Genomeâwide analysis of genetic determinants of circulating factorÂVIIâactivating protease (FSAP) activity

ESSENTIALS: Knowledge of genetic regulators of plasma factor VII activating protease (FSAP) levels is limited. We performed a genomeâwide analysis of variants influencing FSAP activity in Scandinavian cohorts. We replicated an association for Marburgâ1 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: FactorÂVIIâactivating 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 lowâfrequency missense variant MarburgâI (rs7080536) in the FSAPâencoding gene HABP2, determinants of this variation are unclear. OBJECTIVES: To identify novel genetic variants within and outside of the HABP2 locus that influence circulating FSAP activity. PATIENTS/METHODS: We performed an exploratory genomeâwide association study (GWAS) on plasma FSAP activity amongst 3230 Swedish subjects. Directly genotyped rare variants were also analyzed with geneâbased tests. Using GWAS, we confirmed the strong association between the MarburgâI variant and FSAP activity. HABP2 was also significant in the geneâbased analysis, and remained significant after exclusion of MarburgâI carriers. This was attributable to a rare HABP2 stop variant (rs41292628). Carriers of this stop variant showed a similar reduction in FSAP activity as MarburgâI carriers, and this finding was replicated. A secondary genomeâwide significant locus was identified at a 5p15 locus (rs35510613), and this finding requires future replication. This common variant is located upstream of ADCY2, which encodes a protein catalyzing the formation of cAMP. RESULTS AND CONCLUSIONS: This study verified the MarburgâI variant to be a strong regulator of FSAP activity, and identified an HABP2 stop variant with a similar impact on FSAP activity. A novel locus near ADCY2 was identified as a potential additional regulator of FSAP activity.