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Published on: February 13, 2013
Molecular Stratification of Antiphospholipid Syndrome Through Integrative Analysis of the Whole-Blood RNA
Amala Ambati1,2, Feiyang Ma1,3, Katarina Kmetova1
1Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor.
Objective:
Antiphospholipid syndrome (APS) is a thromboinflammatory disorder characterized by clinical and mechanistic heterogeneity that complicates early diagnosis and hinders targeted treatment. We aimed to identify distinct molecular endotypes among antiphospholipid antibody (aPL)-positive patients using whole-blood transcriptomics.
Methods:
Whole-blood RNA sequencing was performed on 174 aPL-positive patients, including those with primary APS (n = 102), secondary APS (n = 29), and aPL positivity without classifiable APS (n = 43). Unsupervised machine learning and immune cell deconvolution defined transcriptomic clusters and immune landscapes.
Results:
Four transcriptionally distinct clusters were identified. At one end of the spectrum, cluster 1 showed up-regulation of ribosomal and metabolic pathways and down-regulation of mechanistic target of rapamycin (mTOR), NETosis, and Hippo/interleukin-6 (IL-6) signaling. In contrast, cluster 4 exhibited the opposite pattern, with strong up-regulation of mTOR, NETosis, and Hippo/IL-6 signaling. Cluster 2 demonstrated modest enrichment in messenger RNA processing and amino acid metabolism, and cluster 3 showed biosynthetic suppression with mild Hippo/IL-6 activation. Clinically, cluster 4 stood out with higher IgG anticardiolipin and anti-β2-glycoprotein I positivity, elevated neutrophil counts, and increased urine protein-to-creatinine ratios. Immune deconvolution revealed distinct cell type profiles: cluster 1 was lymphoid predominant; cluster 2 had a balanced composition; cluster 3 was enriched in Treg cells, natural killer cells, macrophages, mast cells, and memory B cells; and cluster 4 was dominated by myeloid cells, including neutrophils, eosinophils, and dendritic cells. Distinct immune pathway activations were linked to clinical features, including white matter lesions, seizures, and cardiac valve disease.
Conclusion:
This study reveals four endotypes of aPL-positive patients, a step toward personalized medicine for APS through pathway-informed stratification and therapy.
