Frequent mutation of hypoxia-related genes in persistent pulmonary hypertension of the newborn (original) (raw)
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Respiratory Research, 2019
Background: Persistent pulmonary hypertension of the newborn (PPHN) is a severe clinical problem among neonatal intensive care unit (NICU) patients. The genetic pathogenesis of PPHN is unclear. Only a few genetic polymorphisms have been identified in infants with PPHN. Our study aimed to investigate the potential genetic etiology of PPHN. Methods: This study recruited PPHN patients admitted to the NICU of the Children's Hospital of Fudan University from Jan 2016 to Dec 2017. Exome sequencing was performed for all patients. Variants in reported PPHN/pulmonary arterial hypertension (PAH)-related genes were assessed. Single nucleotide polymorphism (SNP) association and gene-level analyses were carried out in 74 PPHN cases and 115 non-PPHN controls with matched baseline characteristics. Results: Among the patient cohort, 74 (64.3%) patients were late preterm and term infants (≥ 34 weeks gestation) and 41 (35.7%) were preterm infants (< 34 weeks gestation). Preterm infants with PPHN exhibited low birth weight and a high frequency of bronchopulmonary dysplasia, respiratory distress syndrome (RDS) and mortality. Nine patients (only one preterm infant) were identified as harboring genetic variants, including three with pathogenic/likely pathogenic variants in TBX4 and BMPR2 and six with variants of unknown significance in BMPR2, SMAD9, TGFB1, KCNA5 and TRPC6. Three SNPs (rs192759073, rs1047883 and rs2229589) in CPS1 and one SNP (rs1044008) in NOTCH3 were significantly associated with PPHN (p < 0.05). CPS1 and SMAD9 were identified as risk genes for PPHN (p < 0.05). Conclusions: In this study, we identified genetic variants in PPHN patients, and we reported CPS1, NOTCH3 and SMAD9 as risk genes for late preterm and term PPHN in a single-center Chinese cohort. Our findings provide additional genetic evidence of the pathogenesis of PPHN and new insight into potential strategies for disease treatment.
Genetics and Genomics of Pulmonary Arterial Hypertension
Journal of the American College of Cardiology, 2013
Major discoveries have been obtained within the last decade in the field of hereditary predisposition to pulmonary arterial hypertension (PAH). Among them, the identification of bone morphogenetic protein receptor type 2 (BMPR2) as the major predisposing gene and activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) as the major gene when PAH is associated with hereditary hemorrhagic telangiectasia. The mutation detection rate for the known genes is approximately 75% in familial PAH, but the mutation shortfall remains unexplained even after careful molecular investigation of these genes. To identify additional genetic variants predisposing to PAH, investigators harnessed the power of next-generation sequencing to successfully identify additional genes that will be described in this report. Furthermore, common genetic predisposing factors for PAH can be identified by genome-wide association studies and are detailed in this paper. The careful study of families and routine genetic diagnosis facilitated natural history studies based on large registries of PAH patients to be set up in different countries. These longitudinal or cross-sectional studies permitted the clinical characterization of PAH in mutation carriers to be accurately described. The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counseling for a severe disease, taking into account that the major predisposing gene has a highly variable penetrance between families. Molecular information can be drawn from the genomic study of affected tissues in PAH, in particular, pulmonary vascular tissues and cells, to gain insight into the mechanisms leading to the development of the disease. High-throughput genomic techniques, on the basis of next-generation sequencing, now allow the accurate quantification and analysis of ribonucleic acid, species, including micro-ribonucleic acids, and allow for a genome-wide investigation of epigenetic or regulatory mechanisms, which include deoxyribonucleic acid methylation, histone methylation, and acetylation, or transcription factor binding.
Gene expression profile in persistent pulmonary hypertension of newborn, preliminary report
2020
Background: Persistent pulmonary hypertension of the newborn (PPHN) is a serious condition with high morbidity and mortality. The therapeutic approach, even today, represents a major challenge. There is considerable interest in the understanding of the signaling pathways that regulate vasoconstriction and pulmonary vascular remodeling. Objective: We set out to identify the expression of genes S100A9 and solutes transporter, as well as their participation in the physiopathological events of PPHN. Design and methods: This is a cross-sectional study that focuses mainly on up- and down-regulated genes involved in endothelial metabolism, hypoxia transporters, ionic and nucleotides metabolism. The total RNA was obtained from blood samples of healthy full-term newborns (negative controls) and patients with PPHN. The preparation of samples for microarray analysis was as follows: control samples were stained with fluorescent nucleotides dUTP-Cy3 and pathological samples with dUTP-Cy5; sample...
