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Barcelona, Spain

Del Rio-Espinola A.,Autonomous University of Barcelona | Fernandez-Cadenas I.,Autonomous University of Barcelona | Giralt D.,Autonomous University of Barcelona | Quiroga A.,Experimental Cardiology Research Laboratory | And 20 more authors.
Annals of Neurology

Objective: Wide interindividual variability exists in response to tissue plasminogen activator (t-PA) treatment in the acute phase of ischemic stroke. We aimed to find genetic variations associated with hemorrhagic transformation (HT) and mortality rates after t-PA. We then generated a clinical-genetic model for predicting t-PA response. Methods: Our prospective study used SNPlex to genotype 140 single nucleotide polymorphisms (SNPs) from 97 candidate genes in 3 patient cohorts. The cohorts included 1,172 patients who were treated with t-PA; 20.9% of them developed HT as evaluated by systematic brain computed tomography scan, and 10.6% died. A predictive model was generated by logistic regression (LR). Functional studies included real time quantitative polymerase chain reaction, nephelometry, and Western blot for alpha-2-macroglobulin (A2M) and activated partial thromboplastin time measurement for coagulation factor XII (FXII). Results: Replication analysis revealed that the SNP rs669 (Val1000Ile) in A2M was associated with HT, and rs1801020 (-4C>T) of F12 was associated with in-hospital death. The rs669 SNP withstood Bonferroni correction for HT (p< 3.57E-4). LR-based scores predicted HT occurrence (p = 9.13E-15) and in-hospital mortality (p = 8.7E-9) and were validated in an independent cohort. Val1000Ile modified A2M serum levels at baseline and after t-PA infusion, but not mRNA expression or protein structure; -4C>T affected FXII activity both prior to and after t-PA treatment. Interpretation: Two functional polymorphisms were consistently associated with t-PA safety. Our validated LR-based score predicts t-PA safety in the Spanish population. Copyright © 2012 American Neurological Association. Source

Valdivielso P.,Lipids Unit | Valdivielso P.,University of Malaga | Puerta S.,Lipids Unit | Rioja J.,University of Malaga | And 6 more authors.
Clinica Chimica Acta

Background: Postprandial hyperlipidemia is a common feature in type 2 diabetes; our aim was to investigate whether there is an association between subclinical peripheral arterial disease (PAD) and the levels of apolipoprotein B48, as a specific marker for postprandial lipidemia. Methods: We enrolled 101 patients with type 2 diabetes and 73 controls free from clinical cardiovascular disease. Main outcome measures were the presence of subclinical PAD, assessed by the ankle-brachial index, and the intestinal particles measured as the concentration of apolipoprotein B48 at fasting and 4 h after a mixed breakfast. Results: No control had subclinical PAD. Of the 101 diabetic patients, 21 had subclinical PAD. The levels of apo B48, both fasting and postprandial, were only significantly raised in the diabetic patients who had PAD. The diabetic patients without vascular disease had similar concentrations of triglycerides and apo B48 to the controls. In binary logistic regression analyses, only smoking and postprandial B48 levels, in addition to diabetes, were independently associated with PAD. On the other hand, PAD but not diabetes was associated with the fasting and postprandial levels of apo B48. Conclusion: Our study suggests that apolipoprotein B48 levels might be a marker of occult PAD in patients suffering from type 2 diabetes mellitus. Accordingly, subclinical PAD should be taken into account in studies on postprandial lipidemia involving patients with diabetes. © 2010 Elsevier B.V. All rights reserved. Source

Alipour A.,Center for Diabetes and Vascular Medicine | Valdivielso P.,Lipids Unit | Elte J.W.F.,Center for Diabetes and Vascular Medicine | Janssen H.W.,St. Franciscus Gasthuis | And 7 more authors.
European Journal of Clinical Investigation

Background Postprandial accumulation of atherogenic remnants has been described in patients with type 2 diabetes mellitus (T2DM), familial combined hyperlipidaemia (FCH), familial hypercholesterolaemia (FH) and coronary artery disease (CAD). Scarce data are available on fasting plasma apolipoprotein (apo) B48 levels in relation to these conditions and atherosclerosis. Design Treated patients with FCH (18), FH (20), T2DM (26), CAD (65), T2DM with CAD (T2DM/CAD) (28) and 33 healthy controls were included. Intima-media thickness (IMT) measurements were carried out to investigate subclinical atherosclerosis. Results LDL-C and total apoB were lowest in patients with T2DM/CAD owing to the more frequent use of lipid-lowering medication. Fasting plasma apoB48 was elevated in patients with FCH (11·38±1·50mg/L) and T2DM/CAD (9·65±1·14mg/L) compared with the other groups (anova, P<0·01). CAD patients (8·09±0·57mg/L) had higher apoB48 levels than controls (5·74±0·55mg/L) and FH patients (5·40±0·51mg/L) (P=0·02). IMT was highest in subjects with T2DM/CAD (0·77±0·03mm) (P<0·01). The lowest IMT was measured in controls (0·56±0·02mm) and FCH patients (0·60±0·03mm). In the total group, the best association for apoB48 was found with fasting triglyceride (Pearson's r=0·72, P<0·001). In the subjects not using statins (n=74), the best correlation was found with IMT (r=0·52; P<0·001), whereas total apoB was not associated with IMT (r=0·20, P=0·12). Conclusions ApoB48 concentrations are highest in patients with FCH and in atherosclerotic subjects with T2DM. In patients not using statins, the surrogate atherosclerosis marker IMT correlates best with apoB48, suggesting that fasting apoB48 may help to detect subjects at risk. © 2011 Stichting European Society for Clinical Investigation Journal Foundation. Source

Clemente-Postigo M.,Laboratorio Of Investigacion Del Hospital Virgen Of La Victoria Of Malaga | Queipo-Ortuno M.,CIBER ISCIII | Valdivielso P.,Lipids Unit | Tinahones F.J.,CIBER ISCIII | And 2 more authors.
Clinical Biochemistry

ObjectivesApolipoprotein C-III (APOC3) is a component of triglyceride rich lipoproteins, and SstI polymorphism has been associated with hypertriglyceridemia. Apolipoprotein A-I (APOA1) is the major component of HDL and MspI polymorphism has been associated with APOA1 and HDL-C levels. Thus, we study the influence of these polymorphisms in the postprandial response in metabolic syndrome (MS). Design and methods73 MS patients and 21 healthy subjects underwent a fat overload, with measurements of their fasting and postprandial lipid profile. The APOC3 SstI and the APOA1. MspI polymorphisms were genotyped. ResultsNo significant differences were found in the lipid profile with respect to the MspI genotype. Patients with the S2S2 APOC3 genotype had significantly higher fasting and postprandial triglyceride levels and postprandial APOC3 and chylomicron-triglyceride levels compared with the other SstI APOC3 genotypes. ConclusionsHomozygosity for the minor allele of the APOC3 SstI polymorphism was associated to a worse postprandial response in MS patients. © 2010 The Canadian Society of Clinical Chemists. Source

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