OC 37.2 - Non-canonical regulation of Endoglin plasma levels by common variants: new molecular and clinical perspectives in hemostasis and thrombotic risk

Background: Endoglin, encoded by the ENG gene, plays a pivotal role in angiogenesis and endothelial cells biology. Its contribution to hemostasis and thrombosis, has only recently come to light.

Aims: To unravel the genetic regulation of plasma Endoglin levels and explore its implication on the risk of venous thrombosis (VT).

Methods: We leveraged publicly available findings from genome wide association studies (GWAS) on plasma Endoglin levels measured in up to 46,000 individuals by the Somascan technology to pinpoint polymorphisms associated with protein levels (pQTLs). Lead significant pQTLs were looked for replication in an independent sample of 966 participants from the 3C study where Endoglin was measured using the Olink platform. Employing Mendelian Randomisation (MR), we assessed the causal link between plasma Endoglin levels and the risk of VT.

Results: Eight loci significantly (p < 5x10-8) associated with endoglin levels: ABO, PLAUR, ENG, TIRAP, NCOA6, B3GNT8, ASGR1 and HBS1L. The 8 lead SNPs explain 7.6% of the variability of Endoglin plasma levels in the 3C study, ABO blood groups explaining 5.8% (p=7.3x10-10) by its own.
Interestingly, the ASGRL1 lead SNP also associated with plasma levels of Plasminogen Activator Urokinase Receptor encoded by PLAUR (p < 2x10-18). In 3C, the biological correlation between PLAUR and ENG plasma levels was (ρ=+0.37, p=2.18x10-33).
In addition to ABO, 3 of the identified lead SNPs showed suggestive statistical evidence for association with VT in the latest INVENT GWAS on VT risk: TIRAP (p=2.1x10-7), NCOA6 (p=6.3x10-6) and ENG (p=0.0051). However, MR analysis failed to substantiate a causal association between increased endoglin levels and VT risk (p=0.06).

Conclusion(s): This study delineates novel loci implicated in the regulation of Endoglin, with a specific focus on the plasminogen activator urokinase pathway. The discovered genetic associations between endoglin and VT risk need further in-depth exploration.