Circulation. Cardiovascular genetics, 2014
Human variation in susceptibility to hypoxia-induced pulmonary hypertension is well recognized. High-altitude residents who do not develop pulmonary hypertension may host protective gene mutations. Exome sequencing was conducted on 24 unrelated Kyrgyz highlanders living 2400 to 3800 m above sea level, 12 (10 men; mean age, 54 years) with an elevated mean pulmonary artery pressure (mean±SD, 38.7±2.7 mm Hg) and 12 (11 men; mean age, 52 years) with a normal mean pulmonary artery pressure (19.2±0.6 mm Hg) to identify candidate genes that may influence the pulmonary vascular response to hypoxia. A total of 140 789 exomic variants were identified and 26 116 (18.5%) were classified as novel or rare. Thirty-three novel or rare potential pathogenic variants (frameshift, essential splice-site, and nonsynonymous) were found exclusively in either ≥3 subjects with high-altitude pulmonary hypertension or ≥3 highlanders with a normal mean pulmonary artery pressure. A novel missense mutation in GUC...
Circulation. Genomic and precision medicine, 2018
Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary arteriole remodeling, elevated arterial pressure and resistance, and subsequent heart failure. Compared with adult-onset disease, pediatric-onset PAH is more heterogeneous and often associated with worse prognosis. Although mutations underlie ≈70% of adult familial PAH (FPAH) cases, the genetic basis of PAH in children is less understood. We performed genetic analysis of 155 pediatric- and 257 adult-onset PAH patients, including both FPAH and sporadic, idiopathic PAH (IPAH). After screening for 2 common PAH risk genes, mutation-negative FPAH and all IPAH cases were evaluated by exome sequencing. We observed similar frequencies of rare, deleterious mutations in pediatric- and adult-onset patients: ≈55% in FPAH and 10% in IPAH patients in both age groups. However, there was significant enrichment of mutations in pediatric- compared with adult-onset patients (IPAH: 10/130 pediatric versus 0/178 adult-ons...
E nvironmental hypoxia is an important cause of pulmonary hypertension worldwide. Reducing alveolar Po 2 causes pulmonary vasoconstriction. 1 Chronic exposure to hypoxia leads to pulmonary vascular remodeling, including increased muscularization of distal arterioles, with extension of muscle into previously unmuscularized vessels, and an increase in the collagen and elastin content of the vessel wall. 2 The increased pressure-load on the right ventricle reduces exercise capacity and can lead to right heart failure. Clinical Perspective on p 929 Variation in susceptibility to hypoxia-induced pulmonary hypertension is well recognized, both between and within species, and has a genetic basis. The Tibetans are notably well-adapted to high-altitude life, having lived >3000 m for thousands of years, 3 and are less susceptible than recent migrants to high-altitude pulmonary hypertension. 4 The Kyrgyz have inhabited the high plains of the Tien-Shen and Background-Human variation in susceptibility to hypoxia-induced pulmonary hypertension is well recognized. Highaltitude residents who do not develop pulmonary hypertension may host protective gene mutations. Methods and Results-Exome sequencing was conducted on 24 unrelated Kyrgyz highlanders living 2400 to 3800 m above sea level, 12 (10 men; mean age, 54 years) with an elevated mean pulmonary artery pressure (mean±SD, 38.7±2.7 mm Hg) and 12 (11 men; mean age, 52 years) with a normal mean pulmonary artery pressure (19.2±0.6 mm Hg) to identify candidate genes that may influence the pulmonary vascular response to hypoxia. A total of 140 789 exomic variants were identified and 26 116 (18.5%) were classified as novel or rare. Thirty-three novel or rare potential pathogenic variants (frameshift, essential splice-site, and nonsynonymous) were found exclusively in either ≥3 subjects with high-altitude pulmonary hypertension or ≥3 highlanders with a normal mean pulmonary artery pressure. A novel missense mutation in GUCY1A3 in 3 subjects with a normal mean pulmonary artery pressure encodes an α 1-A680T soluble guanylate cyclase (sGC) variant. Expression of the α 1-A680T sGC variant in reporter cells resulted in higher cyclic guanosine monophosphate production compared with the wild-type enzyme and the purified α 1-A680T sGC exhibited enhanced sensitivity to nitric oxide in vitro. Conclusions-The α 1-A680T sGC variant may contribute to protection against high-altitude pulmonary hypertension and supports sGC as a pharmacological target for reducing pulmonary artery pressure in humans at altitude. (Circ Cardiovasc Genet. 2014;7:920-929.
