Journal of thrombosis and haemostasis : JTH · 2025
Genome-wide identification of loci associated with plasma coagulation factor IX activity.
СтатьяМетаанализПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Han Jihee, Ten Cate Vincent, Li-Gao Ruifang, Robles Alejandro Pallares, Sulochana Harsini Raaja, Andrade-Navarro Miguel A, Ao Linjun, Noordam Raymond, Martinez-Perez Angel, Sabater-Lleal Maria, Soria José Manuel, Souto Juan Carlos, Rosendaal Frits R, Wild Philipp S, van Hylckama Vlieg Astrid
Аннотация
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 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.
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.
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.
OBJECTIVES: We aimed to identify genetic loci associated with FIX activity.
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.
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.
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.