Unaffected carriers of a pathogenic BMPR2 variant exhibit a distinct pro-inflammatory cytokine profile despite the absence of disease

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Introduction: Pathogenic variants in the BMPR2 gene are a major genetic risk factor for hereditary pulmonary arterial hypertension (PAH). PAH exhibits incomplete penetrance, suggesting other modifying factors may influence disease development. Previous studies have shown that inflammatory cytokines such as IL-10, CXCL-10, IL-15, and IL-1 are altered in PAH patients compared to healthy individuals. Whether the presence of a pathogenic BMPR2 variant in the absence of disease has impact on systemic immune regulation has not yet been explored. Objective: Our study aims to explore whether unaffected carriers (UCs) of a pathogenic BMPR2 mutations may exhibit a distinct cytokine profile. Methods: Blood samples from 23 UCs and 13 healthy controls were collected as part of a prospective longitudinal cohort study (DOLPHIN-GENESIS). Circulating cytokine levels were assessed using a Human XL Cytokine Luminex assay. Results: Screening of 46 cytokines revealed elevated levels of the pro-inflammatory markers TNF-α, IL-1β, Macrophage inflammatory protein (MIP)-3α, MIP-3β, GM-CSF, and the angiostatic cytokine CXCL-10 in UCs compared to controls. Interestingly, UCs showed increased levels of anti-inflammatory cytokine IL-10 and regulatory cytokine IL-15. Unlike the cytokine profiles previously observed in the setting of PAH, no significant differences were observed in IL-4, TRAIL, or G-CSF levels. Conclusion: Despite the absence of overt disease, UCs of a pathogenic BMPR2 variant display a distinct pro-inflammatory cytokine profile. These findings suggest that BMPR2 haploinsufficiency influences systemic immune regulation despite the absence of disease.

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