Genome-wide identification of loci associated with plasma coagulation factor IX activity
Journal of Thrombosis and Haemostasis, 2025
Han J., Cate V., Li-Gao R., Robles A., Sulochana H., Andrade-Navarro M., Ao L., Noordam R., Martinez-Perez A., Sabater-Lleal M., Soria J., Souto J., Rosendaal F., Wild P., van Hylckama Vlieg A.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
CVD | Pathophysiology | Plasma |  Olink Explore 3072/384 |
Abstract
Background
Elevated coagulation factor (F) IX activity is associated with an increased risk of cardiovascular diseases including venous thromboembolism. However, a genome-wide association study for FIX activity remains to be performed.
Objectives
We aimed to identify genetic loci associated with FIX activity.
Methods
We conducted a meta-analysis of genome-wide association studies in two population-based cohorts (n=9,628), followed by conditional and joint analysis, and replication analysis (n=1,894). Using the identified variants, we explored genetic associations between FIX activity and both hemostatic and metabolic phenotypes and conducted Mendelian randomization analysis to investigate potential causal effects on cardiovascular diseases.
Results
We identified 10 genomic loci associated with FIX activity: AHCTF1, GCKR, KNG, HRG, HRG-AS1, F12, ABO, and F9, of which F12 and ABO were replicated at the Bonferroni corrected significance and GCCKR and F9 reached nominal significance. Structural modeling of the F9 missense variant revealed its proximity to a critical cleavage site, providing mechanistic insight into FIX regulation. A polygenic score based on 10 genomic loci was associated with hemostatic phenotypes (activated partial thromboplastin time, FVIII, FXI, and FXII activity) and metabolic phenotypes (triglycerides, gamma-glutamyl transferase, and low-density lipoprotein cholesterol levels). Mendelian randomization analyses suggested potential detrimental effects of FIX activity on venous thromboembolism.
Conclusions
Our findings enhance understanding of biological mechanisms regulating FIX activity and provide evidence for a causal role of FIX activity in the etiology of these cardiovascular conditions.