2016
E nvironmental hypoxia is an important cause of pulmonary hypertension worldwide. Reducing alveolar Po 2 causes pulmonary vasoconstriction. 1 Chronic exposure to hypoxia leads to pulmonary vascular remodeling, including increased muscularization of distal arterioles, with extension of muscle into previously unmuscularized vessels, and an increase in the collagen and elastin content of the vessel wall. 2 The increased pressure-load on the right ventricle reduces exercise capacity and can lead to right heart failure. Clinical Perspective on p 929 Variation in susceptibility to hypoxia-induced pulmonary hypertension is well recognized, both between and within species, and has a genetic basis. The Tibetans are notably well-adapted to high-altitude life, having lived >3000 m for thousands of years, 3 and are less susceptible than recent migrants to high-altitude pulmonary hypertension. 4 The Kyrgyz have inhabited the high plains of the Tien-Shen and Background-Human variation in susceptibility to hypoxia-induced pulmonary hypertension is well recognized. Highaltitude residents who do not develop pulmonary hypertension may host protective gene mutations. Methods and Results-Exome sequencing was conducted on 24 unrelated Kyrgyz highlanders living 2400 to 3800 m above sea level, 12 (10 men; mean age, 54 years) with an elevated mean pulmonary artery pressure (mean±SD, 38.7±2.7 mm Hg) and 12 (11 men; mean age, 52 years) with a normal mean pulmonary artery pressure (19.2±0.6 mm Hg) to identify candidate genes that may influence the pulmonary vascular response to hypoxia. A total of 140 789 exomic variants were identified and 26 116 (18.5%) were classified as novel or rare. Thirty-three novel or rare potential pathogenic variants (frameshift, essential splice-site, and nonsynonymous) were found exclusively in either ≥3 subjects with high-altitude pulmonary hypertension or ≥3 highlanders with a normal mean pulmonary artery pressure. A novel missense mutation in GUCY1A3 in 3 subjects with a normal mean pulmonary artery pressure encodes an α 1-A680T soluble guanylate cyclase (sGC) variant. Expression of the α 1-A680T sGC variant in reporter cells resulted in higher cyclic guanosine monophosphate production compared with the wild-type enzyme and the purified α 1-A680T sGC exhibited enhanced sensitivity to nitric oxide in vitro. Conclusions-The α 1-A680T sGC variant may contribute to protection against high-altitude pulmonary hypertension and supports sGC as a pharmacological target for reducing pulmonary artery pressure in humans at altitude. (Circ Cardiovasc Genet. 2014;7:920-929.
Translational Pediatrics
Background: There is known to be significant genetic involvement in persistent pulmonary hypertension of the newborn (PPHN), but to date there is not a clear understanding of this situation, and clarifying that involvement would be of considerable assistance in devising effective treatments for the disease. This casecontrol study was undertaken to search for genetic variants associated with PPHN in the Thai population using a genome-wide association study (GWAS). Methods: A 659,184 single nucleotide polymorphisms from 387 participants (54 PPHN cases and 333 healthy participants) were genotyped across the human genome using an Illumina Asian Screening Array-24 v1.0 BeadChip Array. After quality control, we obtained 443,063 autosomal SNPs for the GWAS analysis. The FaST-LMM and R packages were used for all statistical analyses. Results: For the case-control analysis, the genomic inflation factor (λ) was 1.016, rs149768622 T>C in the first intron of WWC2 gene showed the strongest association with a P value of 3.76E-08 and odds ratio (OR) of 13.24 (95%
Defining the Clinical Validity of Genes Reported to Cause Pulmonary Arterial Hypertension
ABSTRACTBACKGROUNDPulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. The disease is caused by both genetic and environmental factors, with genetic variants in at least 27 genes displaying putative evidence for disease causality. Genetic testing is currently recommended for adults diagnosed with heritable or idiopathic PAH, and all children diagnosed with PAH. However, testing panels vary in the number and list of genes included, and exome/genome sequencing data may reveal variants in genes with varying levels of evidence for a relationship with PAH.METHODSAn international panel of clinical and scientific experts in PAH was formed to perform an evidence-based review of heritable and idiopathic PAH gene-disease relationships. The panel performed literature searches and applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of PAH gene-dis...
Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways
Pulmonary hypertension (PH) is a serious disorder with high morbidity and mortality rate. We analyzed the right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), lung histology and transcriptomes of six weeks old male rats with PH induced by: 1) hypoxia (HO), 2) administration of monocrotaline (CM) or 3) administration of monocrotaline and exposure to hypoxia (HM). The results in PH rats were compared to those in control rats (CO). After four weeks exposure, increased RVSP and RVH, pulmonary arterial wall thickening, and alteration of the lung transcriptome were observed in all PH groups. The HM group exhibited the largest alterations and also neointimal lesions and obliteration of lumen in small arteries. We found that the PH increased the expression of caveolin1, matrix metallopeptidase 2 and numerous inflammatory and cell proliferation genes. The cell-cycle, vascular smooth muscle contraction and the oxidative phosphorylation pathways, as well as their in...