LB 01.4 - Rare Germline Loss of Function Variants in SERPINH1 (HSP47) are Associated with Increased Risk of Thrombosis

Sunday, June 25, 2023

11:30 – 11:45 ET

Room: 517

Session Available As: Live-Streamed and On-Demand

Presenting Author(s)

Amelia K. Haj, MD, PhD

Postdoctoral scientist
Department of Pathology, Massachusetts General Hospital, Boston, MA
Cambridge, Massachusetts, United States

Co-Author(s)

SJ

Sean Jurgens

Graduate Student
Broad Institute of MIT and Harvard, Cambridge, MA
Amsterdam, Noord-Holland, Netherlands
XW

Xin Wang

Postdoctoral scientist
Broad Institute of MIT and Harvard, Cambridge, MA
Cambridge, Massachusetts, United States
Justine Ryu, MD

Clinical Fellow
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
SC

Seung Hoan Choi

Assistant Professor
Broad Institute of MIT and Harvard, Cambridge, MA
Boston, Massachusetts, United States
Steven P. Grover, PhD

Research Assistant Professor
Division of Hematology and Blood Research Center, University of North Carolina, Chapel Hill
Chapel Hill, North Carolina, United States
PE

Patrick Ellinor

Professor of Medicine
Massachusetts General Hospital
Boston, Massachusetts, United States
PB

Pavan K. Bendapudi

Research Assistant Professor
Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, MA
Boston, Massachusetts, United States

Background: Recent work suggests that downregulation of the chaperone protein HSP47 (SERPINH1) protects against venous thromboembolism (VTE) (Thienel et al., Science 380, 178–187, 2023). However, validation of the role played by HSP47 in human disease remains limited.

Aims: Determine the clinical impact of SERPINH1 loss of function.

Methods: The UK Biobank (UKBB) contains participants’ detailed clinical and whole exome sequencing data (N=415,921). Using Firth’s logistic regression, we evaluated associations between rare (MAF < 0.1%) in silico predicted function-altering (ΔF) variants in SERPINH1 and four thrombotic disorders: VTE, cerebrovascular accident (CVA), myocardial infarction (MI), and peripheral artery disease (PAD). Replication was performed in a composite dataset from the NIH All of Us program and MGB Biobank (N=150,017).

Results: After adjusting for key risk factors, rare germline ΔF variants (100% heterozygous) in SERPINH1 were associated with significantly increased VTE (OR=1.87, 95% CI: 1.21-2.76, P=0.006) (Figure 1), MI (OR=1.98, 95% CI: 1.27-2.96, P=0.003) and PAD (OR=2.37, 95% CI: 1.29-3.98, P=0.007) (Figure 2A). A trend towards higher thrombosis risk was also seen in CVA (OR=1.56, 95% CI: 0.86-2.61, P=0.13). The disease association with VTE independently replicated in the composite dataset (P=0.03). Restricting the analysis to high-confidence loss-of-function (HCLOF) variants (e.g., frameshifts, essential splice site variants, and nonsense mutations) did not change the directionality of these findings and markedly boosted effect size estimates for MI (OR=4.86, 95% CI: 2.18-9.87, P=0.0003) and PAD (OR=4.83, 95% CI: 1.54-11.76, P=0.01) (Figure 2B). Kaplan-Meier analysis revealed significantly greater incident MI (P=0.03) and PAD (P=0.01) in carriers of SERPINH1 ΔF variants (Figure 2C).

Conclusion(s): Loss of function in SERPINH1 is associated with increased disease risk across thrombotic phenotypes. These findings illustrate the value of large-scale genomic datasets in rapidly vetting potential drug targets. Calls for the development of therapeutic HSP47 inhibitors are premature.