Cardiopatie Coronariche e Coagulazione
Blood. 2010 Sep 1. [Epub ahead of print]
Polymorphisms at LDLR locus may be associated with coronary artery disease through modulation of coagulation factor VIII activity and independently from lipid profile.
Martinelli N, Girelli D, Lunghi B, Pinotti M, Marchetti G, Malerba G, Pignatti PF, Corrocher R, Olivieri O, Bernardi F.
Department of Medicine, University of Verona, Verona, Italy;
Abstract
High levels of coagulation factor VIII (FVIII) have been associated with cardiovascular disease. Low-density lipoprotein receptor (LDLR) has been recently demonstrated to contribute to FVIII clearance from plasma. The aim of this study was to evaluate 3 single nucleotide polymorphisms (SNPs) in SMARCA4-LDLR gene locus (rs1122608, rs2228671, and rs688) and FVIII coagulant activity (FVIII:c) in subjects with (n=692) or without (n=291) angiographically confirmed coronary artery disease (CAD). High FVIII:c levels were an independent risk factor for CAD. The rs688 and rs2228671 genotypes were predictors of FVIII:c with T alleles associated with higher FVIII:c levels. The rs2228671T allele was associated also with reduced total and LDL cholesterol levels. With respect to the risk of CAD, no association was found for rs2228671. Consistently with higher FVIII:c levels, the rs688T allele was associated with CAD, while, consistently with a favourable lipid profile, the rs1122608T allele was associated with a decreased CAD prevalence. After adjustment for all classical cardiovascular risk factors, including plasma lipids, rs688 remained associated with CAD (OR for T carriers: 1.67 with 95%CI 1.10-2.54). Haplotypes analysis confirmed such results. Our data suggest that SNPs at LDLR locus modulate FVIII:c levels and may be associated with CAD risk independently from plasma lipids.
PMID: 20810930 [PubMed - as supplied by publisher]
Clin Appl Thromb Hemost. 2009 Feb;15(1):119-22.
Temporal and genotype-driven variation of factor VII levels in patients with acute myocardial infarction.
Ferraresi P, Campo G, Marchetti G, Pinotti M, Valgimigli M, Gemmati D, Ferrari R, Bernardi F.
PMID: 19150996
Nat Genet. 2009 Mar;41(3):334-41. Epub 2009 Feb 8.
Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.
Myocardial Infarction Genetics Consortium, Kathiresan S, Voight BF, Purcell S, Musunuru K, Ardissino D, Mannucci PM, Anand S, Engert JC, Samani NJ, Schunkert H, Erdmann J, Reilly MP, Rader DJ, Morgan T, Spertus JA, Stoll M, Girelli D, McKeown PP, Patterson CC, Siscovick DS, O'Donnell CJ, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Melander O, Altshuler D, Ardissino D, Merlini PA, Berzuini C, Bernardinelli L, Peyvandi F, Tubaro M, Celli P, Ferrario M, Fetiveau R, Marziliano N, Casari G, Galli M, Ribichini F, Rossi M, Bernardi F, Zonzin P, Piazza A, Mannucci PM, Schwartz SM, Siscovick DS, Yee J, Friedlander Y, Elosua R, Marrugat J, Lucas G, Subirana I, Sala J, Ramos R, Kathiresan S, Meigs JB, Williams G, Nathan DM, MacRae CA, O'Donnell CJ, Salomaa V, Havulinna AS, Peltonen L, Melander O, Berglund G, Voight BF, Kathiresan S, Hirschhorn JN, Asselta R, Duga S, Spreafico M, Musunuru K, Daly MJ, Purcell S, Voight BF, Purcell S, Nemesh J, Korn JM, McCarroll SA, Schwartz SM, Yee J, Kathiresan S, Lucas G, Subirana I, Elosua R, Surti A, Guiducci C, Gianniny L, Mirel D, Parkin M, Burtt N, Gabriel SB, Samani NJ, Thompson JR, Braund PS, Wright BJ, Balmforth AJ, Ball SG, Hall AS; Wellcome Trust Case Control Consortium, Schunkert H, Erdmann J, Linsel-Nitschke P, Lieb W, Ziegler A, König I, Hengstenberg C, Fischer M, Stark K, Grosshennig A, Preuss M, Wichmann HE, Schreiber S, Schunkert H, Samani NJ, Erdmann J, Ouwehand W, Hengstenberg C, Deloukas P, Scholz M, Cambien F, Reilly MP, Li M, Chen Z, Wilensky R, Matthai W, Qasim A, Hakonarson HH, Devaney J, Burnett MS, Pichard AD, Kent KM, Satler L, Lindsay JM, Waksman R, Knouff CW, Waterworth DM, Walker MC, Mooser V, Epstein SE, Rader DJ, Scheffold T, Berger K, Stoll M, Huge A, Girelli D, Martinelli N, Olivieri O, Corrocher R, Morgan T, Spertus JA, McKeown P, Patterson CC, Schunkert H, Erdmann E, Linsel-Nitschke P, Lieb W, Ziegler A, König IR, Hengstenberg C, Fischer M, Stark K, Grosshennig A, Preuss M, Wichmann HE, Schreiber S, Hólm H, Thorleifsson G, Thorsteinsdottir U, Stefansson K, Engert JC, Do R, Xie C, Anand S, Kathiresan S, Ardissino D, Mannucci PM, Siscovick D, O'Donnell CJ, Samani NJ, Melander O, Elosua R, Peltonen L, Salomaa V, Schwartz SM, Altshuler D.
Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. skathiresan1@partners.org
Erratum in:
- Nat Genet. 2009 Jun;41(6):762. Knouff, Christopher W [added]; Waterworth, Dawn M [added]; Walker, Max C [added]; Mooser, Vincent [added].
Abstract
We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10(-3)). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.
PMID: 19198609 [PubMed - indexed for MEDLINE]
Combined effect of hemostatic gene polymorphisms and the risk of myocardial infarction in patients with advanced coronary atherosclerosis.
Martinelli N, Trabetti E, Pinotti M, Olivieri O, Sandri M, Friso S, Pizzolo F, Bozzini C, Caruso PP, Cavallari U, Cheng S, Pignatti PF, Bernardi F, Corrocher R, Girelli D.
Department of Clinical and Experimental Medicine, University of Verona, Verona, Italy.
BACKGROUND: Relative little attention has been devoted until now to the combined effects of gene polymorphisms of the hemostatic pathway as risk factors for Myocardial Infarction (MI), the main thrombotic complication of Coronary Artery Disease (CAD). The aim of this study was to evaluate the combined effect of ten common prothrombotic polymorphisms as a determinant of MI. METHODOLOGY/PRINCIPAL FINDINGS: We studied a total of 804 subjects, 489 of whom with angiographically proven severe CAD, with or without MI (n = 307; n = 182; respectively). An additive model considering ten common polymorphisms [Prothrombin 20210G>A, PAI-1 4G/5G, Fibrinogen beta -455G>A, FV Leiden and "R2", FVII -402G>A and -323 del/ins, Platelet ADP Receptor P2Y12 -744T>C, Platelet Glycoproteins Ia (873G>A), and IIIa (1565T>C)] was tested. The prevalence of MI increased linearly with an increasing number of unfavorable alleles (chi(2) for trend = 10.68; P = 0.001). In a multiple logistic regression model, the number of unfavorable alleles remained significantly associated with MI after adjustment for classical risk factors. As compared to subjects with 3-7 alleles, those with few (</=2) alleles had a decreased MI risk (OR 0.34, 95%CIs 0.13-0.93), while those with more (>/=8) alleles had an increased MI risk (OR 2.49, 95%CIs 1.03-6.01). The number of procoagulant alleles correlated directly (r = 0.49, P = 0.006) with endogenous thrombin potential. CONCLUSIONS: The combination of prothrombotic polymorphisms may help to predict MI in patients with advanced CAD.
PMID: 18253477 [PubMed - indexed for MEDLINE]
Gemmati D, Federici F, Campo G, Tognazzo S, Serino ML, De Mattei M, Valgimigli M, Malagutti P, Guardigli G, Ferraresi P, Bernardi F, Ferrari R, Scapoli GL, Catozzi L.
