Verification of immunology-related genetic associations in BPD supports ABCA3 and five other genes

Abstract

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.

Fig. 1. Quantile–quantile plot comparing observed and expected p value minimum of SNP associations with the four investigated phenotypes supplied oxygen, mechanical ventilation, CPAP, and case/control state.

A total of 9469 SNPs in or near 49 candidate genes were investigated. One variant rs45538638-ABCA3 was stronger associated with CPAP than expected by chance accounting for the tested number of SNPs and phenotypes.