We appreciate the comments made by Stoimenis et al1 on our recently published article,2 describing the application of our novel analysis method to Behçet’s disease (BD) genome-wide association study data obtained from the Japanese and Turkish populations. In this study, we analyzed the data in a pathway-related context to identify the disease-related pathways targeted by the single-nucleotide polymorphisms (SNPs).2 Among the identified pathways, Stoimenis et al1 focus on the complement and coagulation pathway since they identified three BD patients with major vessel thrombosis.
We fully agree with Stoimenis et al that in specific ethnic populations there exists a strong prevalence of vascular thrombosis in BD and that there is a positive association between the inherited procoagulant factors and thrombosis in BD.3 According to our analysis, complement and coagulation pathway ranks as the seventh affected pathway in the Turkish population, whereas it ranks tenth in the Japanese population. Commonly targeted genes in this pathway consist of PLAT, F5 and F13A1. All these genes have been previously identified to be associated with BD and thrombosis.3 Especially the mutations in F5 gene in Turkish population have been identified to increase the risk of venous thrombosis.4 Coagulation factor XIII protein is a crucial protein complex in the final step of blood coagulation process. It is made up of two domains produced by two separate genes, F13A and F13B. F13A gene is targeted by the SNPs in both populations, whereas F13B gene is targeted only in the Turkish population, creating a higher risk of venous thrombi.5 All the population-specific SNPs targeting this pathway have different functional impacts yielding to different rankings of this pathway in both the populations.
In conclusion, we agree with Stoimenis et al that our method can elucidate the commonly targeted pathways as well as the population-specific pathways that we strongly believe will be the future direction of analysis to elucidate the marker pathways in complex diseases.
References
Stoimenis D, Petridis N, Papaioannou N : Epistatic interactions between autoimmunity and genetic thrombophilia. Eur J Hum Genet 2015, e-pub ahead of print 14 January 2015 doi:10.1038/ejhg.2014.287.
Bakir-Gungor B, Remmers EF, Meguro A et al: Identification of possible pathogenic pathways in Behçet’s disease using genome-wide association study data from two different populations. Eur J Hum Genet;, e-pub ahead of print 17 September 2014; doi:10.1038/ejhg.2014.158.
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Aleman MM, Byrnes JR, Wang JG : Factor XIII activity mediates red blood cell retention in venous thrombi. J Clin Invest 2014; 124: 3590–3600.
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Bakir-Gungor, B., Remmers, E., Meguro, A. et al. Reply to Stoimenis et al. Eur J Hum Genet 23, 1280 (2015). https://doi.org/10.1038/ejhg.2014.288
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DOI: https://doi.org/10.1038/ejhg.2014.288