Association of the <i>EPAS1</i> rs7557402 Polymorphism with Hemodynamically Significant Patent Ductus Arteriosus Closure Failure in Premature Newborns under Pharmacological Treatment with Ibuprofen
Diana G. Rogel-Ayala,
José Esteban Muñoz-Medina,
Valeria Dejanira Vicente-Juárez,
Patricia Grether-González,
Deneb Algedi Morales-Barquet,
Alfonso de Jesús Martínez-García,
María Olga Leticia Echaniz-Aviles,
Rosalba Sevilla-Montoya,
Alejandro Martínez-Juárez,
Jazmin Artega-Vázquez,
Javier Angeles-Martínez,
Gilberto Vargas-Alarcón,
Alberto Hidalgo-Bravo,
Irma Eloisa Monroy-Muñoz
Affiliations
Diana G. Rogel-Ayala
Reproductive and Perinatal Health Research Department, National Institute of Perinatology, Mexico City 11000, Mexico
José Esteban Muñoz-Medina
Quality of Supplies and Specialized Laboratories Coordination, Mexican Social Security Institute, Mexico City 37320, Mexico
Valeria Dejanira Vicente-Juárez
Reproductive and Perinatal Health Research Department, National Institute of Perinatology, Mexico City 11000, Mexico
Patricia Grether-González
ABC Medical Center, Santa Fe, Mexico City 05348, Mexico
Deneb Algedi Morales-Barquet
Neonatal Intensive Care Unit, National Institute of Perinatology, Mexico City 11000, Mexico
Alfonso de Jesús Martínez-García
Fetal Maternal Medicine Department, National Institute of Perinatology, Mexico City 11000, Mexico
María Olga Leticia Echaniz-Aviles
Newborn Intermediate Care Unit, National Institute of Perinatology, Mexico City 11000, Mexico
Rosalba Sevilla-Montoya
Reproductive and Perinatal Health Research Department, National Institute of Perinatology, Mexico City 11000, Mexico
Alejandro Martínez-Juárez
Cellular Physiology Department, National Institute of Perinatology, Mexico City 11000, Mexico
Jazmin Artega-Vázquez
Department of Genetics, National Institute of Medical Science and Nutrition, Mexico City 14080, Mexico
Javier Angeles-Martínez
Specialized Laboratories Division, Mexican Social Security Institute, Mexico City 06700, Mexico
Gilberto Vargas-Alarcón
Department of Molecular Biology, National Institute of Cardiology, Mexico City 14080, Mexico
Alberto Hidalgo-Bravo
Genomics Medicine Department, National Institute of Rehabilitation, Mexico City 14610, Mexico
Irma Eloisa Monroy-Muñoz
Reproductive and Perinatal Health Research Department, National Institute of Perinatology, Mexico City 11000, Mexico
Patent ductus arteriosus (PDA) is frequent in preterm newborns, and its incidence is inversely associated with the degree of prematurity. The first choice of pharmacological treatment is ibuprofen. Several genes, including EPAS1, have been proposed as probable markers associated with a genetic predisposition for the development of PDA in preterm infants. EPAS 1 NG_016000.1:g.84131C>G or rs7557402 has been reported to be probably benign and associated with familial erythrocytosis by the Illumina Clinical Services Laboratory. Other variants of EPAS1 have been previously reported to be benign for familial erythrocytosis because they decrease gene function and are positive for familial erythrocytosis because the overexpression of EPAS1 is a key factor in uncontrolled erythrocyte proliferation. However, this could be inconvenient for ductal closure, since for this process to occur, cell proliferation, migration, and differentiation should take place, and a decrease in EPAS1 gene activity would negatively affect these processes. Single-nucleotide polymorphisms (SNPs) in EPAS1 and TFAP2B genes were searched with high-resolution melting and Sanger sequencing in blood samples of preterm infants with hemodynamically significant PDA treated with ibuprofen at the National Institute of Perinatology. The variant rs7557402, present in the EPAS1 gene eighth intron, was associated with a decreased response to treatment (p = 0.007, OR = 3.53). The SNP rs7557402 was associated with an increased risk of pharmacological treatment failure. A probable mechanism involved could be the decreased activity of the product of the EPAS1 gene.
