Translating Lung Function Genome-Wide Association Study (GWAS) Findings

Kheirallah, Alexander K.; Miller, Suzanne; Hall, Ian P.; Sayers, Ian

doi:10.1016/bs.adgen.2015.12.002

Cited by 18 publications

(18 citation statements)

References 197 publications

(178 reference statements)

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“…eQTL analyses have suggested that it is the altered expression of INTS12 as a more likely driver of the genetic association for lung function, but this has been based on the data obtained from non-lung tissue [7]. Due to the diversity of tissue gene expression, it is of pivotal importance to use phenotype-relevant datasets [20]. A previous investigation of a lung microarray dataset [55, 56] failed to detect a significant eQTL effect on INTS12.…”

Section: Discussionmentioning

confidence: 99%

“…We have relied on a hypothesis-free approach [20] in order to generate new functional hypotheses about INTS12 function. Following its knockdown with two D-siRNAs, we observed marked downregulation of pathways critical in protein synthesis including tRNA synthetases, unfolded protein response and PERK pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Although a subset of lung function associated genes show evidence of differential expression between various stages of embryonic pulmonary tissue formation [20], there is still an incomplete understanding of the molecular mechanisms behind normal respiratory system development and how the alterations therein contribute to disease pathophysiology. Given that there is no homologous INTS12 in unsegmented C. elegans or unicellular S. cerevisiae , its strong conservation and lethal effect of knockout in M. musculus , this gene may have been important for the evolution of complex metazoan tissue differentiation and specialization.…”

Section: Discussionmentioning

confidence: 99%

“…As no genome-wide molecular assessment of INTS12 perturbation has been performed to date, we use a hypothesis-free approach [20] by combining gene knockdown with RNA sequencing in order to generate new functional hypotheses. We bioinformatically show that INTS12 has homology to epigenetic regulators of gene expression.…”

Section: Introductionmentioning

confidence: 99%

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Lung function associated gene Integrator Complex subunit 12 regulates protein synthesis pathways

et al. 2017

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BackgroundGenetic studies of human lung function and Chronic Obstructive Pulmonary Disease have identified a highly significant and reproducible signal on 4q24. It remains unclear which of the two candidate genes within this locus may regulate lung function: GSTCD, a gene with unknown function, and/or INTS12, a member of the Integrator Complex which is currently thought to mediate 3’end processing of small nuclear RNAs.ResultsWe found that, in lung tissue, 4q24 polymorphisms associated with lung function correlate with INTS12 but not neighbouring GSTCD expression. In contrast to the previous reports in other species, we only observed a minor alteration of snRNA processing following INTS12 depletion. RNAseq analysis of knockdown cells instead revealed dysregulation of a core subset of genes relevant to airway biology and a robust downregulation of protein synthesis pathways. Consistent with this, protein translation was decreased in INTS12 knockdown cells. In addition, ChIPseq experiments demonstrated INTS12 binding throughout the genome, which was enriched in transcriptionally active regions. Finally, we defined the INTS12 regulome which includes genes belonging to the protein synthesis pathways.ConclusionINTS12 has functions beyond the canonical snRNA processing. We show that it regulates translation by regulating the expression of genes belonging to protein synthesis pathways. This study provides a detailed analysis of INTS12 activities on a genome-wide scale and contributes to the biology behind the genetic association for lung function at 4q24.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3628-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lung function associated gene Integrator Complex subunit 12 regulates protein synthesis pathways

et al. 2017

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“…By studying previously identified GWAS, DNA methylation profiling has identified FRMD4A, THSD4, and C10orf11 as the top differentially methylated sites [65]. Although several approaches (in vivo, in vitro, in silico) can be used for functional translation of genetic findings, this translation is still under investigation [66]. In next future identified genes and epigenetic variations might become effective drug targets or specific biomarkers for disease phenotypization.…”

Section: New Horizons: Analysis Of Exhaled Gases Post-processing Imamentioning

confidence: 99%

Aging Airways: between Normal and Disease. A Multidimensional Diagnostic Approach by Combining Clinical, Functional, and Imaging Data

Occhipinti¹,

Larici²,

Bonomo³

et al. 2017

Aging and disease

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The lack of data on lung function decline in the aging process as well as the lack of gold standards to define obstructive and restrictive respiratory disease in older people point out the need for a multidimensional assessment and interpretation of the aging airways. By integrating clinical data together with morphologic and morphometric findings clinicians can assess the airways with a more comprehensive perspective, helpful in the interpretation of the “grey zone” between normal aging and disease. This review focuses on the value of a multidimensional approach in the study of the aging airways, including clinical findings, respiratory function tests, and imaging as parts of a whole. Nowadays this multidimensional diagnostic approach can be used in daily clinical practice. In next future, it can be implemented by the analysis of exhaled gases, post-processing imaging techniques, and genetic analysis, that will hopefully reduce the gaps in knowledge of normal aging and airway disease in older people.

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Zebrafish as a Model for Osteoporosis: Functional Validations of Genome-Wide Association Studies

Ben-Zvi,

Karasik,

Ackert-Bicknell

2023

Curr Osteoporos Rep

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Translating Lung Function Genome-Wide Association Study (GWAS) Findings

Abstract: Chronic respiratory diseases are a major cause of worldwide mortality and morbidity.

Cited by 18 publications

References 197 publications

Lung function associated gene Integrator Complex subunit 12 regulates protein synthesis pathways

Lung function associated gene Integrator Complex subunit 12 regulates protein synthesis pathways

Aging Airways: between Normal and Disease. A Multidimensional Diagnostic Approach by Combining Clinical, Functional, and Imaging Data

Zebrafish as a Model for Osteoporosis: Functional Validations of Genome-Wide Association Studies

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