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Abstract Number: 0814

Rare Variants of PAH Risk Genes Associate with a Distinct Vasculopathy Phenotype and Worse Outcomes in Patients with Systemic Lupus Erythematosus-associated Pulmonary Arterial Hypertension

Junyan Qian1, Xinzhuang Yang2, Yu Fang Ding3, qian wang1, Jiuliang Zhao1, Weida Liu4, Yongtai Liu5, Zhuang Tian5, Yanhong Wang6, Xiaojian Wang7, Mengtao Li1 and Xiaofeng Zeng8, 1Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China 2National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, Beijing, China, 2Center for Bioinformatics, National Infrastructures for Translational Medicine, Institute of Clinical Medicine & Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, 3Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China 2National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, BEIJING, China (People's Republic), 4State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, 5Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China, 6Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China, 7State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China, 8Department of Rheumatology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Beijing, China

Meeting: ACR Convergence 2024

Keywords: , , , ,

Session Information

Date: Saturday, November 16, 2024

Title: Abstracts: SLE – Diagnosis, Manifestations, & Outcomes I: Omics

Session Type: Abstract Session

Session Time: 1:00PM-2:30PM

Background/Purpose: Systemic lupus erythematosus (SLE)-associated pulmonary arterial hypertension (PAH) displays significant clinical heterogeneity; nevertheless, the underlying mechanisms remain unclear. Presently, more than twenty risk genes have been identified to be closely linked to the pathogenesis and prognosis of idiopathic and familial PAH. However, the contribution of rare variants of PAH risk genes to SLE-associated PAH remains largely unknown. Systemic lupus erythematosus (SLE)-associated pulmonary arterial hypertension (PAH) displays significant clinical heterogeneity; nevertheless, the underlying mechanisms remain unclear. Presently, more than twenty risk genes have been identified to be closely linked to the pathogenesis and prognosis of idiopathic and familial PAH. However, the contribution of rare variants of PAH risk genes to SLE-associated PAH remains largely unknown.

Methods: Based on the Chinese SLE Treatment and Research Group-PAH cohort, 241 patients with SLE-associated PAH were recruited and screened for rare deleterious variants in 28 PAH risk genes by whole exome sequencing. Clinical features, hemodynamic characteristics and outcomes were compared between variant carriers and noncarriers.

Results: Fifty-one patients (21.5%) carried rare deleterious variants of PAH risk genes. Compared to noncarriers, carriers had a shorter PAH duration from SLE onset (3.0 ± 3.1 vs. 5.3 ± 5.2 years, P=0.004), a higher proportion of PAH as the onset symptom of SLE (43.1% vs. 15.1%, P< 0.001) and lower SLE disease activity. Carrying rare variants of PAH risk genes was identified as an independent prognostic factor of mortality (hazard ratio [HR]=3.13, 95% CI, 1.10-8.97; P=0.005) and of reaching a low-risk profile of PAH (HR=0.56, 95% CI 0.34-0.94, P=0.027).

Conclusion: We showed for the first time that rare variants of PAH risk genes associated with a distinct vasculopathy phenotype and worse outcomes in patients with SLE-associated PAH, highlighting the significant clinical value in molecular classification.

Supporting image 1

Table 1. Comparison between carriers and noncarriers of variants of PAH risk genes in patients with SLE-associated PAH

Supporting image 2

Figure 1. Study flow chart. * The 28 PAH risk genes included BMPR2, EIF2AK4, TBX4, ATP13A3, GDF2, SOX17, AQP1, ACVRL1, SMAD9, ENG, KCNK3, CAV1, SMAD4, SMAD1, KLF2, BMPR1B, KCNA5, KDR, FBLN2, PDGFD, PTGIS, BMP10, ABCA3, ABCC8, GGCX, KLK1, TOPBP1 and SMAD5.

Supporting image 3

Figure 2. (A) A total of 237 patients with SLE-associated PAH were divided into two groups based on whether they carried rare variants in PAH risk genes. (B) Variant distribution matrix for 51 patients. (C) Pie chart representation of the different mutational types for 58 rare variants. (D) Variant classification according to ACMG Guidelines.

Disclosures: J. Qian: None; X. Yang: None; Y. Ding: None; q. wang: None; J. Zhao: None; W. Liu: None; Y. Liu: None; Z. Tian: None; Y. Wang: None; X. Wang: None; M. Li: None; X. Zeng: None.

To cite this abstract in AMA style:

Qian J, Yang X, Ding Y, wang q, Zhao J, Liu W, Liu Y, Tian Z, Wang Y, Wang X, Li M, Zeng X. Rare Variants of PAH Risk Genes Associate with a Distinct Vasculopathy Phenotype and Worse Outcomes in Patients with Systemic Lupus Erythematosus-associated Pulmonary Arterial Hypertension [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/rare-variants-of-pah-risk-genes-associate-with-a-distinct-vasculopathy-phenotype-and-worse-outcomes-in-patients-with-systemic-lupus-erythematosus-associated-pulmonary-arterial-hypertension/. Accessed .

ACR Meeting Abstracts - https://acrabstracts.org/abstract/rare-variants-of-pah-risk-genes-associate-with-a-distinct-vasculopathy-phenotype-and-worse-outcomes-in-patients-with-systemic-lupus-erythematosus-associated-pulmonary-arterial-hypertension/