The association between STAT4 polymorphism and pulmonary arterial hypertension in Chinese patients with primary Sjögren's syndrome.

Objective: Primary Sjögren's syndrome (pSS) was one of the pivotal causes of pulmonary arterial hypertension (PAH) among connective tissue diseases (CTDs) with adverse outcomes, but genetic studies of pSS-PAH are quite limited. Studies have identified genetic predisposition in both familial PAH (fPAH) and idiopathic PAH (iPAH) cases. Therefore, the aim of this study was to explore the genetic susceptibility of PAH in pSS.

Methods: Forty-three pSS-PAH patients, 92 pSS-non-PAH patients, and 105 healthy controls (HC) were obtained. PAH was diagnosed according to the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines, and ruled out by echocardiogram as estimated PAP < 40 mmHg. Single-nucleotide polymorphism (SNP) sites related to PAH and pSS were selected and then compared between pSS-PAH and pSS-non-PAH groups.

Results: In pSS-PAH group, 97.7% of the patients were female and average age of PAH onset was 37.3 ± 10.6 years. The allele frequency of STAT4 rs10168266 was markedly different between pSS-PAH and pSS-non-PAH groups (p = 0.027, OR = 0.547), with the genotypic frequency of CC/CT/TT 47.6%/38.1%/14.3% versus 25.6%/53.3%/21.1%. While C-allele was much more frequent in pSS-PAH group than in pSS-non-PAH group (66.7% vs. 52.2%), the intron variant rs10168266 (C > T) of signal transductor and activator of transcription (STAT4) gene was speculated to be a protective factor for PAH in pSS patients. A remarkable divergence was also proven in the dominant and additive hereditary model tests between pSS-PAH and pSS-non-PAH groups (p = 0.012, OR = 0.378).

Conclusion: SNP sites identified by genome-wide association study (GWAS) in pSS, especially STAT4 rs1016826, was verified to be correlated with pSS-PAH. Further investigations on the mechanisms were called for early diagnosis and innovative therapeutic targets.