The genetic basis of urate control and gout: Insights into molecular pathogenesis from follow-up study of genome-wide association study loci

Abstract

This review focuses on the post-genome-wide association study (GWAS) era in gout, i.e., the translation of GWAS genetic association signals into biologically informative knowledge. Analytical and experimental follow-up of individual loci, based on the identification of causal genetic variants, reveals molecular pathogenic pathways. We summarize in detail the largest GWAS in urate to date, then we review follow-up studies and molecular insights from ABCG2, HNF4A, PDZK1, MAF, GCKR, ALDH2, ALDH16A1, SLC22A12, SLC2A9, ABCC4, and SLC22A13, including the role of insulin signaling. One common factor in these pathways is the importance of transcriptional control, including the HNF4α transcription factor. The new molecular knowledge reveals new targets for intervention to manage urate levels and prevent gout.