Background The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene–drug combinations. However, the clinical utility of a pre-emptive... Show moreBackground The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene–drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. Methods We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug–gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug–gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug–gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants. Findings Between March 7, 2017, and June 30, 2020, 41696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54–0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61–0·79]; p <0·0001). Interpretation Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe. Show less
Diekstra, M.H.M.; Swen, J.J.; Zanden, L.F.M. van der; Vermeulen, S.H.; E. boven; Mathijssen, R.H.J.; ... ; Guchelaar, H.J. 2022
Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5... Show moreIndividual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 x 10 (8) ) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 x 10 (10), HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 x 10 (8), HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated. Show less
White, S.J.; Laros, J.F.J.; Bakker, E.; Cambon-Thomsen, A.; Eden, M.; Leonard, S.; ... ; Dunnen, J.T. den 2017
The participation of minors in biobank research can offer great benefits for science and health care. However, as minors are a vulnerable population they are also in need of adequate protective... Show moreThe participation of minors in biobank research can offer great benefits for science and health care. However, as minors are a vulnerable population they are also in need of adequate protective measures when they are enrolled in research. Research using biobanked biological samples from children poses additional ethical issues to those raised by research using adult biobanks. For example, small children have only limited capacity, if any, to understand the meaning and implications of the research and to give a documented agreement to it. Older minors are gradually acquiring this capacity. We describe principles for good practice related to the inclusion of minors in biobank research, focusing on issues related to benefits and subsidiarity, consent, proportionality and return of results. Some of these issues are currently heavily debated, and we conclude by providing principles for good practice for policy makers of biobanks, researchers and anyone involved in dealing with stored tissue samples from children. Actual implementation of the principles will vary according to different jurisdictions. Show less
Wichmann, H.E.; Kuhn, K.A.; Waldenberger, M.; Schmelcher, D.; Schuffenhauer, S.; Meitinger, T.; ... ; Zatloukal, K. 2011
More than 1,000 Web-based locus-specific variation databases (LSDBs) are listed on the Website of the Human Genetic Variation Society (HGVS). These individual efforts, which often relate phenotype... Show moreMore than 1,000 Web-based locus-specific variation databases (LSDBs) are listed on the Website of the Human Genetic Variation Society (HGVS). These individual efforts, which often relate phenotype to genotype, are a valuable source of information for clinicians, patients, and their families, as well as for basic research. The initiators of the Human Variome Project recently recognized that having access to some of the immense resources of unpublished information already present in diagnostic laboratories would provide critical data to help manage genetic disorders. However, there are significant ethical issues involved in sharing these data worldwide. An international working group presents second-generation guidelines addressing ethical issues relating to the curation of human LSDBs that provide information via a Web-based interface. It is intended that these should help current and future curators and may also inform the future decisions of ethics committees and legislators. These guidelines have been reviewed by the Ethics Committee of the Human Genome Organization (HUGO). Hum Mutat 31: 1179-1184, 2010. (C) 2010Wiley-Liss, Inc. Show less
Forzano, F.; Borry, P.; Cambon-Thomsen, A.; Hodgson, S.V.; Tibben, A.; Vries, P. de; ... ; Cornel, M. 2010
A few months ago, the controversial debate on connection between genetic variants and antisocial behaviour gained renewed prominence after the sentence of an Italian judge who decided to further... Show moreA few months ago, the controversial debate on connection between genetic variants and antisocial behaviour gained renewed prominence after the sentence of an Italian judge who decided to further reduce the prison sentence of a person convicted of murder by 1 year - from 9 to 8 years - because he was found to be a carrier of a few genetic variants thought to be associated with a predisposition to aggressiveness. We discuss the social implication of this view, the lack of evidence of the clinical utility of this test, and in particular the risks of offering susceptibility testing in the context of legal proceedings. European Journal of Human Genetics (2010) 18, 519-521; doi:10.1038/ejhg.2010.31; published online 10 March 2010 Show less
