Department of Pediatrics/ Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA.
University of Southern California Keck School of Medicine, Los Angeles, CA.
Blood Adv. 2024 Nov 12;8(21):5529-5538. doi: 10.1182/bloodadvances.2024012776.
Through the use of genetic sequencing, molecular variants driving autoimmunity are increasingly identified in patients with chronic and refractory immune cytopenias. With the goal of discovering genetic variants that predispose to pediatric immune thrombocytopenia (ITP) or increase risk for chronic disease, we conducted a genome-wide association study in a large multi-institutional cohort of pediatric patients with ITP. A total of 591 patients were genotyped using an Illumina Global Screening Array BeadChip. Six variants met genome-wide significance in comparison between children with ITP and a cohort of healthy children. One variant in NAV2 was inversely associated with ITP (adjusted odds ratio [aOR], 0.52; P = 3.2 × 10-11). Two other variants in close proximity to NKD1 were also inversely associated with ITP (aOR, 0.43; P = 8.86 × 10-15; aOR, 0.48; P = 1.84 × 10-16). These genes have been linked to the canonical Wnt signaling pathway. No variants met genome-wide significance in comparison of those with ITP that self-resolved in <1 year versus those who developed chronic ITP. This study identifies genetic variants that may contribute to ITP risk and raises a novel pathway with a potential role in ITP pathogenesis.
通过基因测序，越来越多的慢性和难治性免疫性血细胞减少症患者中与自身免疫相关的分子变异被鉴定出来。为了发现易患小儿免疫性血小板减少症 (ITP) 或增加慢性疾病风险的遗传变异，我们对一个大型多机构小儿 ITP 患者队列进行了全基因组关联研究。共对 591 名患者进行了 Illumina 全球筛查阵列珠芯片基因分型。在 ITP 患儿与健康儿童队列之间的比较中，有 6 个变异达到了全基因组显著水平。 NAV2 中的一个变异与 ITP 呈负相关（调整后的优势比[aOR]，0.52；P=3.2×10-11）。另外两个与 NKD1 密切相关的变体也与 ITP 呈负相关（aOR，0.43；P=8.86×10-15；aOR，0.48；P=1.84×10-16）。这些基因与经典 Wnt 信号通路有关。在 ITP 患儿中，那些在 1 年内自行缓解的与发展为慢性 ITP 的相比，没有任何变异达到全基因组显著水平。本研究确定了可能导致 ITP 风险的遗传变异，并提出了一个新的途径，该途径可能在 ITP 发病机制中起作用。
