Novel genetic loci in adolescent-onset gout derived from whole genome sequencing of a Chinese cohort

BackgroundGout is a polygenetic inflammatory disease. Although hundreds of genetic variants associated with gout and serum urate levels have been identified in studies of adults, the pathogenesis of adolescent-onset gout remains unclear. To better characterize the genetic landscape of adolescent-onset gout, a whole genome sequencing study was done in a large Chinese adolescent-onset gout cohort. MethodsWe conducted whole genome sequencing in a discovery adolescent-onset gout cohort of 905 individuals (gout onset 12-19 years) to discover common SNVs, uncommon SNVs, and indels associated with gout. Candidate common SNVs were replicated in an early-onset gout cohort of 2834 individuals (gout onset [&le;] 30 years old). Loci associated with early-onset gout (P < 5.0 x 10-8) were identified after meta-analysis with the discovery and replication cohorts. Transcriptome and epigenomic analyses, RT-qPCR and RNA-seq in human peripheral blood leukocytes, and knock-down experiments in human THP-1 macrophage cells investigated regulation and functions of candidate gene RCOR1. FindingsIn addition to ABCG2, a urate transporter previously linked to pediatric-onset and early-onset gout, we identified four novel loci: VPRBP (rs868933181, Pmeta = 6.27 x 10-9; ORmeta = 1.66), NKILA-MIR4532 (rs72626599, Pmeta = 6.48 x 10-9; ORmeta = 1.58), RCOR1 (rs12887440, Pmeta = 3.37 x 10-8; ORmeta = 1.48), and FSTL5-MIR4454 (rs35213808, Pmeta = 4.02 x 10-8; ORmeta = 1.49). Additionally, we found association at ABCG2 and SLC22A12 that was driven by low frequency SNVs. Furthermore, eight uncommon SNVs and three indels in the exome were predicted to be harmful. SNVs in RCOR1 were linked to heightened blood leukocyte mRNA levels. THP-1 macrophage culture studies revealed the potential of decreased RCOR1 to suppress gouty inflammation. InterpretationPerforming the first comprehensive characterization of adolescent-onset gout genomes identified risk loci of early-onset gout. Loci mediate inflammatory responsiveness to crystals that could mediate gouty arthritis. This study will contribute to risk prediction and therapeutic interventions to prevent adolescent-onset gout. FundingThe National Natural Science Foundation of China and the National Key R&D Program of China. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSGout is a polygenic disease and can present in adolescents and young adults. We searched PubMed for studies published as of Dec 31, 2021, without starting date or language restrictions and with the terms "adolescent-onset gout", "early-onset gout", "whole genome sequencing", and "GWAS", and no reports were found. Although GWAS have identified hundreds of genetic variants associated with gout and serum urate levels, they are all identified in adults (mean age 37.6-76.4 years old). The mechanism of early-onset gout is still unclear. The variants previously associated with early-onset gout are only in ABCG2. Due to the lack of large-scale genetic studies of the adolescent gout population, the mechanism of the early-onset gout is unknown. Added value of this studyTo the best of our knowledge, this is the first report of the comprehensive characterization of adolescent gout genomes. We identified common and uncommon risk loci of early-onset gout, most of which implicated in inflammation response, including RCOR1. SNVs in candidate risk gene RCOR1 displayed expression regulation function. Knockdown of RCOR1 decreased IL-1{beta} levels in THP-1 cells after MSU treatment. These immune-related genetic variants leading to heightened inflammatory responses to monosodium urate (MSU) crystals may contribute to early onset of gout in adolescents. Implications of all the available evidenceThis is the first report of the genetic landscape of adolescent-onset gout and increases our knowledge of the biological mechanisms underlying early-onset gout. The immune-related loci associated with early-onset gout discovered in this study are potential drug targets. Reducing inflammatory MSU crystal inflammatory responses to MSU crystals is a central objective in the prevention and treatment of adolescent-onset gout.