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Two functional polymorphisms were consistently associated with t-PA safety. Our validated LR-based score predicts t-PA safety in the Spanish population.

Human AKR (aldo-keto reductase) 1C proteins (AKR1C1-AKR1C4) exhibit relevant activity with steroids, regulating hormone signalling at the pre-receptor level. In the present study, investigate the activity of the four human AKR1C enzymes with retinol and retinaldehyde. All of the enzymes except AKR1C2 showed retinaldehyde reductase activity with low Km values (~1 μM). The kcat values were also low (0.18-0.6 min-1), except for AKR1C3 reduction of 9-cis-retinaldehyde whose kcat was remarkably higher (13 min-1). Structural modelling of the AKR1C complexes with 9-cis-retinaldehyde indicated a distinct conformation of Trp227, caused by changes in residue 226 that may contribute to the activity differences observed. This was partially supported by the kinetics of the AKR1C3 R226P mutant. Retinol/retinaldehyde conversion, combined with the use of the inhibitor flufenamic acid, indicated a relevant role for endogenous AKR1Cs in retinaldehyde reduction in MCF-7 breast cancer cells. Overexpression of AKR1C proteins depleted RA (retinoic acid) transactivation in HeLa cells treated with retinol. Thus AKR1Cs may decrease RA levels in vivo. Finally, by using lithocholic acid as an AKR1C3 inhibitor and UVI2024 as an RA receptor antagonist, we provide evidence that the pro-proliferative action of AKR1C3 in HL-60 cells involves the RA signalling pathway and that this is in part due to the retinaldehyde reductase activity of AKR1C3.

Background: Variants in the 5-lipoxygenase-activating protein (ALOX5AP) and phosphodiesterase 4D (PDE4D) genes have first been associated with ischemic stroke (IS) through whole-genome linkage screens. However, association studies obtained conflicting results. We aimed to investigate the contribution of selected single nucleotide polymorphisms (SNPs) in these genes for the first time in a large Iberian population. Methods: A case-control design was used to analyze one SNP in ALOX5AP and five SNPs in PDE4D in a total of 1,092 IS patients and 781 healthy controls of two different subsets from Spain and Portugal. The analysis was adjusted for confounding variables and the results were integrated in a meta-analysis of all case-control studies. In addition, ALOX5AP gene expression levels were determined in controls and IS cases. Results: A first meta-analysis of both subsets showed that the T allele of the SG13S114 SNP in ALOX5AP was a risk factor for IS after Bonferroni correction [OR = 1.22 (1.06–1.40); p = 0.006]. A second meta-analysis of white populations confirmed these results [OR = 1.18 (1.07–1.31); p = 0.001]. ALOX5AP gene expression analysis in a subset of controls and cases revealed that the SG13S114 genotypes modulate mRNA levels of ALOX5AP (p = 0.001) and mRNA levels were higher in IS cases (2.8 ± 2.4%) than in controls (1.4 ± 1.3%; p = 0.003). No association of the variants in PDE4D with IS was observed in our study. Conclusions: The ALOX5AP SG13S114 variant is an independent risk factor for IS in the Iberian population and is associated with ALOX5AP expression levels. The role of this gene in stroke merits further investigation.

Stroke is a multifactorial disease responsible for nearly 10% of deaths each year in industrialized countries. While some monogenic forms of stroke have been described, the vast majority result from the common polygenic form of the disease. Progress in molecular genetics has allowed the identification, through genome-wide linkage analysis, of various candidate genes, including the genes encoding PDE4D and ALOX5AP. Since then, genetic research has been extensively performed from single candidate genes to whole-genome scan studies, in parallel with the development of high-throughput technologies in molecular diagnostics. Additionally, the safety and efficacy of tissue plasminogen activator, the only approved therapy for the acute phase of stroke, is modulated by genetic background associated with the occurrence of hemorrhagic transformations and with the revascularization of the cerebral arteries. In the near future, understanding the contribution of stroke genetic factors will lead to improvements in prevention and treatments for neurovascular diseases.

Background and Purpose-There is a great interindividual variability among patients with acute ischemic stroke regarding the response to intravenous tissue-type plasminogen activator treatment. The aim of this study was to identify genetic variants associated with recanalization, and thus treatment efficacy, after tissue-type plasminogen activator administration. Methods-A total of 140 single nucleotide polymorphisms from 97 candidate genes were successfully genotyped by SNPlex in 2 cohorts, accounting for 497 prospectively recruited tissue-type plasminogen activator-treated patients, of whom 33% recanalized during tissue-type plasminogen activator infusion. Functional studies were then performed, including assessment of interleukin 1B mRNA levels and von Willebrand factor, FIII, FVII, FVIII, and FX protein activity. Results-After replication, the following single nucleotide polymorphisms were associated with early recanalization: rs1143627 in IL1B Key Words: genetics Ⅲ pharmacogenetics Ⅲ recanalization Ⅲ stroke Ⅲ tPA I ntravenous tissue-type plasminogen activator (tPA) is the only drug currently approved for acute stroke treatment. The clinical response to intravenous tPA may be poor, because of a lack of efficacy in terms of early recanalization of the occluded vessel in 48% to 65% of patients 1 or because of safety concerns such as symptomatic hemorrhagic transformation occurring in 1.7% to 6.4% of cases and leading to death in 6.5% to 12.7% of cases. 2 A longer time to recanalization highly correlates with a larger infarcted area and worse neurological outcome, overall leading to poor clinical recovery from stroke. 3 The identification of factors predicting tPA efficacy could be useful to improve the management of patients with stroke, especially those not responding well to tPA treatment, because in these patients, the intra-arterial administration of tPA with or without coadjuvant drugs could be more effective than intravenous tPA treatment alone. In previous studies, we already identified some predictors of recanalization efficacy, namely thrombin-antithrombin complex levels and variants in the thrombin activable fibrinolysis inhibitor gene. 4,5 The aim of this study was to identify single nucleotide polymorphisms (SNPs) that could be used by physicians as new predictors of early recanalization to individualize and improve acute ischemic stroke treatment. Methods Study PopulationWhite patients with an acute ischemic stroke with a documented arterial occlusion by transcranial Doppler (TCD) and who received tPA in a standard dose of 0.9 mg/kg (10% bolus, 90% 1-hour continuous infusion) within the first 4.5 hours after onset of symptoms were consecutively recruited in the emergency department.The original The clinical data of both cohorts is available in online-only Data Supplement Table I. Clinical and TCD ProtocolOn admission to the emergency department, a detailed history of vascular risk factors and current medication was obtained from each patient. Stroke severity was assessed with the National In...

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