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

Abstract

OBJECTIVE-To evaluate the association of steroid metabolism and respiratory gene polymorphisms in neonates exposed to antenatal corticosteroids (ACS) with respiratory outcomes, small for gestational age (SGA) and response to repeat ACS.STUDY DESIGN-This candidate gene study is a secondary analysis of women enrolled in a randomized controlled trial of single versus weekly courses of ACS. Nineteen single nucleotide polymorphisms (SNPs) in 13 steroid metabolism and respiratory function genes were evaluated. DNA was extracted from placenta or fetal cord serum and analyzed with TaqMan genotyping. Each SNP was evaluated for association via logistic regression with respiratory distress syndrome (RDS), CPAP/ventilator use (CPV) and SGA.RESULTS-CRHBP, CRH and CRHR1 minor alleles were associated with an increased risk of SGA. HSD11B1 and SCNN1B minor alleles were associated with an increased likelihood of RDS. Carriage of minor alleles in SerpinA6 was associated with an increased risk of CPV. CRH and CRHR1 minor alleles were associated with a decreased likelihood of CPV. HHS Public AccessAuthor manuscript Am J Perinatol. Author manuscript; available in PMC 2016 May 07.CONCLUSION-Steroid metabolism and respiratory gene SNPs are associated with respiratory outcomes and SGA in patients exposed to ACS. Risks for respiratory outcomes are affected by minor allele carriage as well as by treatment with multiple ACS.

Effects of antenatal glucocorticoids on the developing brain

“…In small for gestational age infants, these SNPs have been associated with differences in the reduction in RDS 25 . Clinical data suggests that the effect of antenatal sGC therapy is limited in intrauterine growth restricted fetuses (IUGR) and that ‘it remains unclear if ACS therapy is beneficial due to heterogeneous populations and treatment regimes’ 26 .…”

Decreased CRHBP expression is predictive of poor prognosis in patients with hepatocellular carcinoma

“…CRHBP has been investigated in the field of normal physiologic, metabolic function and oncogenesis ( 12 , 13 ). It was reported that Caucasians and African Americans with low CRHBP expression were associated with an increased risk of breast cancer ( 14 ).…”

Genetic variation in CRHR1 is associated with short-term respiratory response to corticosteroids in preterm infants at risk for bronchopulmonary dysplasia

“…The importance of genetic variation in CRHR1 to corticosteroid response has been described in Chronic Obstructive Pulmonary Disease (COPD)(27) asthma(12) and persistent pulmonary hypertension of the newborn(28). Genetic variation in the ligand for CRHR1 , corticotropin releasing hormone (CRH), is associated with neonatal respiratory response to maternal prenatal corticosteroid therapy (10). Fetuses who carry the risk allele at rs7225082 are more likely to require CPAP/ventilator postnatally (poor response to maternal corticosteroids) and correspondingly in our study, preterm infants who carry the risk allele have a poorer response to postnatal corticosteroids.…”

“…Variant alleles can influence drug metabolism, disposition and drug target sensitivity, and explain some of the heterogeneity in efficacy and toxicity that is observed within a patient population. A recent study (10) links neonatal genetic variation to respiratory phenotype at birth after maternal treatment with antenatal corticosteroids. In asthma, multiple single nucleotide polymorphisms (SNPs) in corticosteroid metabolism and response genes modify clinical response to inhaled corticosteroids(11-17).…”