Hedgehog signaling pathway gene variant influences bronchopulmonary dysplasia in extremely low birth weight infants

Background Genome wide association study identified hedgehog interacting protein gene ( HHIP ) variants with chronic obstructive pulmonary disease and asthma. Loss of HHIP, a key regulator of the hedgehog signaling pathway, leads to impaired lung morphogenesis and lethality in animal models, through unimpeded sonic hedgehog expression blocking mesenchymal-expressed fibroblast growth factor 10 (FGF10). Since bronchopulmonary dysplasia (BPD) is also associated with altered lung development and worsens with stimuli including mechanical ventilation, reactive oxygen species, and inflammation, HHIP and FGF10 may be candidate genes. Methods This was an observational, cohort study including extremely low birth weight infants that who developed BPD and those who did not. DNA was isolated from buccal swabs and subjected to allelic discrimination, using specific HHIP and FGF10 probes. Protein levels were measured in tracheal aspirates. Student's t test, Chi-square, Z test and logistic regression were used. Results Demographic characteristics did not differ except that birth weight (715 ± 153 vs. 835 ± 132 g) and gestational age (25 vs. 26 weeks) were less in babies with BPD. HHIP variant rs13147758 (GG genotype) was found to be independently protective for BPD (odds ratio 0.35, 95% confidence interval 0.15–0.82, P = − 0.02). Early airway HHIP protein levels were increased in infants with BPD compared to those without [median (interquartile range) 130.6 (55.6–297.0) and 41.2 (22.1–145.6) pg/mL, respectively; P = 0.05]. The FGF10 single nucleotide polymorphisms were not associated with BPD. Conclusion HHIP, as a regulator of lung bud formation, affects BPD susceptibility, and may be valuable in understanding the specific mechanisms for this disease as well as for identifying therapeutic targets in the era of personalized medicine.