Center Study Haemostasis and Thrombosis, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Ferrara, Italy. d.gemmati@unife.it
It has been demonstrated recently that coagulation factor XIII (FXIII) plays an extraordinary role in myocardial healing after infarction, improving survival in a mouse model. Common FXIII gene variants (i.e. FXIIIA-V34L and FXIIIB-H95R) significantly influence the molecular activity. To evaluate whether there is a relationship between the two FXIII gene variants and survival in patients after myocardial infarction (MI), V34L and H95R were PCR-genotyped in a cohort of 560 MI cases and follow-up was monitored. Cases with ST-segment elevation MI (STEMI) were 416 (74.3%) and 374 of these were treated with primary percutaneous coronary intervention (PCI) (89.9%). The remaining 144 patients showed non-ST-segment elevation MI (NSTEMI) at enrollment. The combined endpoint was the occurrence of death, re-infarction, and heart failure. Kaplan-Meier analysis at one year yielded an overall rate for adverse events of 24.5% with a lower incidence in the L34-carriers (28.8% vs 17.1%; log-rank, P = 0.00025), similar to that of the 416 STEMI (23.8%) being (28.0% and 16.9%; VV34- and L34-carriers respectively; log-rank, P = 0.001). Primary PCI-group had a slight lower incidence (22.9%) of adverse events (26.8% and 17.1%; VV34- and L34-carriers respectively; log-rank, P = 0.009). During hospitalization, 506 patients received PCI (374 primary PCI and 132 elective PCI). Significance was conserved also in the overall PCI-group (28.6% and 17.8%; VV34- and L34-carriers respectively; log-rank, P = 0.001). Similar findings were observed at 30 days follow-up. Cases carrying both FXIII variants had improved survival rate (log-rank, P = 0.019). On the other hand, minor bleeding complications were found increased in L34-carriers (P = 0.0001) whereas major bleeding complications were not. Finally, more direct evidence on the role of FXIII molecule on survival might come from the fact that despite significant FXIII antigen reductions observed in cases after MI, regardless the FXIII genotype considered, L34-carriers kept almost normal FXIII activity (VV34- vs L34-carriers; P < 0.001). We conclude that FXIII L34-allele improves survival after MI in all the groups analyzed, possibly through its higher activity associated with assumable positive effects on myocardial healing and recovered functions. Genetically determined higher FXIII activity might influence post-MI outcome. This paves the way for using FXIII molecules to improve myocardial healing, recovery of functions, and survival after infarction.
PMID: 17515963 [PubMed - indexed for MEDLINE]
Tissue factor and coagulation factor VII levels during acute myocardial infarction: association with genotype and adverse events.
Campo G, Valgimigli M, Ferraresi P, Malagutti P, Baroni M, Arcozzi C, Gemmati D, Percoco G, Parrinello G, Ferrari R, Bernardi F.
Department of Cardiology, University of Ferrara, 44100 Ferrara, Italy.
OBJECTIVE: We investigated in patients with ongoing myocardial infarction (MI) whether coagulation factor VII (FVII) and tissue factor (TF) levels are affected at admission by genetic components and whether they may predict subsequent cardiovascular events. METHODS AND RESULTS: 256 patients admitted for MI were evaluated for FVII and TF antigen levels before any treatment at entry, and were genotyped for FVII and TF polymorphisms. FVII gene insertions at -323, 11293 and the -402G/A change predicted FVII levels and explained 14% of variance. The -603 TF gene polymorphism failed to affect significantly TF levels (P=0.07). These variables were correlated with the incidence of death (36 patients) and reinfarction (9 patients) after a median follow-up of 397 days. Events were independently predicted by FVII (HR 2.1, 95% CI 1.2 to 5.7) and TF (HR 4.1, 95% CI 2 to 11) levels. Composite end point was significantly worse when both parameters were above the receiver-operating characteristics (ROC) values (HR 8.3, 95% CI 5 to 18, compared with FVII and TF below), and above the ROC value of TF (>630 pg/mL) it differed among FVII genotype groups. CONCLUSIONS: Admission FVII and TF antigen levels, partially predicted by polymorphisms, are independent predictors of mortality and reinfarction in patients with acute MI.
PMID: 17008590 [PubMed - indexed for MEDLINE]
Influence of polymorphisms in the factor VII gene promoter on activated factor VII levels and on the risk of myocardial infarction in advanced coronary atherosclerosis.
Bozzini C, Girelli D, Bernardi F, Ferraresi P, Olivieri O, Pinotti M, Martinelli N, Manzato F, Friso S, Villa G, Pizzolo F, Beltrame F, Corrocher R.
Department of Clinical and Experimental Medicine, University of Verona, Policlinico G.B. Rossi, 37134 Verona, Italy. claudibozz@inwind.it
In this study, we investigate the influence of three factor VII (FVII) gene polymorphisms on activated FVII levels (FVIIa), and also on the risk of myocardial infarction (MI) in patients with advanced coronary atherosclerotic disease (CAD). The -323A2 allele in the promoter is known to be associated with low FVII levels, and has been suggested to protect against MI in some studies. The -402GA promoter polymorphism, that in vitro has been associated with having opposite effect, is less well studied clinically. For this study, plasma FVIIa levels and three FVII gene polymorphisms were assessed in 934 subjects of both sexes, all with an angiographic documentation of coronary vessels. Our results show that two promoter polymorphisms, plasma cholesterol, and gender, were significant predictors of FVIIa levels. The -402A allele was associated to a significant increase of FVIIa levels in males (by 19.2%). In a selected clinical model including the patients with severe CAD, with or without a thrombotic complication (MI), male carriers of the -402A had an increased risk of MI (OR=1.79; 95% CI 1.15-2.80). The -323A2 allele was associated to a significant decrease in FVIIa (by 36.02% in males, and 39.7% in females). Male carriers of the -323A2 were protected from MI (OR=0.6; 95% CI 0.39-0.94), but only after correction for the confounding effect of combined heterozygosity for the promoter polymorphisms. We can conclude that FVII gene polymorphisms with an opposite effect on FVIIa levels may modulate the risk of MI in males with advanced CAD. This study highlights a "within-gene" interaction, and the need to explore polymorphisms in candidate gene(s) in detail.
