Blume Felix, Kirsten Holger, Ahnert Peter, Chakraborty Trinad, Gross Arnd, Horn Katrin, Toliat Mohammad Reza, Nürnberg Peter, Westenfelder Eva-Maria, Goepel Wolfgang, Scholz Markus
Institute for Medical Informatics, Statistics and Epidemiology (IMISE), associated partner of the German Center for Lung Research (DZL), University of Leipzig, Leipzig, Germany.
LIFE - Leipzig Research Centre for Civilisation Diseases, University of Leipzig, Leipzig, Germany.
Pediatr Res. 2022 Jul;92(1):190-198. doi: 10.1038/s41390-021-01689-y. Epub 2021 Aug 31.
Inflammatory processes are key drivers of bronchopulmonary dysplasia (BPD), a chronic lung disease in preterm infants. In a large sample, we verify previously reported associations of genetic variants of immunology-related genes with BPD.
Preterm infants with a gestational age ≤32 weeks from PROGRESS and the German Neonatal Network (GNN) were included. Through a consensus case/control definition, 278 BPD cases and 670 controls were identified. We identified 49 immunity-related genes and 55 single-nucleotide polymorphisms (SNPs) previously associated with BPD through a comprehensive literature survey. Additionally, a quantitative genetic association analysis regarding oxygen supplements, mechanical ventilation, and continuous positive air pressure (CPAP) was performed.
Five candidate SNPs were nominally associated with BPD-related phenotypes with effect directions not conflicting the original studies: rs11265269-CRP, rs1427793-NUAK1, rs2229569-SELL, rs1883617-VNN2, and rs4148913-CHST3. Four of these genes are involved in cell adhesion. Extending our analysis to all well-imputed SNPs of all candidate genes, the strongest association was rs45538638-ABCA3 with CPAP (p = 4.9 × 10, FDR = 0.004), an ABC transporter involved in surfactant formation.
Most of the previously reported associations could not be replicated. We found additional support for SNPs in CRP, NUAK1, SELL, VNN2, and ABCA3. Larger studies and meta-analyses are required to corroborate these findings.
Larger cohort for improved statistical power to detect genetic associations with bronchopulmonary dysplasia (BPD). Most of the previously reported genetic associations with BPD could not be replicated in this larger study. Among investigated immunological relevant candidate genes, additional support was found for variants in genes CRP, NUAK1, SELL, VNN2, and CHST3, four of them related to cell adhesion. rs45538638 is a novel candidate SNP in reported candidate gene ABC-transporter ABCA3. Results help to prioritize molecular candidate pathomechanisms in follow-up studies.
炎症过程是支气管肺发育不良（BPD）的关键驱动因素，BPD是一种早产儿慢性肺部疾病。在一个大样本中，我们验证了先前报道的免疫相关基因的遗传变异与BPD的关联。
纳入来自PROGRESS和德国新生儿网络（GNN）的孕周≤32周的早产儿。通过共识病例/对照定义，确定了278例BPD病例和670例对照。通过全面的文献调查，我们确定了49个与免疫相关的基因和55个先前与BPD相关的单核苷酸多态性（SNP）。此外，还进行了关于氧气补充、机械通气和持续气道正压通气（CPAP）的定量遗传关联分析。
五个候选SNP与BPD相关表型存在名义上的关联，其效应方向与原始研究不冲突：rs11265269 - CRP、rs1427793 - NUAK1、rs2229569 - SELL、rs1883617 - VNN2和rs4148913 - CHST3。其中四个基因参与细胞黏附。将我们的分析扩展到所有候选基因的所有插补良好的SNP，最强的关联是rs45538638 - ABCA3与CPAP（p = 4.9×10，FDR = 0.004），ABCA3是一种参与表面活性剂形成的ABC转运蛋白。
大多数先前报道的关联无法复制。我们发现CRP、NUAK1、SELL、VNN2和ABCA3中的SNP有额外的支持证据。需要更大规模的研究和荟萃分析来证实这些发现。
更大的队列以提高检测与支气管肺发育不良（BPD）遗传关联的统计效力。在这项更大规模的研究中，大多数先前报道的与BPD的遗传关联无法复制。在研究的免疫相关候选基因中，发现CRP、NUAK1、SELL、VNN2和CHST3基因中的变异有额外支持证据，其中四个与细胞黏附有关。rs45538638是报道的候选基因ABC转运蛋白ABCA3中的一个新的候选SNP。研究结果有助于在后续研究中对分子候选发病机制进行优先排序。
