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Surfactant protein-C promoter variants associated with neonatal respiratory distress syndrome reduce transcription.

ABSTRACT: Dominant mutations in coding regions of the surfactant protein-C gene, SFTPC, cause respiratory distress syndrome (RDS) in infants. However, the contribution of variants in noncoding regions of SFTPC to pulmonary phenotypes is unknown. By using a case-control group of infants > or =34 weeks gestation (n = 538), we used complete resequencing of SFTPC and its promoter, genotyping, and logistic regression to identify 80 single nucleotide polymorphisms (SNPs). Three promoter SNPs were statistically associated with neonatal RDS among European descent infants. To assess the transcriptional effects of these three promoter SNPs, we selectively mutated the SFTPC promoter and performed transient transfection using MLE-15 cells and a firefly luciferase reporter vector. Each promoter SNP decreased SFTPC transcription. The combination of two variants in high linkage dysequilibrium also decreased SFTPC transcription. In silico evaluation of transcription factor binding demonstrated that the rare allele at g.-1167 disrupts a SOX (SRY-related high mobility group box) consensus motif and introduces a GATA-1 site, at g.-2385 removes a MZF-1 (myeloid zinc finger) binding site, and at g.-1647 removes a potential methylation site. This combined statistical, in vitro, and in silico approach suggests that reduced SFTPC transcription contributes to the genetic risk for neonatal RDS in developmentally susceptible infants.

SUBMITTER: Wambach JA

PROVIDER: S-EPMC2921462 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Surfactant protein-C promoter variants associated with neonatal respiratory distress syndrome reduce transcription.

Wambach Jennifer A JA Yang Ping P Wegner Daniel J DJ An Ping P Hackett Brian P BP Cole F S FS Hamvas Aaron A

Pediatric research 20100901 3

Dominant mutations in coding regions of the surfactant protein-C gene, SFTPC, cause respiratory distress syndrome (RDS) in infants. However, the contribution of variants in noncoding regions of SFTPC to pulmonary phenotypes is unknown. By using a case-control group of infants > or =34 weeks gestation (n = 538), we used complete resequencing of SFTPC and its promoter, genotyping, and logistic regression to identify 80 single nucleotide polymorphisms (SNPs). Three promoter SNPs were statistically ...[more]

PMID: 20539253

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Project description:Increased nicotinamide phosphoribosyltransferase (NAMPT) transcription is mechanistically linked to ventilator-induced inflammatory lung injury (VILI), with VILI severity attenuated by reduced NAMPT bioavailability. The molecular mechanisms of NAMPT promoter regulation in response to excessive mechanical stress remain poorly understood. The objective of this study was to define the contribution of specific transcription factors, acute respiratory distress syndrome (ARDS)-associated single nucleotide polymorphisms (SNPs), and promoter demethylation to NAMPT transcriptional regulation in response to mechanical stress. In vivo NAMPT protein expression levels were examined in mice exposed to high tidal volume mechanical ventilation. In vitro NAMPT expression levels were examined in human pulmonary artery endothelial cells exposed to 5 or 18% cyclic stretch (CS), with NAMPT promoter activity assessed using NAMPT promoter luciferase reporter constructs with a series of nested deletions. In vitro NAMPT transcriptional regulation was further characterized by measuring luciferase activity, DNA demethylation, and chromatin immunoprecipitation. VILI-challenged mice exhibited significantly increased NAMPT expression in bronchoalveolar lavage leukocytes and in lung endothelium. A mechanical stress-inducible region (MSIR) was identified in the NAMPT promoter from -2,428 to -2,128 bp. This MSIR regulates NAMPT promoter activity, mRNA expression, and signal transducer and activator of transcription 5 (STAT5) binding, which is significantly increased by 18% CS. In addition, NAMPT promoter activity was increased by pharmacologic promoter demethylation and inhibited by STAT5 silencing. ARDS-associated NAMPT promoter SNPs rs59744560 (-948G/T) and rs7789066 (-2,422A/G) each significantly elevated NAMPT promoter activity in response to 18% CS in a STAT5-dependent manner. Our results show that NAMPT is a key novel ARDS therapeutic target and candidate gene with genetic/epigenetic transcriptional regulation in response to excessive mechanical stress.

Project description:Background/Aims: Nasal continuous positive airway pressure (nCPAP) was recommended as the initial respiratory support for spontaneous breathing in infants with very low birth weight and neonatal respiratory distress syndrome (NRDS). Less invasive surfactant administration (LISA) and minimally invasive surfactant therapy (MIST) have been reported to reduce the incidence of bronchopulmonary dysplasia (BPD). This study aimed to explore the applicability of minimally invasive surfactant administration (MISA) in China. Materials and Methods: MISA was a randomized controlled study conducted at eight level III neonatal intensive care units (NICUs) in China. Spontaneously breathing infants born at 25+0 to 31+6 weeks' gestation who progressively developed respiratory distress during the first 6 h after birth were randomly assigned to receive MISA or endotracheal intubation surfactant administration (EISA). The primary outcome was the difference in the morbidity of BPD between two groups of infants with MISA and EISA at 36 weeks corrected gestational age. Results: Demographic and clinical characteristics of the 151 infants in the MISA group were similar to the 147 infants in the EISA group. The comparison showed no clear benefits in the MISA group in the incidence of BPD, while infants from the EISA group had higher rates of patent ductus arteriosus (PDA) (60.5 vs. 41.1%, p = 0.001). The duration of surfactant infusion and the total time of surfactant administration in the MISA group were significantly longer than in the EISA group. A slightly increased heart rate was noted 1 h post surfactant administration in the EISA group. In subgroup analysis, the comparison of 51 smaller (<30 weeks) preterm infants, named MISAs (n = 31) and EISAs (n = 20), showed a significant reduction of BPD (29.0 vs. 70.0%, p = 0.004) and PDA (29.0 vs. 65.0%, p = 0.011). In the subgroup analysis of blood gas, arterial oxygen saturation (SaO2) value at 1 and 12 h and partial pressure of arterial oxygen (PaO2) at 12 h were all higher in the EISA group compared to the MISA group. Conclusion: MISA had no clear benefit on the incidence of BPD, but it was related to a reduction in PDA. It is an appropriate therapy for spontaneous breathing in infants with extremely low birth weight and NRDS.

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Surfactant protein-C promoter variants associated with neonatal respiratory distress syndrome reduce transcription.

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Surfactant protein-C promoter variants associated with neonatal respiratory distress syndrome reduce transcription.

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