Genetics and genomics of pulmonary arterial hypertension Morrell, Nicholas W; Aldred, Micheala A; Chung, Wendy K ...
European respiratory journal/The European respiratory journal,
01/2019, Letnik:
53, Številka:
1
Journal Article
Recenzirano
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Since 2000 there have been major advances in our understanding of the genetic and genomics of pulmonary arterial hypertension (PAH), although there remains much to discover. Based on existing ...knowledge, around 25-30% of patients diagnosed with idiopathic PAH have an underlying Mendelian genetic cause for their condition and should be classified as heritable PAH (HPAH). Here, we summarise the known genetic and genomic drivers of PAH, the insights these provide into pathobiology, and the opportunities afforded for development of novel therapeutic approaches. In addition, factors determining the incomplete penetrance observed in HPAH are discussed. The currently available approaches to genetic testing and counselling, and the impact of a genetic diagnosis on clinical management of the patient with PAH, are presented. Advances in DNA sequencing technology are rapidly expanding our ability to undertake genomic studies at scale in large cohorts. In the future, such studies will provide a more complete picture of the genetic contribution to PAH and, potentially, a molecular classification of this disease.
The Genetics of Pulmonary Arterial Hypertension Austin, Eric D; Loyd, James E
Circulation research,
2014-June-20, 2014-Jun-20, 2014-06-20, 20140620, Letnik:
115, Številka:
1
Journal Article
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Pulmonary arterial hypertension (PAH) is a progressive and fatal disease for which there is an ever-expanding body of genetic and related pathophysiological information on disease pathogenesis. Many ...germline gene mutations have now been described, including mutations in the gene coding bone morphogenic protein receptor type 2 (BMPR2) and related genes. Recent advanced gene-sequencing methods have facilitated the discovery of additional genes with mutations among those with and those without familial forms of PAH (CAV1, KCNK3, EIF2AK4). The reduced penetrance, variable expressivity, and female predominance of PAH suggest that genetic, genomic, and other factors modify disease expression. These multi-faceted variations are an active area of investigation in the field, including but not limited to common genetic variants and epigenetic processes, and may provide novel opportunities for pharmacological intervention in the near future. They also highlight the need for a systems-oriented multi-level approach to incorporate the multitude of biological variations now associated with PAH. Ultimately, an in-depth understanding of the genetic factors relevant to PAH provides the opportunity for improved patient and family counseling about this devastating disease.
The genetic basis of idiopathic pulmonary fibrosis Kropski, Jonathan A; Blackwell, Timothy S; Loyd, James E
European respiratory journal/The European respiratory journal,
06/2015, Letnik:
45, Številka:
6
Journal Article
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Throughout the past decade, there have been substantial advances in understanding the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recently, several large genome-wide association and linkage ...studies have identified common genetic variants in more than a dozen loci that appear to contribute to IPF risk. In addition, family-based studies have led to the identification of rare genetic variants in genes related to surfactant function and telomere biology, and mechanistic studies suggest pathophysiological derangements associated with these rare genetic variants are also found in sporadic cases of IPF. Current evidence suggests that rather than existing as distinct syndromes, sporadic and familial cases of IPF (familial interstitial pneumonia) probably reflect a continuum of genetic risk. Rapidly evolving bioinformatic and molecular biology techniques, combined with next-generation sequencing technologies, hold great promise for developing a comprehensive, integrated approach to defining the fundamental molecular mechanisms that underlie IPF pathogenesis.
Genetics and Genomics of Pulmonary Arterial Hypertension Soubrier, Florent, MD, PhD; Chung, Wendy K., MD, PhD; Machado, Rajiv, PhD ...
Journal of the American College of Cardiology,
12/2013, Letnik:
62, Številka:
25
Journal Article, Conference Proceeding
Recenzirano
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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.
Background: From 1984 to 2006, studies of sleep in patients with interstitial lung disease revealed disturbed sleep, frequent nocturnal
desaturations, nocturnal cough, and obstructive sleep apnea ...(OSA). Our goal was to analyze OSA in an outpatient population
of stable patients with idiopathic pulmonary fibrosis (IPF).
