Session: 301. Vasculature, Endothelium, Thrombosis and Platelets: Basic and Translational: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Bleeding and Clotting, adult, Translational Research, epidemiology, Clinical Research, Genetic Disorders, genomics, bioinformatics, thromboembolism, Diseases, computational biology, Biological Processes, Technology and Procedures, Study Population, Human, omics technologies
Aims: Determine the clinical effects of SERPINH1 loss of function in a large-scale whole exome sequencing dataset.
Methods: The UK Biobank (UKBB) contains paired whole exome sequencing and clinical data on 415,921 subjects in addition to plasma proteomics data for a subset of participants (N= 48,892). We identified all rare (MAF<0.1%) variants in SERPINH1 that were predicted in silico to alter protein activity (functional impact score ≥0.7). Using Firth’s logistic regression, we controlled for age, sex, ancestry, and other risk factors and assessed the association between the presence of qualifying SERPINH1 variants and four thrombotic disorders: venous thromboembolism (VTE), non-cardioembolic ischemic stroke (NCEIS), myocardial infarction (MI), and peripheral arterial disease (PAD). Replication was performed in a composite dataset from the NIH All of Us program and the Mass General Brigham (MGB) Biobank (N=150,017). We also evaluated differences in the plasma levels of 1,472 proteins (Olink Explore 1536 proteomics panel) between carriers and non-carriers of qualifying SERPINH1 variants.
Results: Rare qualifying variants in SERPINH1 were identified in 382 UKBB participants (100% heterozygous). On average, SERPINH1 variant carriers were of significantly shorter stature (P=3.97 x 10-5) and lower weight (P=0.006) than individuals without such variants, and this effect was more pronounced in subjects with higher functional impact scores (Figure 1). By contrast, bone mineral density did not differ significantly as measured by calcaneal quantitative ultrasound and femur shaft dual x-ray absorptiometry. The presence of SERPINH1 variants was associated with significantly increased risk of VTE (OR=1.87, 95% CI: 1.21-2.76, P=0.006), MI (OR=1.98, 95% CI: 1.27-2.96, P=0.003), PAD (OR=2.37, 95% CI: 1.29-3.98, P=0.007), and NCEIS (OR=2.67, 95% CI: 1.24-4.98, P=0.015). Restricting the analysis to high-confidence loss-of-function variants (i.e., nonsense, frameshift, and essential splice site mutations) markedly boosted effect size estimates for MI, PAD, and NCEIS. The VTE and MI disease associations replicated in the composite dataset (VTE OR=3.29, 95% CI: 1.46-7.39, P=0.004; MI OR=2.31, 95% CI: 1.05-5.08, P=0.038). Additionally, the association with NCEIS demonstrated a strong trend towards significance in the replication dataset (OR=2.08, 95% CI: 0.90-4.83, P=0.088). Plasma proteome analysis showed a significant increase in several proteins related to asthma, atopic inflammation, and/or eosinophil activation among individuals with qualifying SERPINH1 variants, including RNASE3, DPP10, TSPAN1, CCL20, and IL10RA (Figure 2). In order to further investigate these differences in circulating protein profile, we assessed the risk of obstructive asthma in a meta-analysis of the UKBB, All of Us, and MGB datasets (total N=565,455) and found that SERPINH1 variant carriers were significantly more likely to have disease (OR=1.32, 95% CI: 1.03-1.69, P=0.026).
Conclusions: Loss of function in SERPINH1 is associated with a significantly increased risk of both venous and arterial thrombosis, raising concerns that long-term therapeutic inhibition of HSP47 may not be a safe or effective antithrombotic strategy. Our data indicate that SERPINH1 variant carriers experience higher levels of eosinophil-driven inflammation, which has consistently been linked to cardiovascular disease. Further, heterozygous SERPINH1 variant carriers appear to have an intermediate OI phenotype characterized by shorter stature but without significant differences in bone mineral density compared to non-carriers.
Disclosures: Grover: CSL Behring: Research Funding. Ellinor: Bayer AG: Consultancy, Research Funding; Novartis: Consultancy. Bendapudi: Alexion Pharmaceuticals: Consultancy; Takeda Pharmaceuticals: Consultancy.