Patterns of gene expression in the ductus arteriosus are related to environmental and genetic risk factors for persistent ductus patency.
Three independent risk factors (immature gestation, absence of antenatal glucocorticoid exposure, and presence of the rs2817399(A) allele of the gene TFAP2B) are associated with patent ductus arteriosus (PDAs) that fail to close during prostaglandin inhibition. We hypothesized that these three factors may affect a common set of genes that increase the risk of persistent PDA after birth. We studied baboon ductus from term, preterm, and glucocorticoid-treated preterm fetuses and found that both immature gestation and absence of antenatal glucocorticoid exposure decreased RNA expression of calcium- and potassium-channel genes involved in oxygen-induced constriction, and phosphodiesterase genes (that modulate cAMP/cGMP signaling). Ductus obtained from second trimester human pregnancies were genotyped for TFAP2B polymorphisms. When present, the rs2817399(A) allele also was associated with decreased expression of calcium- and potassium-channel genes. In contrast, alleles of two other TFAP2B polymorphisms, rs2817419(G) and rs2635727(T), which are not related to the incidence of PDA after birth, had no effect on RNA expression. In conclusion, three calcium- and potassium-channel genes (CACNA1G/ alpha1G, CACNB 2/CaL-beta2, and KCNA2/ Kv1.2) were similarly affected by each of the PDA risk factors. We speculate that these channels may play a significant role in closing the preterm ductus during prostaglandin inhibition and may be potential targets for future pharmacologic manipulations.
Waleh
Nahid
N
Pharmaceutical Discovery Division, SRI International, Menlo Park, California 94025, USA.
Hodnick
Ryan
R
Jhaveri
Nami
N
McConaghy
Suzanne
S
Dagle
John
J
Seidner
Steven
S
McCurnin
Donald
D
Murray
Jeffrey C
JC
Ohls
Robin
R
Clyman
Ronald I
RI
D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics; D020747:Calcium Channels, T-Type / Q000235:genetics; D004334:Drug Administration Schedule; D004373:Ductus Arteriosus / Q000196:embryology*; D004374:Ductus Arteriosus, Patent / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D005865:Gestational Age; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D051663:Kv1.2 Potassium Channel / Q000235:genetics; D016014:Linear Models; D016015:Logistic Models; D010215:Papio; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis; D018570:Risk Assessment; D012307:Risk Factors
C121855:CACNA1G protein, human; C107597:CACNB2 protein, human; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D005938:Glucocorticoids; C496969:KCNA2 protein, human; D051663:Kv1.2 Potassium Channel; D012333:RNA, Messenger