Genome‐wide analysis of genetic determinants of circulating factor? VII VII ‐activating protease ( FSAP FSAP ) activity

摘要

Summary Essentials Knowledge of genetic regulators of plasma factor VII activating protease (FSAP) levels is limited. We performed a genome‐wide analysis of variants influencing FSAP activity in Scandinavian cohorts. We replicated an association for Marburg‐1 and identified an association for a HABP2 stop variant. We identified a novel locus near ADCY2 as a potential additional regulator of FSAP activity. Summary Background Factor? VII ‐activating protease ( FSAP ) has roles in both coagulation and fibrinolysis. Recent data indicate its involvement in several other processes, such as vascular remodeling and inflammation. Plasma FSAP activity is highly variable among healthy individuals and, apart from the low‐frequency missense variant Marburg‐I (rs7080536) in the FSAP ‐encoding gene HABP 2 , determinants of this variation are unclear. Objectives To identify novel genetic variants within and outside of the HABP 2 locus that influence circulating FSAP activity. Patients/Methods We performed an exploratory genome‐wide association study ( GWAS ) on plasma FSAP activity amongst 3230 Swedish subjects. Directly genotyped rare variants were also analyzed with gene‐based tests. Using GWAS , we confirmed the strong association between the Marburg‐I variant and FSAP activity. HABP 2 was also significant in the gene‐based analysis, and remained significant after exclusion of Marburg‐I carriers. This was attributable to a rare HABP 2 stop variant (rs41292628). Carriers of this stop variant showed a similar reduction in FSAP activity as Marburg‐I carriers, and this finding was replicated. A secondary genome‐wide significant locus was identified at a 5p15 locus (rs35510613), and this finding requires future replication. This common variant is located upstream of ADCY 2 , which encodes a protein catalyzing the formation of cAMP . Results and Conclusions This study verified the Marburg‐I variant to be a strong regulator of FSAP activity, and identified an HABP 2 stop variant with a similar impact on FSAP activity. A novel locus near ADCY 2 was identified as a potential additional regulator of FSAP activity.