Tseng Yu-Ping, Chang Ya-Sian, Mekala Venugopala R, Liu Ting-Yuan, Chang Jan-Gowth, Shieh Grace S
Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan.
Front Genet. 2024 Sep 25;15:1423714. doi: 10.3389/fgene.2024.1423714. eCollection 2024.
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 ( < 3.8 × 10) 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 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 that interacts with which has the most significant effect on serum urate. Note that gene-gene interaction 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; = 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.
为了鉴定痛风的罕见变异（RVs），我们对321名男性痛风患者的全基因组进行了测序，并将这些数据与台湾生物银行中64名男性痛风患者及682名正常对照的数据相结合。我们进行了ACAT-O分析，以鉴定出682个聚集在1号、7号、10号、16号和18号染色体上的显著罕见变异（<3.8×10）。为了有效地对因果变异进行优先级排序，对于那些没有CADD评分的变异，我们通过联合注释依赖损耗评分>10或|效应大小|≥1.5来筛选。特别是，据我们所知，我们首次鉴定出罕见变异rs559954634、rs186763678以及13 - 85340782 - G - A与台湾男性痛风相关。重要的是，罕见变异rs559954634对痛风有正向影响，其邻近基因参与血清尿酸盐代谢并在肾组织中表达。肾脏在调节尿酸水平中起主要作用。这表明rs559954634可能参与痛风发病机制。此外，rs186763678位于与对血清尿酸盐影响最为显著的基因相互作用的基因的内含子中。注意，基因 - 基因相互作用在意大利MICROS人群和克罗地亚人群中与血清尿酸盐显著相关。而且，13 - 85340782 - G - A显著影响痛风易感性（优势比6.0；P = 0.038）。这些潜在致病（保护性）罕见变异在病例组（对照组）中>1%的携带频率表明所揭示的关联可能是真实的；这些罕见变异的作用机制值得进一步研究。最后，多因素逻辑回归分析表明，罕见变异rs559954634和13 - 85340782 - G - A共同与痛风易感性显著相关。
