ABSTRACT
Title
Pharmacogenetic research and its applications in current clinical practice
Authors
Era Daniel
Doctorate School of Nanotechnology, Dept. of Life Sciences – University of Trieste, Italy
Doctorate School of Nanotechnology, Dept. of Life Sciences – University of Trieste, Italy
Abstract
The general aim of the PhD project is to provide evidence, in a translational perspective, of the value of the application in the community medical care of pharmacogenetics, with the aim to improve the appropriateness of drugs’ use. Warfarin is widely used for oral anticoagulant therapy, and a careful monitoring of therapy is required, because of the narrow therapeutic window and high inter-individual variability in the dose needed which exposes the patients to a relevant risk of thrombotic or bleeding complications. Anticoagulative response to warfarin is influenced by a number of clinical and genetic factors. Single nucleotide polymorphisms in genes affecting warfarin metabolism (CYP2C9) and pharmacodynamic response (VKORC1) have been strongly associated with warfarin responsiveness (The International Warfarin Pharmacogenetics Consortium 2009). 53 patients from the local Centre for Cardiovascular Disease have been recruited and genotyped so far. The analysis of the variance of the data (ANOVA) confirms the role of VKORC1 in determining the warfarin dose required (df=2; F=7.283; p=0.002). On the other hand, no significant difference has been presently observed concerning the effect of CYP2C9 alone (df=3; F=1.776; p=0.166), although a tendency for a higher reduction of the dose in patients carrying the *2/*3 genotype is apparent. Linear regression analysis, conducted to identify the clinical and genetic data mainly influencing dosing, indicates that cigarette smoking is the major factor determining warfarin dosage, in comparison to the other clinical characteristics considered. Smoking is a cardiovascular risk factor, it affects drug metabolism and blood flow in tissues, and this finding thus appears to deserve further consideration. The enrollment and analysis of more patients continues, also including selected subgroups with a high variability in the optimal dosage as identified by the routine use of INR.
SSRIs antidepressant drugs (AD) are extensively prescribed also by general practitioners, and the available literature indicates that drug response significantly depend on the genetic polymorphism of serotonin transporter (5-HTTLPR), which is highly penetrant and functionally relevant. This polymorphismhas been associated with difficulties of adaptation to stresful life events, causing an increased risk of depression (Caspi et al., 2003); the therapeutic response to SSRIs has been also shown to depend on the same polymorphism (Serretti et al., 2007; Luddington et al., 2009). The role played by 5-HTTLPR is therefore being evaluated retrospectively in the patients cared for by the Department of Mental Health in Trieste. Patients with a depressive event (F32) or a depressive syndrome (F33), diagnosed using ICD-10, are psychologically evaluated by the Montgomery-Asberg Depression Rating Scale (MADRS), and provide a sample of buccal mucosa for genotyping. Out of the 30 patients evaluated and genotyped so far, 21 were treated with a AD during 2008 and 2009. The MADRS scores of the patients carrying the L/L genotype display a tendency towards reduction in comparison with those of the carriers of one or two S alleles (12.83±2.74 vs 17.33±2.97, p=0.335).
The results presented indicate that the findings, and the accompanying difficulties, which are obtained when the evaluation of the drug use is made in the complex context of medical practice, are in general agreement with those available in literature, and encourage further research.
This work was made possible by the generous contribution of Fondazione Benefica Alberto & Kathleen Foreman Casali of Trieste, Italy, of “Beneficentia Stiftung”of Valduz, Liechtenstein and by Azienda per I Servizi Sanitari N° 1, Trieste, Italy.
References
The International Warfarin Pharmacogenetics Consortium (2009) N Engl J Med 360 (8):753
Caspi A et al. (2003) Science 301: 386
Serretti A et al. (2007) Psychiatry Res 149:185
Luddington NS et al. (2009) Prim Care Companion J Clin Psychiatry 11:93
SSRIs antidepressant drugs (AD) are extensively prescribed also by general practitioners, and the available literature indicates that drug response significantly depend on the genetic polymorphism of serotonin transporter (5-HTTLPR), which is highly penetrant and functionally relevant. This polymorphismhas been associated with difficulties of adaptation to stresful life events, causing an increased risk of depression (Caspi et al., 2003); the therapeutic response to SSRIs has been also shown to depend on the same polymorphism (Serretti et al., 2007; Luddington et al., 2009). The role played by 5-HTTLPR is therefore being evaluated retrospectively in the patients cared for by the Department of Mental Health in Trieste. Patients with a depressive event (F32) or a depressive syndrome (F33), diagnosed using ICD-10, are psychologically evaluated by the Montgomery-Asberg Depression Rating Scale (MADRS), and provide a sample of buccal mucosa for genotyping. Out of the 30 patients evaluated and genotyped so far, 21 were treated with a AD during 2008 and 2009. The MADRS scores of the patients carrying the L/L genotype display a tendency towards reduction in comparison with those of the carriers of one or two S alleles (12.83±2.74 vs 17.33±2.97, p=0.335).
The results presented indicate that the findings, and the accompanying difficulties, which are obtained when the evaluation of the drug use is made in the complex context of medical practice, are in general agreement with those available in literature, and encourage further research.
This work was made possible by the generous contribution of Fondazione Benefica Alberto & Kathleen Foreman Casali of Trieste, Italy, of “Beneficentia Stiftung”of Valduz, Liechtenstein and by Azienda per I Servizi Sanitari N° 1, Trieste, Italy.
References
The International Warfarin Pharmacogenetics Consortium (2009) N Engl J Med 360 (8):753
Caspi A et al. (2003) Science 301: 386
Serretti A et al. (2007) Psychiatry Res 149:185
Luddington NS et al. (2009) Prim Care Companion J Clin Psychiatry 11:93