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Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn.

ABSTRACT: Persistent pulmonary hypertension of the newborn (PPHN) is associated with substantial infant morbidity and mortality. Recently, genetic associations have been found in idiopathic pulmonary arterial hypertension.PPHN was significantly (P < 0.05) associated with genetic variants in corticotropin-releasing hormone (CRH) receptor 1, CRHR1 and CRH-binding protein, CRHBP. Association with CRHR1 rs4458044 passed the Bonferroni threshold for significance. No mutations were found in the bone morphogenetic protein receptor type II (BMPR2) gene.We describe previously unreported genetic associations between PPHN and CRHR1 and CRHBP. These findings may have implications for further understanding the pathophysiology of PPHN and treatment.We performed a family-based candidate gene study to examine a genetic association with PPHN and sequenced the BMPR2 gene in 72 individuals. We enrolled 110 families with infants diagnosed with PPHN based on inclusion criteria. After medical chart review, 22 subjects were excluded based on predefined criteria, and DNA samples from 88 affected infants and at least one parent per infant were collected and genotyped. Thirty-two single-nucleotide polymorphisms in 12 genes involved in vasoconstriction/vasodilation, lung development, surfactant regulation, or vascular endothelial cell function were investigated using family-based association tests.

SUBMITTER: Byers HM

PROVIDER: S-EPMC3718388 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn.

Byers Heather M HM Dagle John M JM Klein Jonathan M JM Ryckman Kelli K KK McDonald Erin L EL Murray Jeffrey C JC Borowski Kristi S KS

Pediatric research 20111221 2

<h4>Introduction</h4>Persistent pulmonary hypertension of the newborn (PPHN) is associated with substantial infant morbidity and mortality. Recently, genetic associations have been found in idiopathic pulmonary arterial hypertension.<h4>Results</h4>PPHN was significantly (P < 0.05) associated with genetic variants in corticotropin-releasing hormone (CRH) receptor 1, CRHR1 and CRH-binding protein, CRHBP. Association with CRHR1 rs4458044 passed the Bonferroni threshold for significance. No mutatio ...[more]

PMID: 22258127

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Project description:BACKGROUND:Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome characterized by suboptimal oxygenation as a result of sustained elevation in pulmonary vascular resistance after birth. Currently, the therapeutic mainstay for PPHN is optimal lung inflation and selective vasodilatation with inhaled nitric oxide (iNO). However, iNO is not available in all countries and not all infants will respond to iNO. Milrinone is a phosphodiesterase III inhibitor which induces pulmonary vasodilatation by its actions through a cyclic adenylate monophosphate mediated signaling pathway. OBJECTIVES:To assess efficacy and safety in infants with PPHN either treated with: milrinone compared with placebo or no treatment; milrinone compared with iNO; milrinone as an adjunct to iNO compared with iNO alone; milrinone compared with potential treatments for PPHN other than iNO. SEARCH STRATEGY:We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2010), MEDLINE and EMBASE databases from their inception until January 2010. We searched the reference lists of potentially relevant studies without any language restriction. SELECTION CRITERIA:Fully published randomized controlled trials (RCTs) and quasi-RCTs comparing milrinone with placebo, iNO or potential treatments other than iNO in neonates with PPHN were included if trials reported any clinical outcome. DATA COLLECTION AND ANALYSIS:We found no studies meeting the criteria for inclusion in this review. MAIN RESULTS:We found no studies meeting the criteria for inclusion in this review. AUTHORS' CONCLUSIONS:The efficacy and safety of milrinone in the treatment of PPHN are not known and its use should be restricted within the context of RCTs. Such studies should address a comparison of milrinone with placebo (in clinical situations where iNO is not available) or, in well resourced countries, should compare milrinone with iNO or as an adjunct to iNO compared with iNO alone.

Project description:AIMS:Persistent pulmonary hypertension of the newborn (PPHN) is characterized by sustained high levels of pulmonary vascular resistance after birth with etiology unclear; Arterial blood oxygen saturation of Tibetan newborns at high latitudes is higher than that of Han newborns at low latitudes, suggesting that genetic adaptation may allow sufficient oxygen to confer Tibetan populations with resistance to pulmonary hypertension; We have previously identified genetic factors related to PPHN through candidate gene sequencing; In this study, we first performed whole exome sequencing in PPHN patients to screen for genetic-related factors. METHODS AND RESULTS:In this two-phase genetic study, we first sequenced the whole exome of 20 Tibetan PPHN patients and compared it with the published genome sequences of 50 healthy high-altitude Tibetanshypoxia-related genes, a total of 166 PPHN-related variants were found, of which 49% were from 43 hypoxia-related genes; considering many studies have shown that the differences in the genetic background between Tibet and Han are characterized by hypoxia-related genetic polymorphisms, so it is necessary to further verify whether the association between hypoxia-related variants and PPHN is independent of high-altitude life. During the validation phase, 237 hypoxia-related genes were sequenced in another 80 Han PPHN patients living in low altitude areas, including genes at the discovery stage and known hypoxia tolerance, of which 413 variants from 127 of these genes were shown to be significantly associated with PPHN.hypoxia-related genes. CONCLUSIONS:Our results indicates that the association of hypoxia-related genes with PPHN does not depend on high-altitude life, at the same time, 21 rare mutations associated with PPHN were also found, including three rare variants of the tubulin tyrosine ligase-like family member 3 gene (TTLL3:p.E317K, TTLL3:p.P777S) and the integrin subunit alpha M gene (ITGAM:p.E1071D). These novel findings provide important information on the genetic basis of PPHN.