Methods: Patients with IPF who had been followed up in the Vanderbilt Pulmonary Clinic were asked to participate. All patients were
given a diagnosis of IPF by the 2000 American Thoracic Society consensus statement criteria. Subjects completed an Epworth
sleepiness scale (ESS) questionnaire and a sleep apnea scale of sleep disorders questionnaire (SA-SDQ) before undergoing nocturnal
polysomnography (NPSG). OSA was defined as an apnea-hypopnea index (AHI) of > 5 events per hour.
Results: Fifty subjects enrolled and completed a NPSG. The mean age was 64.9 years, and the mean BMI was 32.3. OSA was diagnosed in
88% of subjects. Ten subjects (20%) had mild OSA (AHI, 5 to 15 events per hour), and 34 subjects (68%) had moderate-to-severe
OSA (AHI, > 15 events per hour). Only 6 subjects (12%) had a normal AHI. One patient was asymptomatic as determined by ESS
and SA-SDQ, but had an AHI of 24 events per hour. The sensitivity of the ESS was 75% with a specificity of 15%, whereas the
SA-SDQ had a sensitivity of 88% with a specificity of 50%. BMI did not correlate strongly with AHI ( r = 0.30; p = 0.05).
Conclusions: OSA is prevalent in patients with IPF and may be underrecognized by primary care providers and specialists. Neither ESS nor
SA-SDQ alone or in combination was a strong screening tool. Given the high prevalence found in our sample, formal sleep evaluation
and polysomnography should be considered in patients with IPF.
Variants in the gene encoding mucin 5B (
MUC5B
) have been associated with interstitial fibrosis. This study shows a relationship between the presence of the associated variants in
MUC5B
and ...interstitial lung abnormalities in participants in a Framingham study cohort.
Subclinical interstitial lung abnormalities are relatively common findings on imaging studies in smokers and elderly persons.
1
Accumulating evidence suggests that these abnormalities may precede the development of clinically relevant pulmonary fibrosis.
1
–
7
However, it is not known whether there is a genetic association between interstitial lung abnormalities and pulmonary fibrosis in the general population.
Recently, a single-nucleotide polymorphism (SNP) (rs35705950) in the promoter of the gene encoding mucin 5B (
MUC5B
) was shown to be associated with both familial interstitial pneumonia and sporadic idiopathic pulmonary fibrosis.
8
In addition, the
MUC5B
variant was associated with increased expression of MUC5B in . . .
Analysis of the age of onset in heritable pulmonary arterial hypertension (HPAH) has led to the hypothesis that genetic anticipation causes younger age of onset and death in subsequent generations. ...With accrual of pedigree data over multiple decades, we retested this hypothesis using analyses that eliminate the truncation of data that exists with shorter duration of follow-up.
To analyze the pedigrees of families with mutations in bone morphogenetic protein receptor type 2 (BMPR2), afflicted in two or more generations with HPAH, eliminating time truncation bias by including families for whom we have at least 57 years of data.
We analyzed 355 individuals with BMPR2 mutations from 53 families in the Vanderbilt Pulmonary Hypertension Registry. We compared age at diagnosis or death in affected individuals (n = 249) by generation within families with multigenerational disease. We performed linear mixed effects models and we limited time-truncation bias by restricting date of birth to before 1955. This allowed for 57 years of follow-up (1955-2012) for mutation carriers to develop disease. We also conducted Kaplan-Meier analysis to include currently unaffected mutation carriers (n = 106).
Differences in age at diagnosis by generation were found in a biased analysis that included all birth years to the present, but this finding was eliminated when the 57-year observation limit was imposed. By Kaplan-Meier analysis, inclusion of currently unaffected mutation carriers strengthens the observation that bias of ascertainment exists when recent generations are included.
Genetic anticipation is likely an artifact of incomplete time of observation of kindreds with HPAH due to BMPR2 mutations.
