Downie Mallory L, Gupta Sanjana, Voinescu Catalin, Levine Adam P, Sadeghi-Alavijeh Omid, Dufek-Kamperis Stephanie, Cao Jingjing, Christian Martin, Kari Jameela A, Thalgahagoda Shenal, Ranawaka Randula, Abeyagunawardena Asiri, Gbadegesin Rasheed, Parekh Rulan, Kleta Robert, Bockenhauer Detlef, Stanescu Horia C, Gale Daniel P
Department of Renal Medicine, University College London, London, UK.
Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Kidney Int Rep. 2023 May 27;8(8):1562-1574. doi: 10.1016/j.ekir.2023.05.018. eCollection 2023 Aug.
Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of kidney disease in children worldwide. Genome-wide association studies (GWAS) have demonstrated the association of SSNS with genetic variation at and have identified several non- loci that aid in further understanding of disease pathophysiology. We sought to identify additional genetic loci associated with SSNS in children of Sri Lankan and European ancestry.
We conducted a GWAS in a cohort of Sri Lankan individuals comprising 420 pediatric patients with SSNS and 2339 genetic ancestry matched controls obtained from the UK Biobank. We then performed a transethnic meta-analysis with a previously reported European cohort of 422 pediatric patients and 5642 controls.
Our GWAS confirmed the previously reported association of SSNS with (rs9271602, = 1.12 × 10, odds ratio [OR] = 2.75). Transethnic meta-analysis replicated these findings and identified a novel association at (rs2746432, = 2.79 × 10, OR = 1.37), which was also replicated in an independent South Asian cohort. is implicated in ciliary protein transport and immune dysregulation, with rare variation in this gene contributing to Joubert syndrome type 3.
Common variation in confers risk of the development of SSNS in both Sri Lankan and European populations. The association with common variation in further supports the role of immune dysregulation in the pathogenesis of SSNS and demonstrates that variation across the allele frequency spectrum in a gene can contribute to disparate monogenic and polygenic diseases.
类固醇敏感性肾病综合征（SSNS）是全球儿童中最常见的肾脏疾病形式。全基因组关联研究（GWAS）已证明SSNS与[具体基因位点]的基因变异相关联，并确定了几个非[具体基因位点]位点，有助于进一步了解疾病的病理生理学。我们试图在斯里兰卡和欧洲血统的儿童中识别与SSNS相关的其他基因位点。
我们对一组斯里兰卡个体进行了GWAS，其中包括420名患有SSNS的儿科患者和从英国生物银行获得的2339名遗传血统匹配的对照。然后，我们与先前报道的由422名儿科患者和5642名对照组成的欧洲队列进行了跨种族荟萃分析。
我们的GWAS证实了先前报道的SSNS与[具体基因位点]（rs9271602，P = 1.12 × 10⁻⁸，优势比[OR] = 2.75）的关联。跨种族荟萃分析重复了这些发现，并在[具体基因位点]（rs2746432，P = 2.79 × 10⁻⁸，OR = 1.37）发现了一种新的关联，这在一个独立的南亚队列中也得到了重复。[具体基因位点]与纤毛蛋白运输和免疫失调有关，该基因的罕见变异导致3型乔伯特综合征。
[具体基因位点]的常见变异在斯里兰卡和欧洲人群中均赋予了发生SSNS的风险。与[具体基因位点]常见变异的关联进一步支持了免疫失调在SSNS发病机制中的作用，并表明基因中等位基因频率谱的变异可导致不同的单基因和多基因疾病。
