Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome.
Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome.
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DOI：
10.1016/j.ekir.2023.05.018
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发表时间：
2023-08
影响因子：
6
通讯作者：
Gale, Daniel P.
中科院分区：
文献类型：
--
作者：
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.
类固醇敏感性肾病综合征（SSNS）是全世界儿童中最常见的肾脏疾病。全基因组关联研究 (GWAS) 证明了 SSNS 与 HLA-DQ/DR 遗传变异之间的关联，并确定了几个有助于进一步了解疾病病理生理学的非 HLA 位点。我们试图在斯里兰卡和欧洲血统的儿童中鉴定与 SSNS 相关的其他遗传位点。我们对斯里兰卡个体队列进行了 GWAS，其中包括 420 名 SSNS 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患者。然后，我们对先前报道的欧洲队列（包括 422 名儿科患者和 5642 名对照者）进行了跨种族荟萃分析。我们的 GWAS 证实了之前报道的 SSNS 与 HLA-DR/DQ 的关联（rs9271602，P = 1.12 × 10−27，比值比 [OR] = 2.75）。跨种族荟萃分析重复了这些发现，并在 AHI1 上发现了一种新的关联（rs2746432，P = 2.79 × 10−8，OR = 1.37），这也在一个独立的南亚队列中得到了重复。 AHI1 与纤毛蛋白转运和免疫失调有关，该基因的罕见变异会导致 3 型 Joubert 综合征。AHI1 的常见变异会导致斯里兰卡和欧洲人群发生 SSNS 的风险。与 AHI1 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，并证明基因中等位基因频谱的变异可能导致不同的单基因和多基因疾病。
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 HLA-DQ/DR and have identified several non-HLA 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 HLA-DR/DQ (rs9271602, P = 1.12 × 10−27, odds ratio [OR] = 2.75). Transethnic meta-analysis replicated these findings and identified a novel association at AHI1 (rs2746432, P = 2.79 × 10−8, OR = 1.37), which was also replicated in an independent South Asian cohort. AHI1 is implicated in ciliary protein transport and immune dysregulation, with rare variation in this gene contributing to Joubert syndrome type 3. Common variation in AHI1 confers risk of the development of SSNS in both Sri Lankan and European populations. The association with common variation in AHI1 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.
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影响因子：
5.5
作者：
通讯作者：
--
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
21.3
作者：
Chih, Ben;Liu, Peter;Peterson, Andrew S.
通讯作者：
Peterson, Andrew S.