Pulmonary fibrosis (PF) is a form of chronic lung disease characterized by pathologic epithelial remodeling and accumulation of extracellular matrix (ECM). To comprehensively define the cell types, ...mechanisms, and mediators driving fibrotic remodeling in lungs with PF, we performed single-cell RNA sequencing of single-cell suspensions from 10 nonfibrotic control and 20 PF lungs. Analysis of 114,396 cells identified 31 distinct cell subsets/states. We report that a remarkable shift in epithelial cell phenotypes occurs in the peripheral lung in PF and identify several previously unrecognized epithelial cell phenotypes, including a
/
pathologic, ECM-producing epithelial cell population that was highly enriched in PF lungs. Multiple fibroblast subtypes were observed to contribute to ECM expansion in a spatially discrete manner. Together, these data provide high-resolution insights into the complexity and plasticity of the distal lung epithelium in human disease and indicate a diversity of epithelial and mesenchymal cells contribute to pathologic lung fibrosis.
Idiopathic pulmonary arterial hypertension (IPAH) is usually without an identified genetic cause, despite clinical and molecular similarity to bone morphogenetic protein receptor type 2 ...mutation-associated heritable pulmonary arterial hypertension (PAH). There is phenotypic heterogeneity in IPAH, with a minority of patients showing long-term improvement with calcium channel-blocker therapy.
We sought to identify gene variants (GVs) underlying IPAH and determine whether GVs differ in vasodilator-responsive IPAH (VR-PAH) versus vasodilator-nonresponsive IPAH (VN-PAH).
We performed whole-exome sequencing (WES) on 36 patients with IPAH: 17 with VR-PAH and 19 with VN-PAH. Wnt pathway differences were explored in human lung fibroblasts.
We identified 1,369 genes with 1,580 variants unique to IPAH. We used a gene ontology approach to analyze variants and identified overrepresentation of several pathways, including cytoskeletal function and ion binding. By mapping WES data to prior genome-wide association study data, Wnt pathway genes were highlighted. Using the connectivity map to define genetic differences between VR-PAH and VN-PAH, we found enrichment in vascular smooth muscle cell contraction pathways and greater genetic variation in VR-PAH versus VN-PAH. Using human lung fibroblasts, we found increased stimulated Wnt activity in IPAH versus controls.
A pathway-based analysis of WES data in IPAH demonstrated multiple rare GVs that converge on key biological pathways, such as cytoskeletal function and Wnt signaling pathway. Vascular smooth muscle contraction-related genes were enriched in VR-PAH, suggesting a potentially different genetic predisposition for VR-PAH. This pathway-based approach may be applied to next-generation sequencing data in other diseases to uncover the contribution of unexpected or multiple GVs to a phenotype.
Genetics and Genomics of Pulmonary Arterial Hypertension Machado, Rajiv D., PhD; Eickelberg, Oliver, MD; Elliott, C. Gregory, MD ...
Journal of the American College of Cardiology,
06/2009, Letnik:
54, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Pulmonary arterial hypertension (PAH) is a rare disorder that may be hereditable (HPAH), idiopathic (IPAH), or associated with either drug-toxin exposures or other medical conditions. Familial cases ...have long been recognized and are usually due to mutations in the bone morphogenetic protein receptor type 2 gene ( BMPR2 ), or, much less commonly, 2 other members of the transforming growth factor-β superfamily, activin-like kinase-type 1 ( ALK1 ) and endoglin ( ENG ), which are associated with hereditary hemorrhagic telangiectasia. In addition, approximately 20% of patients with IPAH carry mutations in BMPR2 . We provide a summary of BMPR2 mutations associated with HPAH, most of which are unique to each family and are presumed to result in loss of function. We review the finding of missense variants and variants of unknown significance in BMPR2 in IPAH/HPAH, fenfluramine exposure, and PAH associated with congenital heart disease. Clinical testing for BMPR2 mutations is available and may be offered to HPAH and IPAH patients but should be preceded by genetic counseling, since lifetime penetrance is only 10% to 20%, and there are currently no known effective preventative measures. Identification of a familial mutation can be valuable in reproductive planning and identifying family members who are not mutation carriers and thus will not require lifelong surveillance. With advances in genomic technology and with international collaborative efforts, genome-wide association studies will be conducted to identify additional genes for HPAH, genetic modifiers for BMPR2 penetrance and genetic susceptibility to IPAH. In addition, collaborative studies of BMPR2 mutation carriers should enable identification of environmental modifiers, biomarkers for disease development and progression, and surrogate markers for efficacy end points in clinical drug development, thereby providing an invaluable resource for trials of PAH prevention.