An EGLN1 mutation may regulate hypoxic response in cyanotic congenital heart disease through the PHD2/HIF-1A pathway.

Cyanotic congenital heart disease (CCHD), a term describing the most severe congenital heart diseases are characterized by the anatomic malformation of a right to left shunt. Although the incidence of CCHD are far less than the that of congenital heart diseases (CHD), patients with CCHD always present severe clinical features such as hypoxia, dyspnea, and heart failure. Chronic hypoxia induces hypoxemia that significantly contributes to poor prognosis in CCHD. Current studies have demonstrated that the prolyl-4-hydroxylase2 ( encoded by )/hypoxia-inducible factor-1A () pathway is a key regulator of hypoxic response. Thus, we aim to assess the associations of single polymorphisms (SNPs) of the gene and hypoxic response in CCHD. A missense variant of c.380G>C (rs1209790) was found in 46 patients (46/126), with lower hypoxia incidence and higher rate of collateral vessel formation, compared with the wild type ( < 0.05). experiments, during hypoxia, mutation reduced expression compared with the wild type, with higher , and expression levels in the mutant. No difference in HK1 expression was observed between the mutant and wild type. CCHD patients with c.380G>C showed improved response to hypoxia compared with the wild-type counterparts. The c.380G>C mutation improves hypoxic response through the pathway, which may provide a molecular mechanism for hypoxic response in CCHD. The effects of the c.380G>C mutation on CCHD prognosis deserve further investigation.