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Prognostic value of annexin A5 −1 C/T polymorphism in a long term follow‐up after premature myocardial infarction

2007; Elsevier BV; Volume: 5; Issue: 4 Linguagem: Inglês

10.1111/j.1538-7836.2007.02419.x

1538-7933

Vanessa Roldán, Francisco Marı́n, Rocío Gónzález‐Conejero, Javier Corral, Vicente Vicente,

Atrial Fibrillation Management and Outcomes

Annexin A5 is the most representative member of the annexin family, and possesses a broad range of functions, most of these related to its phospholipid‐binding capacity [1Thiagarajan P. Tait J.F. Binding of annexin V/placental anticoagulant protein I to platelets.J Biol Chem. 1990; 265: 17420-3Abstract Full Text PDF PubMed Google Scholar, 2Tait J.F. Gibson D. Measurement of membrane phospholipid asymmetry in normal and sickle‐cell erythrocytes by means of annexin V binding.J Lab Clin Med. 1994; 123: 741-8PubMed Google Scholar]. Thus, in the hemostatic system annexin A5 behaves as a potent anticoagulant molecule [3Andree H.A. Stuart M.C. Hermens W.T. Reutelingsperger C.P. Hemker H.C. Frederik P.M. Willems G.M. Clustering of lipid‐bound annexin V may explain its anticoagulant effect.J Biol Chem. 1992; 267: 17907-12Abstract Full Text PDF PubMed Google Scholar, 4Ravanat C. Archipoff G. Beretz A. Freund G. Cazenave J.P. Freyssinet J.M. Use of annexin V to demonstrate the role of phosphatidyl‐serine exposure in the maintenance of haemostatic balance by endothelial cells.Biochem J. 1992; 282: 7-13Crossref PubMed Scopus (60) Google Scholar, 5Van Heerde W.L. De Groot P.G. Reutelingsperger C.P.M. The complexity of the phospholipid binding protein annexin V.Thromb Haemost. 1995; 73: 172-9Crossref PubMed Scopus (199) Google Scholar]. A preliminary report described a C to T transition in exon 2 of the annexin A5 gene, affecting the nucleotide preceding the initiation ATG codon (position −1) [6Van Heerde W. Jumilly A.L. Lux P. Meyer D. Hamulyak K. Lavergne J.M. Reutelingsperger C.P.M. Mutations in the annexin V gene, a new risk factor for venous thrombosis.Thromb Haemost. 1999; S: 537Google Scholar]. We have demonstrated that this polymorphism affects the efficiency of translation; the −1 T allele is associated with a 5.9‐fold increase in the capacity of protein synthesis compared with the −1 C allele [7González‐Conejero R. Corral J. Roldán V. Martínez C. Marín F. Rivera J. Iniesta J.A. Lozano M.L. Marco P. Vicente V. A common polymorphism in the Annexin V Kozak sequence (−1 C to T) increases translation efficiency and plasma levels of annexin V, and decreases the risk of myocardial infarction in young patients.Blood. 2002; 100: 2081-6Crossref PubMed Google Scholar]. Indeed, although there are conflictive data [8Van Heerde W.L. Kenis H. Schoormans S. Lap P. Reutelingsperger C.P. The −1 C > T mutation in the annexin A5 gene does not affect plasma levels of annexin A5.Blood. 2003; 101: 4223-4Crossref PubMed Scopus (11) Google Scholar], we observed that carriers of the −1 CC genotype displayed lower plasmatic levels of annexin A5 than carriers of the −1 T allele [7González‐Conejero R. Corral J. Roldán V. Martínez C. Marín F. Rivera J. Iniesta J.A. Lozano M.L. Marco P. Vicente V. A common polymorphism in the Annexin V Kozak sequence (−1 C to T) increases translation efficiency and plasma levels of annexin V, and decreases the risk of myocardial infarction in young patients.Blood. 2002; 100: 2081-6Crossref PubMed Google Scholar], which supported a protective role for the annexin A5 −1 T allele in premature myocardial infarction (MI) [7González‐Conejero R. Corral J. Roldán V. Martínez C. Marín F. Rivera J. Iniesta J.A. Lozano M.L. Marco P. Vicente V. A common polymorphism in the Annexin V Kozak sequence (−1 C to T) increases translation efficiency and plasma levels of annexin V, and decreases the risk of myocardial infarction in young patients.Blood. 