Project description:The association between selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and risk of persistent pulmonary hypertension of the newborn (PPHN) has been controversial since the US Food and Drug Administration issued a public health advisory in 2006.To examine the risk of PPHN associated with exposure to different antidepressant medication classes late in pregnancy.Cohort study nested in the 2000-2010 Medicaid Analytic eXtract for 46 US states and Washington, DC. Last follow-up date was December 31, 2010.A total of 3,789,330 pregnant women enrolled in Medicaid from 2 months or fewer after the date of last menstrual period through at least 1 month after delivery. The source cohort was restricted to women with a depression diagnosis and logistic regression analysis with propensity score adjustment applied to control for potential confounders. EXPOSURES FOR OBSERVATIONAL STUDIES: SSRI and non-SSRI monotherapy use during the 90 days before delivery vs no use.Recorded diagnosis of PPHN during the first 30 days after delivery.A total of 128,950 women (3.4%) filled at least 1 prescription for antidepressants late in pregnancy: 102,179 (2.7%) used an SSRI and 26,771 (0.7%) a non-SSRI. Overall, 7630 infants not exposed to antidepressants were diagnosed with PPHN (20.8; 95% CI, 20.4-21.3 per 10,000 births) compared with 322 infants exposed to SSRIs (31.5; 95% CI, 28.3-35.2 per 10,000 births), and 78 infants exposed to non-SSRIs (29.1; 95% CI, 23.3-36.4 per 10,000 births). Associations between antidepressant use and PPHN were attenuated with increasing levels of confounding adjustment. For SSRIs, odds ratios were 1.51 (95% CI, 1.35-1.69) unadjusted and 1.10 (95% CI, 0.94-1.29) after restricting to women with depression and adjusting for the high-dimensional propensity score. For non-SSRIs, the odds ratios were 1.40 (95% CI, 1.12-1.75) and 1.02 (95% CI, 0.77-1.35), respectively. Upon restriction of the outcome to primary PPHN, the adjusted odds ratio for SSRIs was 1.28 (95% CI, 1.01-1.64) and for non-SSRIs 1.14 (95% CI, 0.74-1.74).Evidence from this large study of publicly insured pregnant women may be consistent with a potential increased risk of PPHN associated with maternal use of SSRIs in late pregnancy. However, the absolute risk was small, and the risk increase appears more modest than suggested in previous studies.

Project description:IntroductionPersistent pulmonary hypertension of the newborn (PPHN) is a life-threatening condition characterized by hypoxemia due to elevated pulmonary vascular resistance. PPHN commonly arises secondary to various underlying conditions, including infection, meconium aspiration, and respiratory distress syndrome. Management includes pulmonary vasodilators, mechanical ventilation, oxygen supplementation, vasopressors, and volume replacement. Stüve-Wiedemann syndrome (SWS), a rare genetic disorder characterized by bone dysplasia, respiratory distress, hyperthermia, and swallowing difficulties, may present with pulmonary hypertension, indicating a poor prognosis.Case descriptionA term female neonate presented with secondary respiratory failure and severe PPHN of unknown etiology on the second day of life, necessitating intubation. Clinical findings included facial dysmorphia, camptodactyly, skeletal anomalies, and generalized muscular hypotonia. High-frequency oscillation ventilation and surfactant administration yielded marginal improvement. On the third day of life, a severe pulmonary hypertensive crisis necessitated inhaled and systemic pulmonary vasodilators along with volume and catecholamine therapy. Whole exome sequencing revealed a homozygous mutation in the leukemia inhibitory factor receptor (LIFR) gene, consistent with Stüve-Wiedemann syndrome.Discussion/conclusionThe case underscores the importance of considering and prompting evaluation of rare genetic causes in the differential diagnosis of PPHN, especially when other abnormalities are present and conventional therapies prove inadequate. Therapeutic strategies must account for the different pathophysiology of primary PPHN including vascular remodeling, as seen in SWS, which may not respond to pulmonary vasodilators typically employed in secondary PPHN due to vasoconstriction. In this case, the patient responded well to treatment for primary PPHN, but the use of high-frequency oscillation ventilation and surfactant was not helpful.

Project description:ObjectiveTo examine the risk for persistent pulmonary hypertension of the newborn associated with antenatal exposure to antidepressants.DesignSystematic review and meta-analysis.Data sourcesEmbase, Medline, PsycINFO, and CINAHL from inception to 30 December 2012.EligibilityEnglish language studies reporting persistent pulmonary hypertension of the newborn associated with exposure to antidepressants. Two independent reviewers extracted data and assessed the quality of each article.ResultsOf the 3077 abstracts reviewed, 738 papers were retrieved and seven included. All seven studies were above our quality threshold. Quantitative analysis was only possible for selective serotonin reuptake inhibitors (SSRIs). Although exposure to SSRIs in early pregnancy was not associated with persistent pulmonary hypertension of the newborn (odds ratio 1.23, 95% confidence interval 0.58 to 2.60; P=0.58), exposure in late pregnancy was (2.50, 1.32 to 4.73; P=0.005). Effects were not significant for any of the moderator variables examined, including study design, congenital malformations, and meconium aspiration. It was not possible to assess for the effect of caesarean section, body mass index, or preterm delivery. The absolute risk difference for development of persistent pulmonary hypertension of the newborn after exposure to SSRIs in late pregnancy was 2.9 to 3.5 per 1000 infants; therefore an estimated 286 to 351 women would need to be treated with an SSRI in late pregnancy to result in an average of one additional case of persistent pulmonary hypertension of the newborn.ConclusionsThe risk of persistent pulmonary hypertension of the newborn seems to be increased for infants exposed to SSRIs in late pregnancy, independent of the potential moderator variables examined. A significant relation for exposure to SSRIs in early pregnancy was not evident. Although the statistical association was significant, clinically the absolute risk of persistent pulmonary hypertension of the newborn remained low even in the context of late exposure to SSRIs.

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Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn.

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Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn.

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