216 - Genetic Foundation for Responsiveness to Ibuprofen Treatment of Patent Ductus Arteriosus in Extremely Low Birthweight Infants

In utero, the fetal ductus arteriosus directs oxygenated blood away from the non-breathing fluid-filled lungs into systemic circulation. The ductus remains patent (PDA) in 88% of infants born less than 25 weeks gestation and in infants 25-28 weeks with RDS. Placental production of prostaglandins (PGs) maintain patency in utero. PGs may also be over-produced perinatally from inflammatory stimuli. Pulmonary 15-hydroxy-prostaglandin-dehydrogenase (PGDH) is the primary enzyme responsible for PG breakdown. Removal of the placenta combined with increased pulmonary circulation decreases placental PGs. Coggins et al studied ductal closure and remodeling in wild-type and PGDH-knockout mice. Knockout mice all died within 12-48 hours, had PDAs without remodeling, and had significantly higher PGE2 levels. Functional genetic variants of PGDH may alter PG breakdown but have not been studied in preterm infants with PDAs. Given that persistent ductal patency can lead to pulmonary over-circulation and systemic under-perfusion, a better understanding and predictability of PDA closure and response to treatment would be beneficial in this ELBW population.

Objective:

To evaluate the relationship between PDA closure and PGDH genetic variants.

Design/Methods:

ELBW infants were evaluated for PDAs and response to treatment following informed parental consent. Treatments included medical-ibuprofen; or surgical ligation/piccolo device closure. DNA was collected by buccal swabs and analyzed for 3 PGDH genetic variants: rs8752, rs2612656, and rs9312555, utilizing allele-specific Taqman probes during RT-PCR. Statistical analyses included: Kruskal-Wallis and Fisher exact tests for demographic data and Fisher exact test for genotype distribution, p< 0.05 considered significant.

Results:

There was an expected difference in distribution of GA among the PDA groups. The incidence of no PDA/spontaneous closure or medical closure was significantly higher versus surgical ligation/piccolo device closure in the presence of the minor alleles of rs8752 (p=0.027) and rs2612656 (p=0.035). There was no significant difference among the rs9312555 groups with respect to PDA (p=0.09).

Conclusion(s):

There was a different genotype distribution-in both recessive and dominant models for the rs8752 genetic variant of the PGDH gene-as it relates to the mode of treatment for ELBW infants with PDAs. We speculate that this variant-which is found in the 3’UTR of the PGDH gene-alters mRNA stability and accelerates PG breakdown, as those ELBW infants with this variant had fewer PDAs that required surgical closure/piccolo device closure.