PMID: 15351850 [PubMed - indexed for MEDLINE]
Angiotensin-converting enzyme insertion/deletion polymorphism and risk of restenosis after directional coronary atherectomy followed by stent implantation.
Canosi U, Angelica Merlini P, Bernardi F, Repetto A, Bramucci E, Ferrario M, Angoli L, Gnecchi M, Ferraresi P, Marchetti G, Tavazzi L, Ardissino D.
Divisione di Cardiologia IRCCS Policlinico San Matteo, Piazza Golgi 2, 27100 Pavia, Italy. laboratorio.emodinamica@smatteo.pv.it
The D allele of the insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene is associated with higher plasma and tissue ACE levels, which enhance the stimulus for neo-intimal hyperplasia. Plaque debulking before stenting reduces the plaque-related determinants of in-stent restenosis and provides an ideal clinical model for studying neointimal hyperplasia. We prospectively studied 113 consecutive patients undergoing elective DCA followed by stent implantation. The presence of I/D in ACE genome DNA was analysed by means of polymerase chain reaction. Follow-up coronary angiography was performed 6-12 months after DCA, and all of the angiograms were quantitatively analysed. The baseline clinical and angiographic characteristics of the patients with a D/D (33%), I/D (52%) and I/I (15%) genotype were well balanced. There were no significant differences in minimal lumen diameter before and after the procedure or at follow-up, and no significant differences in acute gain, late loss or the loss index. Our results indicate that ACE I/D polymorphism does not influence the risk of developing angiographic restenosis in patients undergoing DCA followed by stent implantation.
PMID: 15045142 [PubMed - indexed for MEDLINE]
Polymorphisms in the factor VII gene and the risk of myocardial infarction in patients with coronary artery disease.
Girelli D, Russo C, Ferraresi P, Olivieri O, Pinotti M, Friso S, Manzato F, Mazzucco A, Bernardi F, Corrocher R.
Department of Clinical and Experimental Medicine, University of Verona, Italy. digigi@borgoroma.univr.it
BACKGROUND: High plasma levels of coagulation factor VII have been suggested to be predictors of death due to coronary artery disease. Since polymorphisms in the factor VII gene contribute to variations in factor VII levels, such polymorphisms may be associated with the risk of myocardial infarction, which is precipitated by thrombosis. METHODS: We studied a total of 444 patients, 311 of whom had severe, angiographically documented coronary atherosclerosis. Of these 311 patients, 175 had documentation of a previous myocardial infarction. As a control group, 133 patients with normal coronary arteriograms were also included. We measured the levels of activated factor VII and assessed three polymorphisms in the factor VII gene, one involving the promoter (A1 and A2 alleles), one involving the catalytic region (R353Q), and one involving intron 7. RESULTS: Each of the polymorphisms influenced factor VII levels. Patients with the A2A2 and QQ genotypes had the lowest levels of activated factor VII (66 percent and 72 percent lower, respectively, than the levels in patients with the wild-type genotypes). The frequencies of the various genotypes in the patients free of coronary artery disease were similar to those in the entire population of patients with coronary artery disease. In the latter group, there were significantly more heterozygotes and homozygotes for the A2 and Q alleles among those who had not had a myocardial infarction than among those who had had an infarction (P=0.008 for the presence of the promoter polymorphism and P=0.01 for the presence of the R353Q polymorphism by chi-square analysis). The adjusted odds ratio for myocardial infarction among the patients with the A1A2 or RQ genotype was 0.47 (95 percent confidence interval, 0.27 to 0.81). CONCLUSIONS: Our findings suggest that certain factor VII genotypes have a role in protection against myocardial infarction. This may explain why some patients do not have myocardial infarction despite the presence of severe coronary atherosclerosis.
PMID: 10984565 [PubMed - indexed for MEDLINE]
