution of serum urate concentrations and gout[1,11,12], suggesting the need for transancestral studies to identify population-specific loci that affect the pathogenesis of gout. This study systematically analyzed the genetic effects on the pathogenesis of gout from elevated serum urate
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