Abstract
The aims of this study were to identify candidate pathways associated with serum urate and to explore the genetic effect of those pathways on the risk of gout. Pathway analysis of the loci identified in genome-wide association studies (GWASs) showed that the ion transmembrane transporter activity pathway (GO: 0015075) and the secondary active transmembrane transporter activity pathway (GO: 0015291) were both associated with serum urate concentrations, with PFDR values of 0.004 and 0.007, respectively. In a Chinese population of 4,332 individuals, the two pathways were also found to be associated with serum urate (PFDR = 1.88E-05 and 3.44E-04, separately). In addition, these two pathways were further associated with the pathogenesis of gout (PFDR = 1.08E-08 and 2.66E-03, respectively) in the Chinese population and a novel gout-associated gene, SLC17A2, was identified (OR = 0.83, PFDR = 0.017). The mRNA expression of candidate genes also showed significant differences among different groups at pathway level. The present study identified two transmembrane transporter activity pathways (GO: 0015075 and GO: 0015291) were associations with serum urate concentrations and the risk of gout. SLC17A2 was identified as a novel gene that influenced the risk of gout.
Highlights
Uric acid is the final catabolic product of purine oxidation in humans
Among the nine candidate genes, SLC17A2 and SLC5A6 were two novel genes associated with serum urate concentration (Table 1 and Table S1)
We analyzed the genetic variants in candidate pathways affecting the concentration of serum urate and the risk of gout, and we identified two candidate pathways
Summary
Uric acid is the final catabolic product of purine oxidation in humans. Because of the loss of important genes in the urate degradation pathway during human evolution, uric acid cannot be metabolized into allantoin[1,2]. Genome-wide association studies (GWASs) have identified several genetic variant loci in various genes associated with serum urate concentrations[8,9,10,11,12,13,14,15]. It is necessary to identify additional genetic factors influencing serum urate concentrations and the pathogenesis of gout using pathway analysis. We aimed to identify serum urate- and gout-associated candidate genes and biological pathways using a four-step approach. The transcription levels of candidate genes were tested at the pathway level Using this strategy, this study identified two transmembrane transporter activity-related pathways that influenced serum urate levels and the pathogenesis of gout
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