TY - JOUR
T1 - Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension
AU - Groen, Karlijn
AU - Huitema, Marloes P.
AU - van der Vis, Joanne J.
AU - Post, Marco C.
AU - Grutters, Jan C.
AU - Baughman, Robert P.
AU - van Moorsel, Coline H.M.
N1 - Funding Information:
K.G., M.P.H., J.J.v.d.V, J.C.G. and C.H.M.v.M declare no conflict of interest. M.C.P. receives funding from Janssen. R.P.B. had received funding from Gilead for maintaining the registry of sarcoidosis associated pulmonary hypertension. He has also received funding for studies of treatment of sarcoidosis associated pulmonary hypertension from Actelion, United Therapeutics, and Bayer.
Funding Information:
R.P.B. received an unrestricted grant from Gilead for the SAPH registry. M.C.P. received funding form ZonMw Topzorg (project 842001006).
Publisher Copyright:
© 2022 by the authors.
PY - 2022/10/21
Y1 - 2022/10/21
N2 - 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.
AB - 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.
KW - BMPR2
KW - genetic variants
KW - NOTCH3
KW - pulmonary hypertension
KW - sarcoidosis
UR - http://www.scopus.com/inward/record.url?scp=85140793431&partnerID=8YFLogxK
U2 - 10.3390/diagnostics12102564
DO - 10.3390/diagnostics12102564
M3 - Article
C2 - 36292254
AN - SCOPUS:85140793431
SN - 2075-4418
VL - 12
JO - Diagnostics
JF - Diagnostics
IS - 10
M1 - 2564
ER -