Zhao Weian, Chen Yijing, Yu Zhongsu, Wang Zhouping, He Renke, Cai Simian, Chen Zhongzhong, Cheng Liangping
Department of Anesthesiology Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, China.
Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
Intractable Rare Dis Res. 2025 Feb 28;14(1):36-45. doi: 10.5582/irdr.2024.01064.
With improved survival rates among congenital heart disease (CHD) patients, pulmonary arterial hypertension (PAH) linked to CHD becomes more prevalent in both children and adults. PAH remains a significant contributor to morbidity and mortality in this population. Although genome-wide association studies (GWAS) have identified potential genetic variants with PAH risk and prognosis, the identification of circulating biomarkers with causal roles in CHD-PAH remains unclear. We employed the summary data-based Mendelian randomization (SMR) method, integrating expression profile data from the Gene Expression Omnibus (GEO) database related to CHD-PAH. This approach aimed to pinpoint genes causally associated with risk of CHD-PAH. We used a two-sample Mendelian randomization (MR) approach to efficiently screen for circulating proteins affecting CHD-PAH, leveraging publicly available genetic data from the UK biobank Pharma Proteomics Project (UKB-PPP) (54,219 UKB participants). Genetic determinants (cis-SNPs) of circulating proteins were used as instruments, and MR analyses assessed the influence of these proteins on CHD-PAH susceptibility in the largest PAH GWAS (2085 cases and 9659 controls). We conducted colocalization analyses to ensure shared genetic signals between circulating proteins and PAH and performed immune cell infiltration analysis to understand immune regulatory mechanisms in CHD-PAH. We found that a 1 SD increase in circulating S100 calcium binding protein A3 (S100A3) levels correlated with a reduced PAH risk (OR: 0.073, 95% CI: 0.020-0.267; = 0.00799). Sensitivity analyses including various cis-SNPs, provided consistent estimates for (inverse variance weighted (IVW) OR: 0.085, 95% CI: 0.032-0.225; = 7.5 × 10 and MR-Egger OR: 0.212, 95% CI: 0.013-3.376; = 0.387). Colocalization analyses confirmed a shared genetic signal for and PAH, with a posterior probability of 99.9%. Transcriptomic investigations further highlighted 's protective role in CHD-PAH. Our study using SMR and GEO data identified as a gene associated with a reduced risk of PAH in CHD patients. Elevated circulating levels of S100A3 were linked to a reduced PAH risk, and transcriptomic evidence further supported its protective function in CHD-PAH.
随着先天性心脏病（CHD）患者生存率的提高，与CHD相关的肺动脉高压（PAH）在儿童和成人中变得更加普遍。PAH仍然是这一人群发病和死亡的重要原因。尽管全基因组关联研究（GWAS）已经确定了与PAH风险和预后相关的潜在基因变异，但在CHD-PAH中具有因果作用的循环生物标志物的识别仍不清楚。我们采用基于汇总数据的孟德尔随机化（SMR）方法，整合来自基因表达综合数据库（GEO）中与CHD-PAH相关的表达谱数据。这种方法旨在找出与CHD-PAH风险有因果关系的基因。我们使用两样本孟德尔随机化（MR）方法，利用来自英国生物银行药物蛋白质组学项目（UKB-PPP）（54219名UKB参与者）的公开可用遗传数据，有效筛选影响CHD-PAH的循环蛋白。循环蛋白的遗传决定因素（顺式单核苷酸多态性，cis-SNPs）被用作工具变量，MR分析评估这些蛋白在最大的PAH GWAS（2085例病例和9659例对照）中对CHD-PAH易感性的影响。我们进行了共定位分析，以确保循环蛋白和PAH之间共享遗传信号，并进行了免疫细胞浸润分析，以了解CHD-PAH中的免疫调节机制。我们发现，循环S100钙结合蛋白A3（S100A3）水平每增加1个标准差，PAH风险降低（OR：0.073，95%CI：0.020-0.267；P = 0.00799）。包括各种顺式单核苷酸多态性的敏感性分析，对P提供了一致的估计（逆方差加权（IVW）OR：0.085，95%CI：0.032-0.225；P = 7.5×10⁻⁶和MR-Egger OR：0.212，95%CI：0.013-3.376；P = 0.387）。共定位分析证实了S100A3和PAH之间共享遗传信号，后验概率为99.9%。转录组学研究进一步突出了S100A3在CHD-PAH中的保护作用。我们使用SMR和GEO数据的研究确定S100A3是与CHD患者PAH风险降低相关的基因。循环S100A3水平升高与PAH风险降低有关，转录组学证据进一步支持其在CHD-PAH中的保护功能。