2002; 100: 2081-6Crossref PubMed Google Scholar]. The aim of this study was to evaluate whether the presence of a −1 T annexin A5 allele in young patients who survived a first MI episode might also protect for subsequent coronary events during a large follow‐up. We included 222 consecutive patients (91% male, aged 43 ± 6 years) who survived a first premature acute MI occurring before 45 years, and were followed during a long period (36 months) in the same unique cardiology outpatient clinic with a homogeneous therapy according to current guidelines [9Antman E.M. Anbe D.T. Armstrong P.W. Bates E.R. Green L.A. Hand M. Hochman J.S. Krumholz H.M. Kushner F.G. Lamas G.A. Mullany C.J. Ornato J.P. Pearle D.L. Sloan M.A. Smith Jr, S.C. American College of Cardiology; American Heart Association; Canadian Cardiovascular SocietyACC/AHA guidelines for the management of patients with ST‐elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction).J Am Coll Cardiol. 2004; 44: 671-719Crossref PubMed Scopus (1911) Google Scholar]. During follow‐up, adverse events were considered as cardiac death, new MI or unstable angina, and urgent revascularization (surgery or percutaneous transluminal angioplasty). All subjects included gave their informed consent to enter the study, which had been approved by the local Ethics Committee, and was performed according to the declaration of Helsinki. Genotyping of the annexin A5 −1 C/T was performed by polymerase chain reaction–allele‐specific restriction analysis (PCR–ASRA) with mutated primers, essentially as indicated elsewhere [7González‐Conejero R. Corral J. Roldán V. Martínez C. Marín F. Rivera J. Iniesta J.A. Lozano M.L. Marco P. Vicente V. A common polymorphism in the Annexin V Kozak sequence (−1 C to T) increases translation efficiency and plasma levels of annexin V, and decreases the risk of myocardial infarction in young patients.Blood. 2002; 100: 2081-6Crossref PubMed Google Scholar]. Categorical data were compared using the chi‐square test. Univariate analysis by Cox regression was performed. Multiple analysis was performed using multivariate Cox regression analysis (forward conditional method, SPSs statistical package for windows 10.0 software). The differences with a two‐tailed P‐value < 0.05 were considered significant. Clinical characteristics are recorded in Fig. 1. 42 adverse events were recorded during the follow‐up period (18.9%). Attending to the genotype, only 2/39 −1 T carriers (5.1%) suffered any event, compared with 40/183 CC patients (21.9%; P = 0.024). Fig. 1 also shows a Kaplan–Maier survival plot showing the new events according to the annexin A5 −1 C/T genotype. The adverse events were four cardiac deaths (all of them CC), 39 new MI or unstable angina (2 T carriers and 37 CC patients), and 29 urgent revascularization (only one T carrier and 28 CC patients). After multivariate analysis, only diabetes [P < 0.01; hazard ratio (HR) 4.28] and the annexin A5 −1 T allele (P = 0.045; HR 0.23) showed an independent and significant influence in the prognosis (Fig. 1). Accordingly, we analyzed the interaction between annexin A5 polymorphism and diabetes. The worst combination (CC genotype and the presence of diabetes at the moment of the MI) displays an adjusted HR of 21.61 (95% CI, 2.75−170.08; P = 0.035) to suffer a new adverse event. There were no differences between insulin (51%) and not insulin (49%) dependent diabetes. Therapy was not related with the prognosis (betablockers P = 0.887; statins P = 0.826 and ACE or ARB P = 0.316). As the description by Weiss et al. [10Weiss E.J. Bray P.F. Tayback M. Schulman S.P. Kickler T.S. Becker L.C. Weiss J.L. Gerstenblith G. Goldschmidt‐Clermont P.J. