Hemodynamic and Clinical Profiles of Pulmonary Arterial Hypertension Patients with GDF2 and BMPR2 Variants

Mei-Tzu Wang; Ken-Pen Weng; Sheng-Kai Chang; Wei-Chun Huang; Lee-Wei Chen

doi:10.3390/ijms25052734

Hemodynamic and Clinical Profiles of Pulmonary Arterial Hypertension Patients with GDF2 and BMPR2 Variants

Int J Mol Sci. 2024 Feb 27;25(5):2734. doi: 10.3390/ijms25052734.

Authors

Mei-Tzu Wang^{1

2}, Ken-Pen Weng³, Sheng-Kai Chang⁴, Wei-Chun Huang^{2

5

6}, Lee-Wei Chen^{1

7

8}

Affiliations

¹ Institute of Emergency and Critical Care Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
² Department of Critical Care Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan.
³ Congenital Structural Heart Disease Center, Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan.
⁴ Excelsior Biopharma Inc., Taipei 115, Taiwan.
⁵ Department of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
⁶ Department of Physical Therapy, Fooyin University, Kaohsiung 813, Taiwan.
⁷ Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan.
⁸ Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 813, Taiwan.

Abstract

Asians have a higher carrier rate of pulmonary arterial hypertension (PAH)-related genetic variants than Caucasians do. This study aimed to identify PAH-related genetic variants using whole exome sequencing (WES) in Asian idiopathic and heritable PAH cohorts. A WES library was constructed, and candidate variants were further validated by polymerase chain reaction and Sanger sequencing in the PAH cohort. In a total of 69 patients, the highest incidence of variants was found in the BMPR2, ATP13A3, and GDF2 genes. Regarding the BMPR2 gene variants, there were two nonsense variants (c.994C>T, p. Arg332*; c.1750C>T, p. Arg584*), one missense variant (c.1478C>T, p. Thr493Ile), and one novel in-frame deletion variant (c.877_888del, p. Leu293_Ser296del). Regarding the GDF2 variants, there was one likely pathogenic nonsense variant (c.259C>T, p. Gln87*) and two missense variants (c.1207G>A, p. Val403Ile; c.38T>C, p. Leu13Pro). The BMPR2 and GDF2 variant subgroups had worse hemodynamics. Moreover, the GDF2 variant patients were younger and had a significantly lower GDF2 value (135.6 ± 36.2 pg/mL, p = 0.002) in comparison to the value in the non-BMPR2/non-GDF2 mutant group (267.8 ± 185.8 pg/mL). The BMPR2 variant carriers had worse hemodynamics compared to the patients with the non-BMPR2/non-GDF2 mutant group. Moreover, there was a significantly lower GDF2 value in the GDF2 variant carriers compared to the control group. GDF2 may be a protective or corrected modifier in certain genetic backgrounds.

Keywords: BMPR2; GDF2; heritable pulmonary arterial hypertension; pulmonary arterial hypertension; whole exome sequencing.

MeSH terms

Adenosine Triphosphatases / genetics
Bone Morphogenetic Protein Receptors, Type II / genetics
Familial Primary Pulmonary Hypertension / genetics
Growth Differentiation Factor 2 / genetics
Hemodynamics
Humans
Membrane Transport Proteins / genetics
Mutation
Mutation, Missense
Pulmonary Arterial Hypertension* / genetics
Sequence Deletion

Substances

Bone Morphogenetic Protein Receptors, Type II
ATP13A3 protein, human
Adenosine Triphosphatases
Membrane Transport Proteins
BMPR2 protein, human
GDF2 protein, human
Growth Differentiation Factor 2

Grants and funding

This study was supported by grants from Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan (Grant No. KSVGH111-007, KSVGH110-077, VGHKS109-132, VAC110-001-4), and the Ministry of Science and Technology (grant numbers: MOST107-2314-B-075B-008-MY2 and MOST108-2314-B-075B-007-MY2).