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BRIEF RESEARCH REPORT article

Front. Genet.
Sec. Genetics of Common and Rare Diseases
Volume 15 - 2024 | doi: 10.3389/fgene.2024.1423714
This article is part of the Research Topic Community Series in Advances in Pathogenesis and Therapies of Gout: Volume II View all 5 articles

Whole-genome sequencing reveals rare variants associated with gout in Taiwanese males

Provisionally accepted
Yu-Ping Tseng Yu-Ping Tseng 1*Ya-Sian Chang Ya-Sian Chang 2,3*Venugopala R. Mekala Venugopala R. Mekala 1*Ting-Yuan Liu Ting-Yuan Liu 4Jan-Gowth Chang Jan-Gowth Chang 5,6*Grace S. Shieh Grace S. Shieh 1*
  • 1 Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
  • 2 Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan
  • 3 Precision and Cell Center,, Show Chwan Memorial Hospital, Changhua, Taiwan
  • 4 Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
  • 5 Office of Superintendent, Hualien Tzu Chi Hospital, Hualien, Taiwan
  • 6 Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan

The final, formatted version of the article will be published soon.

    To identify rare variants (RVs) of gout, we sequenced the whole genomes of 321 male gout patients and combined these with those of 64 male gout patients and 682 normal controls at Taiwan Biobank. We performed ACAT-O to identify 682 significant RVs (P < 3.8×10 -8 ) clustered on chromosomes 1, 7, 10, 16, and 18. To prioritize causal variants effectively, we sifted them by Combined Annotation-Dependent Depletion score >10 or |effect size| ≥ 1.5 for those without CADD scores. In particular, to the best of our knowledge, we identified the rare variants rs559954634, rs186763678, and 13-85340782-G-A for the first time to be associated with gout in Taiwanese males.Importantly, the RV rs559954634 positively affects gout, and its neighboring gene NPHS2 is involved in serum urate and expressed in kidney tissues. The kidneys play a major role in regulating uric acid levels. This suggests that rs559954634 may be involved in gout. Furthermore, rs186763678 is in the intron of NFIA that interacts with SLC2A9, which has the most significant effect on serum urate. Note that gene-gene interaction NFIA-SLC2A9 is significantly associated with serum urate in the Italian MICROS population and a Croatian population. Moreover, 13-85340782-G-A significantly affects gout susceptibility (odds ratio 6.0; P = 0.038).The >1% carrier frequencies of these potentially pathogenic (protective) RVs in cases (controls) suggest the revealed associations may be true; these RVs deserve further studies for the mechanism. Finally, multivariate logistic regression analysis shows that the rare variants rs559954634 and 13-85340782-G-A jointly are significantly associated with gout susceptibility.

    Keywords: association study, CADD, Gout, rare variant, SERUM URATE, Whole-genome sequencing

    Received: 26 Apr 2024; Accepted: 28 Aug 2024.

    Copyright: © 2024 Tseng, Chang, Mekala, Liu, Chang and Shieh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Yu-Ping Tseng, Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
    Ya-Sian Chang, Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan
    Venugopala R. Mekala, Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
    Jan-Gowth Chang, Office of Superintendent, Hualien Tzu Chi Hospital, Hualien, Taiwan
    Grace S. Shieh, Institute of Statistical Science, Academia Sinica, Taipei, Taiwan

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