| Title: | Genome-wide identification of loci associated with plasma coagulation factor IX activity |
| Journal: | Journal of Thrombosis and Haemostasis |
| Published: | 27 Oct 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41161418/ |
| DOI: | https://doi.org/10.1016/j.jtha.2025.10.005 |
Publication 19131
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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.</p>
OBJECTIVES: We aimed to identify genetic loci associated with FIX activity.</p>
METHODS: We conducted a meta-analysis of genome-wide association studies across 2 population-based cohorts (N = 9628), followed by conditional and joint analyses and replication analyses (N = 1894). 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.</p>
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 a Bonferroni-corrected significance, and GCKR 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 and FVIII, FXI, and FXII activity) and metabolic phenotypes (triglycerides, γ-glutamyl transferase, and low-density lipoprotein cholesterol levels). Mendelian randomization analyses suggested potential detrimental effects of FIX activity on venous thromboembolism.</p>
CONCLUSION: 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.</p>
12 Keywords
- Blood Coagulation
- Cardiovascular Diseases
- Factor IX
- Genetic Loci
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Hemostasis
- Humans
- Mendelian Randomization Analysis
- Phenotype
- Polymorphism, Single Nucleotide
- Risk Factors
15 Authors
- Jihee Han
- Vincent Ten Cate
- Ruifang Li-Gao
- Alejandro Pallares Robles
- Harsini Raaja Sulochana
- Miguel A Andrade-Navarro
- Linjun Ao
- Raymond Noordam
- Angel Martinez-Perez
- Maria Sabater-Lleal
- José Manuel Soria
- Juan Carlos Souto
- Frits R Rosendaal
- Philipp S Wild
- Astrid van Hylckama Vlieg
Enabling scientific discoveries that improve human health