Volume 6 • Issue 1 • 1000143 J Pharmacogenomics Pharmacoproteomics ISSN: 2153-0645 JPP, an open access journal Research Article Open Access Borges et al., J Pharmacogenomics Pharmacoproteomics 2015, 6:1 DOI: 10.4172/2153-0645.1000143 Research Article Open Access Polymorphisms in Genes Encoding Metalloproteinase 9 and Lymphotoxin- Alpha can Influence Warfarin Treatment Jéssica B Borges 1* , Thiago DC Hirata 2 , Alvaro Cerda 1 , Cristina M Fajardo 1 , Raony CC Cesar 3 , João ID França 3 , Jéssica C Santos 2 , Hui-Tzu L Wang 2 , Idelzuita L. Liporace 2 , Lara R Castro 2 , Marcelo F Sampaio 2 , Amanda G.M.R. Souza 2 , Rosario DC Hirata 1 , Mario H Hirata 1 1 Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil 2 Laboratory of Molecular Research in Cardiology, Institute of Cardiology Dante Pazzanese, São Paulo, Brazil 3 Laboratory of Epidemiology and Statistic, Institute of Cardiology Dante Pazzanese, São Paulo, Brazil *Corresponding author: Jéssica Bassani Borges, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil, Tel: +55 11 3091-3660; FAX: +55 11 3813-9187; E-mail: jessica.bassani.borges@gmail.com Received January 06, 2015; Accepted February 13, 2015; Published February 18, 2015 Citation: Borges JB, Hirata TDC, Cerda A, Fajardo CM, Cesar RCC,et al. (2015) Polymorphisms in Genes Encoding Metalloproteinase 9 and Lymphotoxin-Alpha can Infuence Warfarin Treatment. J Pharmacogenomics Pharmacoproteomics 6: 143. doi:10.4172/2153-0645.1000143 Copyright: © 2015 Borges JB, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Keywords: Gene polymorphism; INR; LTA; MMP9; TNFSF14; Warfarin. Introduction Anticoagulant therapy has been increasingly used due to its efciency and applicability in various pathologies [1]. Te most commonly indicated anticoagulant is warfarin, an oral drug that acts inhibiting the synthesis of vitamin K dependent clotting factor [2]. Indications include prevention and treatment of infammation triggering diseases such as deep vein thrombosis, extensive anterior myocardial infarction, valve prostheses and bioprosthetic (frst three months), atrial fbrillation, intracardiac thrombus, among other cardiovascular diseases, which lately are the leading cause of morbidity and mortality worldwide [3]. It is known that coumarin-type drugs cause many adverse efects, especially risk of bleeding, justifying the need of very strict therapeutic control [4]. In order to decrease the chance of side efects, warfarin treatment has to be continuously monitored by international normalized ratio (INR). Maintaining the patients within a narrow target range of INR does not always guarantee therapy safety and efectiveness [2]. Interestingly, age, concomitant drugs, comorbidities, vitamin K intake and other environmental factors alongside genetic predispositions are responsible for almost half of warfarin dose variability [5]. Polymorphisms in genes encoding warfarin target (VKORC1) and metabolism (CYP2C9) have been shown to infuence dose and time to reach target INR in patients treated with warfarin [6-8]. Diferent ethnic groups are also observed to have variations in polymorphisms frequencies [9]. Other candidate SNPs have been studied in relation to warfarin dosage, like in gamma-glutamyl carboxylase (GGCX), calumenin (CALU), CYP2C19, epoxide hydrolase I (EPHX1) and CYP4F2 [10- 13]. However, scarce studies include genes related to infammation, a process deeply connected to main warfarin indications in cardiovascular diseases. Te infammatory response caused by these diseases can induce the activation of coagulation. Infammation and coagulation have reciprocal amplifying efects, potentially constituting an environment that is highly proinfammatory and procoagulant in severe disease states. Elucidating these mechanisms increases our understanding of the pathological and pathophysiological events of severe clinical diseases, and may yield new therapeutic targets in the near future [14]. Te aim of this study was to verify associations between variability of warfarin response and polymorphisms in infammation related genes: tumor necrosis factor superfamily member 14 also known as LIGHT (TNFSF14) (rs2291668 and rs344560), lymphotoxin-alpha (LTA) (rs1041981 and rs909253) and metalloproteinase 9 (MMP9) (rs17576). Abstract Objectives: Warfarin treatment is infuenced by environmental and genetic factors. The infuence of polymorphisms in genes encoding metalloproteinase 9 (MMP9), lymphotoxin-alpha (LTA) andTNFSF14 (LIGHT), related to the infammatory process of coronary artery disease, on warfarin dose and time to reach target was investigated in this study. Methods: Outpatients on warfarin treatment (n=227), 20 to 92 years, were enrolled at the Institute Dante Pazzanese of Cardiology (IDPC). Genomic DNA was obtained from peripheral whole blood to evaluate MMP9 rs17576 (Gln279Arg, A>G), LTA rs1041981 (Thr60Asn, C>A) and rs909253 (c.252T>C) and TNFSF14rs2291668 (c.147C>T) and rs344560 (Lys214Glu, G>A) polymorphisms by pyrosequencing in Q24PyroMark. Results: The patients carrying MMP9 rs17576GG genotype were more likely to require a lower warfarin weekly dose (OR: 2.73, 95% CI: 1.01-7.41, p=0.048). Also, LTA rs909253 variant was associated with a longer time to reach the target international normalized ratio (INR) (OR: 1.98, 95% CI: 1.02-3.86, p=0.043). Age was inversely correlated with the target INR (r=-0.387, p<0.001), and dose was directly correlated with time to reach target INR (r=0.244, p<0.001). Conclusion: MMP9 rs17576 variant may have an important infuence on warfarin weekly dose, and that LTA rs909253 polymorphism may also infuence the time to reach the target INR. Journal of Pharmacogenomics & Pharmacoproteomics J o u r n a l o f P h a r m a c o g e n o m i c s & P h a r m a c o p r o t e o m i c s ISSN: 2153-0645