Department of Nephrology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
J Am Soc Nephrol. 2023 Nov 1;34(11):1900-1913. doi: 10.1681/ASN.0000000000000222. Epub 2023 Oct 2.
Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.
Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated.
We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression.
We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03).
Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.
全基因组关联研究已经确定了近 20 个 IgA 肾病易感性位点。然而，大多数非同义编码变异，特别是那些罕见或低频发生的变异，尚未得到很好的研究。作者对 8529 例 IgA 肾病患者和 23224 例对照进行了基于芯片的 IgA 肾病关联研究。他们在编码血管内皮生长因子 A（VEGFA）的基因中发现了一个罕见的变异，该变异与 IgA 肾病的风险增加两倍显著相关，这一结果通过测序分析得到了进一步证实。他们还在 PKD1L3 中发现了一个新的常见变异，该变异与较低的触珠蛋白蛋白水平显著相关。这项研究具有充分的能力来检测具有中等至大效应大小的低频变异，有助于扩大我们对 IgA 肾病易感性遗传基础的理解。
全基因组关联研究已经确定了近 20 个 IgA 肾病的易感性位点。然而，大多数非同义编码变异，特别是那些罕见或低频发生的变异，尚未得到很好的研究。
我们对 8529 例 IgA 肾病患者和 23224 例对照进行了三阶段基于外显子组的编码变异关联研究，所有研究对象均为汉族。进行测序分析以研究外显子组芯片未覆盖的罕见编码变异。我们使用分子动力学模拟来描述 VEGFA 突变对蛋白质结构和功能的影响。我们还探讨了鉴定出的变异与疾病进展风险之间的关系。
我们在 VEGFA 中发现了一个新的罕见非同义风险变异（优势比，1.97；95%置信区间[95%CI]，1.61 至 2.41；P = 3.61×10-11）。对 VEGFA 的进一步测序显示，在 2148 例病例中，有两倍多的患者携带 2732 例对照中罕见的其他变异。我们还在 PKD1L3 中发现了一个常见的非同义风险变异（优势比，1.16；95%CI，1.11 至 1.21；P = 1.43×10-11），该变异与较低的触珠蛋白蛋白水平相关。罕见的 VEGFA 突变可导致构象改变，并增加 VEGFA 与其受体的结合亲和力。此外，该变异与 IgA 肾病中肾脏疾病进展风险的增加相关（风险比，2.99；95%CI，1.09 至 8.21；P = 0.03）。
我们的研究在 VEGFA 和 PKD1L3 中确定了两个 IgA 肾病的新风险变异，有助于扩大我们对 IgA 肾病易感性遗传基础的理解。