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis.N Engl J Med. 1996; 334: 1090-4Crossref PubMed Scopus (702) Google Scholar] of the association between the PlA2 polymorphism of the glycoprotein IIIa gene and acute coronary thrombosis, hundreds of studies have evaluated the role of thousands polymorphisms in the development of MI [11Ozaki K. Tanaka T. Genome‐wide association study to identify SNPs conferring risk of myocardial infarction and their functional analyses.Cell Mol Life Sci. 2005; 62: 1804-13Crossref PubMed Scopus (46) Google Scholar]. These polymorphisms might have a stronger role in patients with early MI as these patients usually have fewer coronary lesions, and their risk factor profile is also different, with a higher proportion of smokers and familiar history of ischemic heart disease [12Zimmerman F.H. Cameron A. Fisher L.D. Ng G. Myocardial infarction in young adults: angiographic characterization, risk factors and prognosis (Coronary Artery Surgery Study Registry).J Am Coll Cardiol. 1995; 26: 654-61Crossref PubMed Scopus (414) Google Scholar, 13Atherosclerosis, Thrombosis, and Vascular Biology Italian Study GroupNo evidence of association between prothrombotic gene polymorphisms and the development of acute myocardial infarction at a young age.Circulation. 2003; 107: 1117-22Crossref PubMed Scopus (202) Google Scholar]. However, only a few studies have explored the prognostic impact of common polymorphisms on the follow‐up after the acute event, despite the fact that after MI, the risk of suffering from a new adverse event is even higher than before the first episode, despite the antitrombotic treatment [14Antithrombotic Triallists CollaborationCollaborative meta‐analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.BMJ. 2002; 324: 71-86Crossref PubMed Google Scholar]. Functional polymorphisms affecting the hemostatic function are good candidates to play a role in MI [15Lane D.A. Grant P.J. Role of hemostatic gene polymorphisms in venous and arterial thrombotic disease.Blood. 2000; 95: 1517-32Crossref PubMed Google Scholar], particularly at a young age, where thrombus formation as a result of plaque erosion or rupture has been suggested as the main mechanism [16Williams M.J. Restieaux N.J. Low C.J.S. Myocardial infarction in young people with normal coronary arteries.Heart. 1998; 79: 191-4Crossref PubMed Scopus (95) Google Scholar]. Accordingly, we have studied whether the annexin A5 −1 C/T polymorphism could continue playing its anticoagulant role after the acute event. Certainly, we found that the protection of the annexin A5 −1 T allele (associated with high plasma annexin A5 levels) observed in the first thrombotic event [7González‐Conejero R. Corral J. Roldán V. Martínez C. Marín F. Rivera J. Iniesta J.A. Lozano M.L. Marco P. Vicente V. A common polymorphism in the Annexin V Kozak sequence (−1 C to T) increases translation efficiency and plasma levels of annexin V, and decreases the risk of myocardial infarction in young patients.Blood. 2002; 100: 2081-6Crossref PubMed Google Scholar] was maintained in the follow‐up, and carriers of the annexin A5 −1 T allele have a 4‐fold lower risk of developing a new event. From all other risk factors, only diabetes played a role in the prognosis after a premature MI, increasing 4.3‐fold the risk of a new event. Our first study was performed in patients who survived an acute thrombotic episode. Therefore, a survival bias cannot be avoided in the disease‐association study, and likely early mortality in patients could lead to an underestimation of the annexin A5 −1 C/T polymorphism. In the present study, this possible selection bias has been avoided, and the long follow‐up (36 months) of a wide cohort of homogeneous treated young MI patients has allowed us to suggest that the protective role of this polymorphism against thrombotic episodes might be maintained after the first episode. However, our study has relevant limitations including potential confounding by population stratification, and limited statistical power. Therefore, further studies performed in other populations including large samples are necessary to confirm our results. Thus, our results have to be taken into account as preliminary data. The authors state that they have no conflict of interest. JC and RG‐C are contratados de investigación Ramón y Cajal from Universidad de Murcia, Spain. This study was supported by grants FIS 00/0328, SAF 2003‐00840, and Fundación Séneca (00583/PI/04).