Effects of Advancing Gestation and Non-Caucasian Race on Ductus Arteriosus Gene Expression

Abstract

Objective To identify genes affected by advancing gestation and racial/ethnic origin in human ductus arteriosus (DA). Study design We collected three sets of DA tissue (n=93, n=89, n=91; total = 273 fetuses) from second trimester pregnancies. We examined four genes, with DNA polymorphisms that distribute along racial lines, to identify "Caucasian" and "Non-Caucasian" DA. We used RT-PCR to measure RNA expression of 48 candidate genes involved in functional closure of the DA, and used multivariable regression analyses to examine the relationships between advancing gestation, "Non-Caucasian" race, and gene expression. Results Mature gestation and Non-Caucasian race are significant predictors for identifying infants who will close their patent DA when treated with indomethacin. Advancing gestation consistently altered gene expression in pathways involved with oxygen-induced constriction (e.g., calcium-channels, potassium-channels, and endothelin signaling), contractile protein maturation, tissue remodeling, and prostaglandin and nitric oxide signaling in all three tissue sets. None of the pathways involved with oxygen-induced constriction appeared to be altered in "Non-Caucasian" DA. Two genes, SLCO2A1 and NOS3, (involved with prostaglandin reuptake/metabolism and nitric oxide production, respectively) were consistently decreased in "Non-Caucasian" DA. Conclusions Prostaglandins and nitric oxide are the most important vasodilators opposing DA closure. Indomethacin inhibits prostaglandin production, but not nitric oxide production. Because decreased SLCO2A1 and NOS3 expression can lead to increased prostaglandin and decreased nitric oxide concentrations, we speculate that prostaglandin-mediated vasodilation may play a more dominant role in maintaining the "Non-Caucasian" PDA, making it more likely to close when inhibited by indomethacin.

Vascular endothelial growth factor polymorphism rs2010963 status does not affect patent ductus arteriosus incidence or cyclooxygenase inhibitor treatment success in preterm infants

“…18 One striking finding is the different ethnic response to cyclooxygenase inhibitor treatment. 19 Our study has only been conducted in a single centre and is therefore unable to examine those relationships. Furthermore, only one polymorphism has been examined and it cannot be excluded that other vascular endothelial growth factor polymorphisms modify ductal closure or pharmacological treatment response.…”

Comparison of Mortality and Morbidity in Syrian and Turkish Premature Babies with Patent Ductus Arteriosus

“…(24) Waleh et al showed that the expression of SLCO2A1 and NOS3 decreased the success of indomethacin and ibuprofen in ductus closure by increasing the prostaglandin synthesis in the Caucasian race. (25) Waleh et al demonstrated that three calcium and potassium-channel genes (CACNA1G/ alpha1G, CACNB2/CaL-beta2, and KCNA2/Kv1.2), were associated with prostaglandin inhibition and emphasized the consideration of these genes in the development of future medical treatment strategies for PDA closure. (26) In another study, Mangones et al investigated the prevalence of congenital heart diseases (CHD) and showed that PDA was most commonly seen in non-hispanic whites.…”

Identification of differentially regulated genes in human patent ductus arteriosus

“…22,23 This is consistent with a number of other studies implying that it may play an important role in ductal transition. [21][22][23][24] In addition, in several human gene polymorphism studies, specific TFAP2B and PTGER4 SNPs were associated with PDA in term and preterm infants, 5,25,26 although another study detected no such association of TFAP2B or AGTR1 SNPs with PDA. 27 Another gene, DLX1, a transcription factor expressed in the embryonic caudal pharyngeal arch complex, where the ductus develops, has been hypothesized to direct BMP4 expression to cause vascular remodeling in DA during late gestation.…”