Association Study Identified HLA‐DQA1 as a Novel Genetic Risk of Systemic Lupus Erythematosus‐Associated Pulmonary Arterial Hypertension

Abstract

ObjectivePulmonary arterial hypertension (PAH) is a severe complication of systemic lupus erythematosus (SLE). However, the genetic signatures of SLE‐associated PAH have not been well studied. We aimed to identify genetic variants implicated in SLE‐associated PAH susceptibility within the major histocompatibility complex (MHC) region and assess the contribution to clinical outcomes.MethodsA total of 172 patients with SLE‐associated PAH confirmed by right heart catheterization, 1,303 patients with SLE without PAH, and 9,906 healthy controls were included. Deep sequencing of the MHC region was performed to identify alleles, single‐nucleotide polymorphisms, and amino acids. We compared patients with SLE‐associated PAH with patients with SLE without PAH and healthy controls. Clinical association study was conducted to explore the contribution to phenotypes.ResultsA 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 (P = 5.68 × 10−12) and authenticated in an independent replication cohort (P = 1.30 × 10−9). 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. Clinical association study demonstrated that patients with SLE‐associated PAH with HLA‐DQA1*03:02 had significantly lower rates of target role achievement (P = 0.005) and survival (P = 0.04).ConclusionThis study, based on the largest cohort of SLE‐associated PAH, is the first to investigate how MHC region genetic variants contribute to SLE‐associated PAH susceptibility. HLA‐DQA1*03:02 is a novel genetic risk factor and a prognostic factor in SLE‐associated PAH. Patients with SLE with this allele require regular monitoring and careful follow‐up for early diagnosis and interventions for potential PAH.