european crystal network workshop

    RECENT FINDINGS IN CLINICO-GENETICS ANALYSES FOR CLINICALLY-DEFINED GOUT

     

    Hirotaka Matsuo 1), Masahiro Nakatochi 2), Akiyoshi Nakayama 1), Yusuke Kawamura 1), Yu Toyoda 1), Seiko Shimizu 1), Tappei Takada 3), Kimiyoshi Ichida 4), Nariyoshi Shinomiya 1), Yukinori Okada 5)

    1) Department Of Integrative Physiology And Bio-Nano Medicine, National Defense Medical College 2) Division Of Department Of Nursing, Nagoya University Graduate School Of Medicine 3) Department Of Pharmacy, The University Of Tokyo Hospital 4) Department Of Pathophysiology, Tokyo University Of Pharmacy And Life Science 5) Department Of Statistical Genetics, Osaka University Graduate School Of Medicine

     

    Gout has strong genetic factors. Here, we show our recent findings in the associations between gout and genetic factors as followings:

     

    1) OAT10/URAT2 variant decreases gout risk
    Background:
    OAT10/SLC22A13 has been identified as a urate transporter by in vitro analyses; however, its physiological impact on urate handling remains to be elucidated. We therefore investigated the association between genetic variation of OAT10 gene and gout susceptibility.

     

    Methods: We examined all exons of OAT10 in 480 gout cases and 480 controls of Japanese male, followed by a replication study. Also, we characterized a newly identified OAT10 variant using cell-based functional analyses.

     

    Results: We found that OAT10 c.1129C>T (R377C) has a significant protective effect on gout susceptibility(OR = 0.67; reciprocal OR = 1.49). Functional assay demonstrated that the R377C variant is functionally null as a urate transporter.

     

    Conclusion: Considering the reported expression of OAT10 on the apical side of the renal proximal tubular cells, our results suggest that functional OAT10 could be physiologically involved in a supply route of urate into the blood as a novel renal urate reabsorber “URAT2”.

     

    Reference: Higashino et al., Dysfunctional missense variant of OAT10/SLC22A13 decreases gout risk and serum uric acid levels. Ann Rheum Dis. 2020 79(1):164–6.

     

     

    2) Subtype gout GWAS and selection pressure
    Background:
    Gout can be classified into four distinct subtypes according to two clinical parameters. Genome-wide association studies (GWASs) of these subtypes were, however, never conducted. A recent study has also revealed genetic adaptive evolution of gout in the Japanese populations. Therefore, we performed subtype genome-wide meta-analyses of clinically defined gout cases to identify the subtype-specific gout susceptibility loci. We also conducted the evaluation using selection pressure analysis with these loci to investigate genetic risks characteristics of gout in the Japanese population over the last 2000-3000 years.

     

    Methods: Two GWASs using two platforms with Japanese male population (3053 cases and 4554 controls from Japanese male) were performed. About 7.2 million single-nucleotide polymorphisms (SNPs) were meta-analyzed after imputation. Gout cases were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type, and normal type) and meta-analyses were conducted. Selection pressure analysis using singleton density score was also performed on each subtype.

     

    Results: In addition to the eight loci we reported previously, a GWAS meta-analysis of all gout cases identified two novel loci, PIBF1 and ACSM2B, at a genome-wide significance level (p<5.0E-8). Another two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, were identified from a GWAS of normal type gout cases. Selection pressure analysis revealed significant enrichment of selection pressure on two genes, ABCG2 and ALDH2, on all subtypes except for normal type gout.

     

    Conclusion: Our present findings will lead to elucidation of the molecular pathophysiology and evolutionary involvement of each gout/hyperuricemia subtype and also enable us to develop novel subtype-specific genome tailor-made medicine/prevention of gout and hyperuricemia.

     

    Reference: Nakayama et al., Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients. Ann Rheum Dis. 2020 79(5):657–65.

     

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