Complex genetics of pulmonary diseases: lessons from genome-wide association studies and next-generation sequencing

Pouladi, Nima; Bime, Christian; Garcia, Joe G.N.; Lussier, Yves A.

doi:10.1016/j.trsl.2015.04.016

Cited by 13 publications

(9 citation statements)

References 91 publications

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“…This approach has great strengths but also limitations, especially in polygenic, complex diseases. For example, previously identified polymorphisms from several large genome-wide association studies only explain a fraction of the variability in lung function 28 and are associated with a minority of asthma or chronic obstructive pulmonary disease cases 29 . Furthermore, it can be argued that the genetic background for many diseases comes from a combination of several, fairly common, weakly active SNPs, which can co-exist in the same individual and additively create a strong pull toward a particular effect 30 .…”

Section: Discussionmentioning

confidence: 99%

Toll-like Receptor 4 Pathway Polymorphisms Interact with Pollution to Influence Asthma Diagnosis and Severity

Schurman

Bravo

Innes

et al. 2018

Sci Rep

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Asthma is a common chronic lung disease, the incidence and severity of which may be influenced by gene-environment interactions. Our objective was to examine associations between single nucleotide polymorphisms (SNPs) and combinations of SNPs in the toll-like receptor 4 (TLR4) pathway, residential distance to roadway as a proxy for traffic-related air pollution exposure, and asthma diagnosis and exacerbations. We obtained individual-level data on genotype, residential address, and asthma diagnosis and exacerbations from the Environmental Polymorphisms Registry. Subjects (n = 2,704) were divided into three groups (hyper-responders, hypo-responders, and neither) based on SNP combinations in genes along the TLR4 pathway. We geocoded subjects and calculated distance, classified as <250 m or ≥250 m, between residence and nearest major road. Relationships between genotype, distance to road, and odds of asthma diagnosis and exacerbations were examined using logistic regression. Odds of an asthma diagnosis among hyper-responders <250 m from a major road was 2.37(0.97, 6.01) compared to the reference group (p < 0.10). Hypo-responders ≥250 m from the nearest road had lower odds of activity limitations (0.46 [0.21, 0.95]) and sleeplessness (0.36 [0.12, 0.91]) compared to neither-responders (p < 0.05). Specific genotype combinations when combined with an individual’s proximity to roadways, possibly due to traffic-related air pollution exposure, may affect the likelihood of asthma diagnosis and exacerbations.

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Section: Discussionmentioning

confidence: 99%

Toll-like Receptor 4 Pathway Polymorphisms Interact with Pollution to Influence Asthma Diagnosis and Severity

Schurman

Bravo

Innes

et al. 2018

Sci Rep

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“…Clarifying both genetic and other factors that result in different subtypes of NAFLD could lead to more accurate prediction of disease progression and more effective treatments based on individualized drivers of disease. Disease subclassification of this type has been pursued in pulmonary disease, for example, but has not yet yielded therapeutic advances 16 .…”

Section: Clinical Disease Progressionmentioning

confidence: 99%

Mechanisms of NAFLD development and therapeutic strategies

Friedman

Neuschwander‐Tetri

Rinella

et al. 2018

Nat Med

2,854

2,598

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There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.

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“…Pathologic characteristics of lung diseases are very complex due to the involvement of environmental and genetic interactions (Pouladi et al, 2015 ) and do not always reflect the underlying molecular mechanisms. Dysfunction of a single gene may contribute to multiple lung diseases leading to development of different phenotypes or, vice versa, similar disease phenotypes can be caused by dysfunctions of different genes and (Lewis et al, 2008 ; Pennings et al, 2008 ).…”

Section: Introductionmentioning

confidence: 99%

Cartography of Pathway Signal Perturbations Identifies Distinct Molecular Pathomechanisms in Malignant and Chronic Lung Diseases

et al. 2016

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Lung diseases are described by a wide variety of developmental mechanisms and clinical manifestations. Accurate classification and diagnosis of lung diseases are the bases for development of effective treatments. While extensive studies are conducted toward characterization of various lung diseases at molecular level, no systematic approach has been developed so far. Here we have applied a methodology for pathway-centered mining of high throughput gene expression data to describe a wide range of lung diseases in the light of shared and specific pathway activity profiles. We have applied an algorithm combining a Pathway Signal Flow (PSF) algorithm for estimation of pathway activity deregulation states in lung diseases and malignancies, and a Self Organizing Maps algorithm for classification and clustering of the pathway activity profiles. The analysis results allowed clearly distinguish between cancer and non-cancer lung diseases. Lung cancers were characterized by pathways implicated in cell proliferation, metabolism, while non-malignant lung diseases were characterized by deregulations in pathways involved in immune/inflammatory response and fibrotic tissue remodeling. In contrast to lung malignancies, chronic lung diseases had relatively heterogeneous pathway deregulation profiles. We identified three groups of interstitial lung diseases and showed that the development of characteristic pathological processes, such as fibrosis, can be initiated by deregulations in different signaling pathways. In conclusion, this paper describes the pathobiology of lung diseases from systems viewpoint using pathway centered high-dimensional data mining approach. Our results contribute largely to current understanding of pathological events in lung cancers and non-malignant lung diseases. Moreover, this paper provides new insight into molecular mechanisms of a number of interstitial lung diseases that have been studied to a lesser extent.

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Complex genetics of pulmonary diseases: lessons from genome-wide association studies and next-generation sequencing

Cited by 13 publications

References 91 publications

Toll-like Receptor 4 Pathway Polymorphisms Interact with Pollution to Influence Asthma Diagnosis and Severity

Toll-like Receptor 4 Pathway Polymorphisms Interact with Pollution to Influence Asthma Diagnosis and Severity

Mechanisms of NAFLD development and therapeutic strategies

Cartography of Pathway Signal Perturbations Identifies Distinct Molecular Pathomechanisms in Malignant and Chronic Lung Diseases

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