医学
人类白细胞抗原
免疫学
肺动脉高压
内科学
抗原
作者
Jianfei Qian,Ying Chen,Xinzhuang Yang,Qian Wang,Jiuliang Zhao,Xiaoyue Deng,Shengjie Li,Yongtai Liu,Zhuang Tian,Juan Shen,Qijun Liao,Yanhong Wang,Xianbo Zuo,Xuejun Zhang,Mengtao Li,Yong Cui,Xueqing Yu,Xiaofeng Zeng
出处
期刊:Social Science Research Network
[Social Science Electronic Publishing]
日期:2022-01-01
摘要
Background: Pulmonary arterial hypertension (PAH) is a rare and severe complication of systemic lupus erythematosus (SLE). This study aimed to identify genetic variants implicated in SLE-associated PAH susceptibility within the major histocompatibility complex (MHC) region and to assess the contribution to clinical outcomes.Methods: A total of 172 patients with SLE-associated PAH confirmed by right heart catheterization (RHC), 1,303 patients with SLE without PAH (SLE-nonPAH) and 9,906 healthy controls were included. Deep sequencing of the MHC region was performed to identify alleles, single-nucleotide polymorphisms and amino acids. To determine the genetic variants specifically associated with SLE-associated PAH, we compared SLE-associated PAH patients with two control groups, SLE-nonPAH patients and healthy controls. Functional analysis was then performed to analysis the effects of genetic mutations on gene expression. Finally, we conducted a clinical association study in SLE-associated PAH patients to explore the contribution of genetic variants to phenotypes.Findings: A total of 19,881 genetic variants were identified within the MHC region. HLA-DQA1*03:02 was identified as a novel genetic variant associated with SLE-associated PAH in the discovery cohort and was authenticated in an independent replication cohort. The strongest associated amino acid position was mapped to HLA-DQα1 in the region affecting MHC/peptide-CD4+ T-cell receptor affinity and antigen binding. Five SNPs were independently significantly associated with SLE-associated PAH. Colocalization analysis revealed that rs2395310 in HLA-DOA/DPA1 affects the gene expression of HLA-DPA1 and HLA-DPB2 in the heart, arteries and lungs. Clinical association study demonstrated that SLE-associated PAH patients with HLA-DQA1*03:02 had lower rates of target role achievement and survival than patients without the allele.Interpretation: This study is based on the largest cohort of SLE-associated PAH and the first to investigate MHC region genetic variants that contribute to SLE-associated PAH susceptibility. HLA-DQA1*03:02 is a novel genetic risk factor for further development of PAH in SLE patients and a prognostic factor in SLE-associated PAH. SLE patients with this allele require regular monitoring and careful follow-up for early diagnosis and interventions for possible PAH.Funding Information: This study was supported by the Chinese National Key Technology R&D Program, Ministry of Science and Technology (2021YFC2501301-5, 2017YFC0907601-3), Beijing Municipal Science & Technology Commission (No.Z201100005520022, 23, 25-27), CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-005) and Youth Program of National Natural Science Foundation of China (81900054, 31900481).Declaration of Interests: All authors declare no related conflict of interest in this paper.Ethics Approval Statement: This study was approved by the Peking Union Medical College Hospital Institutional Review Board (ethical number JS-2038), and we obtained written informed consent from each patient.
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