Background

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.

Methods

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.

Results

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 × 10⁻⁷, FDR = 0.004), an ABC transporter involved in surfactant formation.

Conclusions

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.

Impact

• 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.

中文翻译：

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BPD中免疫学相关遗传关联的验证支持ABCA3和其他五个基因

背景

炎症过程是支气管肺发育不良 (BPD) 的关键驱动因素，BPD 是早产儿的一种慢性肺病。在一个大样本中，我们验证了先前报道的免疫学相关基因的遗传变异与 BPD 的关联。

方法

包括来自 PROGRESS 和德国新生儿网络 (GNN) 的胎龄≤32 周的早产儿。通过共识病例/对照定义，确定了 278 个 BPD 病例和 670 个对照。我们通过全面的文献调查确定了 49 个免疫相关基因和 55 个单核苷酸多态性 (SNP) 以前与 BPD 相关。此外，还对氧气补充、机械通气和持续正压通气 (CPAP) 进行了定量遗传关联分析。

结果

五个候选 SNP 名义上与 BPD 相关表型相关，其作用方向与原始研究不冲突：rs11265269- CRP、rs1427793 -NUAK1、rs2229569- SELL、rs1883617 -VNN2和 rs4148913 -CHST3。其中四个基因与细胞粘附有关。将我们的分析扩展到所有候选基因的所有良好估算的 SNP，最强的关联是 rs45538638- ABCA3与 CPAP ( p  = 4.9 × 10 ^-7，FDR = 0.004)，一种参与表面活性剂形成的 ABC 转运蛋白。

结论

大多数先前报告的关联都无法复制。我们在CRP、NUAK1、SELL、VNN2和ABCA3中发现了对 SNP 的额外支持。需要更大规模的研究和荟萃分析来证实这些发现。

影响

• 更大的队列以提高统计能力以检测与支气管肺发育不良 (BPD) 的遗传关联。

• 大多数先前报道的与 BPD 的遗传关联无法在这项更大的研究中复制。

• 在研究的免疫学相关候选基因中，发现了对基因CRP、NUAK1、SELL、VNN2和CHST3变体的额外支持，其中四个与细胞粘附有关。

• rs45538638 是报道的候选基因 ABC-转运蛋白 ABCA3 中的一个新的候选SNP。

• 结果有助于在后续研究中优先考虑分子候选病理机制。