Gene Mutation Annotation and Pedigree for Pulmonary Arterial Hypertension Patients in Han Chinese Patients

Abstract

Background:The etiology of pulmonary arterial hypertension (PAH) in the Han Chinese population is poorly understood. Objectives: The aim of this study was to assess gene variants and associated functional annotations for PAH in Han Chinese patients. Methods: This is an ethnicity-based multi-centre study. Blood samples were collected from 20 PAH patients who volunteered for the study, and genetic tests were performed. The DAVID database was used to functionally annotate the genes BMPR2, ALK1, KCNK3, CAV1, and ENG. Associated diseases, functional categories, gene ontology, and protein interactions were analysed using the Functional Annotation Tool in the DAVID database. GEO and ClinVar databases were also used for further comparison with gene mutations in our study. Results: PAH patient with gene mutations were female predominant except for a single male with a BMPR2 mutation. Locus variants in our study included 'G410DfsX1' in BMPR2, 'ex7 L300P, ' 'ex4 S110PfsX40,' and 'ex7 E295Afs96X' in ALK1,' in CAV1, and 'ex8 D366H' in ENG were not found in the ClinVar database associated with PAH. In addition to BMP and TGF-β pathways, gene ontology of input genes in the DAVID database also included pathways associated with nitric oxide signaling and regulation. Conclusions: This Multi-centre study indicated that 'G410DfsX1' in BMPR2, 'ex7 L300P,' 'ex4 S110PfsX40,' 'ex7 E295Afs96X' in ALK1, 'c.-2C>A (IVS1-2 C>A)' in CAV1, and 'ex8 D366H' in ENG were identified in Han Chinese patients with PAH. Females were more susceptible to PAH, and a relatively young age distribution was observed for patients with BMPR2 mutations.

Physiological and pathophysiological roles of the KCNK3 potassium channel in the pulmonary circulation and the heart

“…Later, in different PAH cohorts from different countries, 22 additional missense variants were identified in KCNK3: G203D, A114T, A114V, L214R, L214P, K145M, R51L, R390H, F225L, G174S, Y85H, R359T, V206M, E182Q, G236A, V206L, L214P and S31W (Best et al, 2017;Cunningham et al, 2019a;Eichstaedt et al, 2022) (Table 1 and Fig. 3; Eyries et al, 2019;Gräf et al, 2018;Haarman et al, 2020;Higasa et al, 2017;Liang et al, 2014;Navas Tejedor et al, 2017;Wang et al, 2019Wang et al, , 2021Xi et al, 2016;Yang et al, 2018;Zhang et al, 2019;Zhu et al, 2018Zhu et al, , 2019. In addition, Wang et al identified a variant in the 5 UTR of KCNK3 in the PAH cohort (Liang et al, 2014;Wang et al, 2019) (Table 1).…”

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

“…The present study reported five female patients with BMPR2 variants. Although male patients have been reported to have a higher BMPR2 mutation rate compared to female patients [ 23 ], the female patients had higher penetrance than the males, with 42% and 14%, respectively [ 4 , 24 , 25 ]. Moreover, it has been shown that being female is the single most definitive modifier for the penetrance of BMPR2 mutations in PAH [ 6 , 25 ].…”

“…ATP13A3 encodes a P-type ATPase, a cation channel transporter, and has been reported to be associated with PAH [ 6 , 19 , 47 ]. The monoallelic ATP13A3 variant has been associated with adult-onset PAH [ 2 , 4 , 5 , 20 ], and Machado et al demonstrated that biallelic ATP13A3 variants in childhood-onset PAH are characterized by extreme morbidity and mortality [ 48 ]. The PAH patients with or without ATP13A3 genetic variants are reported in Supplemental Table S4 , which illustrates that there were higher mPAP values (52 ± 7 vs. 38 ± 13 mmHg, p = 0.043) in the ATP13A3 variant subgroup compared to the non-ATP13A3 variant carriers.…”

“…As PH progresses, right ventricular heart failure develops once the right ventricle fails to supply adequate cardiac output, and the death rate ranges from 4.5 to 12.3 per million population [3]. There are similar sex and age distributions of PH patients in the Han population compared to Western population-based studies; however, a lower 1-year survival rate for Chinese PH patients was reported in a previous registry, which could be attributed to the unique genetic variants of Asian PH patients [4,5].…”

Application of homocysteine as a non-invasive and effort-free measurements for risk assessment of patients with pulmonary hypertension

“…Pulmonary arterial hypertension (PAH) is defined as mean pulmonary arterial pressure (mPAP) > 20 mmHg at rest as assessed by right heart catheterization, pulmonary arterial wedge pressure ≤ 15 mmHg, and pulmonary vascular resistance > 2 wood units, according to the classification of 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines [ 1 ]. Pathologic progressions of vascular remodeling leads to pulmonary hypertension, right-sided heart failure, and death, once compensatory mechanisms have failed [ 2 – 4 ].…”