Identification of genetic susceptibility in preterm newborns with bronchopulmonary dysplasia by whole-exome sequencing: BIVM gene may play a role

Abstract

Bronchopulmonary dysplasia (BPD) is a common chronic respiratory disease in preterm infants caused by multifactorial etiology. Genetic factors are involved in the occurrence of BPD, but studies have found that candidate genes have poor reproducibility and are influenced by ethnic heterogeneity; therefore, more exploration is still needed. We performed whole-exon sequencing in 34 preterm infants with BPD and 32 non-BPD control neonates. The data were analyzed and interpreted by Fisher difference comparison, PLINK and eQTL association analysis, KEGG and GO enrichment analysis, STRING tool, Cytoscape software, ProtParam tool, HOPE online software, and GEOR2 analysis on NCBI GEO dataset. BPD has a highly heterogeneity in different populations, and we found 35 genes overlapped with previous whole-exon sequencing studies, such as APOB gene. Arterial and epithelial cell development and energy metabolism pathways affect BPD. In this study, 24 key genes were identified, and BIVM rs3825519 mutation leads to prolonged assisted ventilation in patients with BPD. A novel DDAH1 mutation site (NM_012137: exon1: c.89 T > G: p.L30R) was found in 9 BPD patients.

Conclusion: BIVM gene rs3825519 mutation may play a role in the pathogenesis of BPD by affecting cilia movement, and the DDAH1 and APOB genes mutations may have a pathogenic role in BPD.

What is known: • Genetic factors are involved in the occurrence of bronchopulmonary dysplasia. • The candidate genes have poor reproducibility and are influenced by ethnic heterogeneity, therefore, more exploration is still needed.

What is new: • We identified the role of susceptible SNPs in BPD in Shenzhen, China, and identified 24 key genes that influence the pathogenesis of BPD, and also found 35 genes overlapped with previous whole exon sequencing studies, such as APOB gene. • We found that BIVM and DDAH1 genes may play a pathogenic role in the pathogenesis of BPD.

Keywords: BIVM gene; Bronchopulmonary dysplasia; Genetic susceptibility; Single-nucleotide polymorphisms; Whole-exome sequencing.

Fig. 1

PCA plot of association test statistics in the WES-based discovery data

Fig. 2

Manhattan plot of results from exome-wide association analysis of 34 BPD and 32 non-BPD infants

Fig. 3

The mutant genes in our study were overlapped with those in previous studies. The genes with red color are core genes

Fig. 4

Predicted 3D structure of DDAH1 wild type and mutant. Close-up of the mutation. Wild-type, and mutant side chain are shown in green and red respectively, the rest of the protein is shown in gray

Fig. 5

Venn diagram of risk genes for BPD development reported in four previous studies [–19] and ours

Fig. 6

Linkage disequilibrium analysis among the top 10 SNPs associated with BPD

Fig. 7

GO and KEGG enrichment analysis of differential genes associated with BPD. a GO enrichment analysis biological process, b GO enrichment analysis, cellular component, c GO enrichment analysis molecular function, d KEGG enrichment analysis