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Verification of immunology-related genetic associations in BPD supports ABCA3 and five other genes
Felix Blume1, Holger Kirsten1,2, Peter Ahnert1
1Institute for Medical Informatics, Statistics and Epidemiology (IMISE), associated partner of the German Center for Lung Research (DZL), University of Leipzig, Leipzig, Germany.
Insights
This study investigated genetic variants linked to bronchopulmonary dysplasia (BPD) in preterm infants. While most prior associations weren't replicated, new evidence supports roles for CRP, NUAK1, SELL, VNN2, and ABCA3 genes in BPD development.
Area of Science:
- Genetics
- Neonatology
- Immunology
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease in preterm infants, significantly driven by inflammatory processes.
- Genetic factors, particularly variants in immunology-related genes, are implicated in BPD pathogenesis.
- Previous studies suggested associations between specific genetic variants and BPD risk.
Purpose of the Study:
- To verify previously reported associations of genetic variants in immunology-related genes with BPD in a large cohort.
- To identify novel genetic associations with BPD and its related phenotypes, such as oxygen supplementation, mechanical ventilation, and CPAP.
- To provide a foundation for future research by prioritizing candidate molecular mechanisms.
Main Methods:
- A large cohort of preterm infants (gestational age ≤32 weeks) from the PROGRESS and German Neonatal Network (GNN) studies was analyzed.
- A consensus definition identified 278 BPD cases and 670 controls.
- 49 immunity-related genes and 55 single-nucleotide polymorphisms (SNPs) previously linked to BPD were investigated, alongside a quantitative genetic association analysis.
Main Results:
- Five candidate SNPs (rs11265269-CRP, rs1427793-NUAK1, rs2229569-SELL, rs1883617-VNN2, rs4148913-CHST3) showed nominal association with BPD phenotypes, with four genes involved in cell adhesion.
- The strongest association identified was rs45538638-ABCA3 with CPAP (p=4.9×10⁻⁷), implicating an ABC transporter in surfactant formation.
- Most previously reported genetic associations with BPD could not be replicated in this larger sample.
Conclusions:
- This study provides additional support for the role of SNPs in CRP, NUAK1, SELL, VNN2, and ABCA3 in BPD.
- A novel candidate SNP, rs45538638 in the ABCA3 gene, was associated with CPAP use.
- Larger studies and meta-analyses are necessary to confirm these findings and further elucidate the genetic underpinnings of BPD.
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.
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