Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is associated with substantial infant morbidity and mortality. Recently, genetic associations have been found in idiopathic pulmonary arterial hypertension. We performed a family-based candidate gene study to examine a genetic association to PPHN and sequenced the BMPR2 gene in 72 individuals. We enrolled 110 families with infants diagnosed with PPHN based on inclusion criteria. After medical chart review, 22 subjects were excluded based on predefined criteria, DNA samples from 88 affected infants and at least one parent were collected and genotyped. Thirty-two single nucleotide polymorphisms (SNPs) in twelve genes involved in vasoconstriction/vasodilation, lung development, surfactant regulation, or vascular endothelial cell function were investigated using family-based association tests. PPHN was significantly (p<0.05) associated with genetic variants in corticotropin releasing hormone receptor 1, CRHR1 (rs4458044, p=9.9×10−5; rs173365, p=0.02) and corticotropin releasing hormone-binding protein, CRHBP (rs10062367, p=0.009 and rs10055255, p=0.003). Association with CRHR1 rs4458044 passed the Bonferroni threshold for significance. No mutations were found in the BMPR2 gene. We describe previously unreported genetic associations between PPHN and CRHR1 and CRHBP. These findings may have implications for further understanding the pathophysiology of PPHN and treatment.

Neonatal Genetic Variation in Steroid Metabolism and Key Respiratory Function Genes and Perinatal Outcomes in Single and Multiple Courses of Corticosteroids

“…Genetic variation in CRHR1 has also been associated with persistent pulmonary hypertension of the newborn suggesting a possible role with pulmonary disease in the newborn. 20 Prior studies also suggest a role for the corticotrophin releasing hormone system regulation of birthweight and SGA which we again identified in our study. 21,22,23 …”

Advances in Neonatal Pulmonary Hypertension

“…In a Dutch cohort with excellent early ascertainment, PPHN was documented in 5.2% of Down syndrome infants [15] and other studies have shown that Down syndrome infants are overrepresented in neonates requiring ECMO support [16]. A recent single-center study reported the results of rigorous genotype analysis of 88 neonates with documented PPHN [17]. No differences were noted in most candidate genes, including BMPR2 and nitric oxide (NO) synthase.…”

The Pulmonary Circulation in Neonatal Respiratory Failure

“…Recent identification of genetic variations involving corticotropin-releasing hormone in patients with PPHN, as well as the effectiveness of hydrocortisone in improving oxygenation in lambs with PPHN, suggest that glucocorticoids may have a role in prevention and management of PPHN and HRF. 37,38 …”