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Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension

Background: Pulmonary hypertension (PH) is a severe complication of sarcoidosis in a minority of patients. Several genetic defects are known to cause hereditary or sporadic PH, but whether variants in PH-associated genes are also involved in sarcoidosis-associated PH (SAPH) is unknown. Methods: 40 p...

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Autores principales: Groen, Karlijn, Huitema, Marloes P., van der Vis, Joanne J., Post, Marco C., Grutters, Jan C., Baughman, Robert P., van Moorsel, Coline H. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9601358/
https://www.ncbi.nlm.nih.gov/pubmed/36292254
http://dx.doi.org/10.3390/diagnostics12102564
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author Groen, Karlijn
Huitema, Marloes P.
van der Vis, Joanne J.
Post, Marco C.
Grutters, Jan C.
Baughman, Robert P.
van Moorsel, Coline H. M.
author_facet Groen, Karlijn
Huitema, Marloes P.
van der Vis, Joanne J.
Post, Marco C.
Grutters, Jan C.
Baughman, Robert P.
van Moorsel, Coline H. M.
author_sort Groen, Karlijn
collection PubMed
description Background: Pulmonary hypertension (PH) is a severe complication of sarcoidosis in a minority of patients. Several genetic defects are known to cause hereditary or sporadic PH, but whether variants in PH-associated genes are also involved in sarcoidosis-associated PH (SAPH) is unknown. Methods: 40 patients with SAPH were individually matched to 40 sarcoidosis patients without PH (SA). Whole exome sequencing was performed to identify rare genetic variants in a diagnostic PH gene panel of 13 genes. Additionally, an exploratory analysis was performed to search for other genes of interest. From 572 genes biologically involved in PH pathways, genes were selected in which at least 15% of the SAPH patients and no more than 5% of patients without PH carried a rare variant. Results: In the diagnostic PH gene panel, 20 different rare variants, of which 18 cause an amino-acid substitution, were detected in 23 patients: 14 SAPH patients carried a variant, as compared to 5 SA patients without PH (p = 0.018). Most variants were of yet unknown significance. The exploratory approach yielded five genes of interest. First, the NOTCH3 gene that was previously linked to PH, and furthermore PDE6B, GUCY2F, COL5A1, and MMP21. Conclusions: The increased frequency of variants in PH genes in SAPH suggests a mechanism whereby the presence of such a genetic variant in a patient may increase risk for the development of PH in the context of pulmonary sarcoidosis. Replication and studies into the functionality of the variants are required for further understanding the pathogenesis of SAPH.
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spelling pubmed-96013582022-10-27 Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension Groen, Karlijn Huitema, Marloes P. van der Vis, Joanne J. Post, Marco C. Grutters, Jan C. Baughman, Robert P. van Moorsel, Coline H. M. Diagnostics (Basel) Article Background: Pulmonary hypertension (PH) is a severe complication of sarcoidosis in a minority of patients. Several genetic defects are known to cause hereditary or sporadic PH, but whether variants in PH-associated genes are also involved in sarcoidosis-associated PH (SAPH) is unknown. Methods: 40 patients with SAPH were individually matched to 40 sarcoidosis patients without PH (SA). Whole exome sequencing was performed to identify rare genetic variants in a diagnostic PH gene panel of 13 genes. Additionally, an exploratory analysis was performed to search for other genes of interest. From 572 genes biologically involved in PH pathways, genes were selected in which at least 15% of the SAPH patients and no more than 5% of patients without PH carried a rare variant. Results: In the diagnostic PH gene panel, 20 different rare variants, of which 18 cause an amino-acid substitution, were detected in 23 patients: 14 SAPH patients carried a variant, as compared to 5 SA patients without PH (p = 0.018). Most variants were of yet unknown significance. The exploratory approach yielded five genes of interest. First, the NOTCH3 gene that was previously linked to PH, and furthermore PDE6B, GUCY2F, COL5A1, and MMP21. Conclusions: The increased frequency of variants in PH genes in SAPH suggests a mechanism whereby the presence of such a genetic variant in a patient may increase risk for the development of PH in the context of pulmonary sarcoidosis. Replication and studies into the functionality of the variants are required for further understanding the pathogenesis of SAPH. MDPI 2022-10-21 /pmc/articles/PMC9601358/ /pubmed/36292254 http://dx.doi.org/10.3390/diagnostics12102564 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Groen, Karlijn
Huitema, Marloes P.
van der Vis, Joanne J.
Post, Marco C.
Grutters, Jan C.
Baughman, Robert P.
van Moorsel, Coline H. M.
Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension
title Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension
title_full Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension
title_fullStr Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension
title_full_unstemmed Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension
title_short Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension
title_sort pulmonary hypertension associated genetic variants in sarcoidosis associated pulmonary hypertension
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9601358/
https://www.ncbi.nlm.nih.gov/pubmed/36292254
http://dx.doi.org/10.3390/diagnostics12102564
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