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1.
Eur Heart J ; 33(17): 2143-50, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22450429

ABSTRACT

AIMS: Clinical trials have established the value of clopidogrel therapy in a wide spectrum of patients with cardiovascular diseases. Both loss- and gain-of-function single nucleotide variants of CYP2C19 genes have been identified that affect clopidogrel metabolism and anti-platelet response. We sought to determine the impact of CYP2C19 polymorphisms on ischaemic and bleeding events. METHODS AND RESULTS: A subset of patients from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial who consented to genotyping was analysed. Patients with clinically evident cardiovascular disease or multiple risk factors were enrolled in the trial. The rates of ischaemic and bleeding events were compared between carriers and non-carriers of loss-of-function and gain-of-function alleles in patients randomized to clopidogrel vs. placebo. A total of 4819 patients were genotyped and available for the analysis. Carriers of CYP2C19 loss-of-function alleles did not have an increased rate of ischaemic events. However, clopidogrel-treated patients did have a significantly lower rate of any bleeding in carriers: 36.1% (240/665) vs. 42.5% (681/1601) in non-carriers, HR: 0.80, 95% CI: 0.69-0.93, P = 0.003 (genotype/treatment interaction, P-value = 0.023). The CYP2C19 gain-of-function alleles did not affect ischaemic or bleeding endpoints. CONCLUSION: No relationship was seen between CYP2C19 status and ischaemic outcomes in stable patients treated with clopidogrel. There was, however, significantly less bleeding with clopidogrel in carriers of the loss-of-function allele, suggesting less anti-platelet response. Although several prior studies, including mainly stented patients, have emphasized the relationship between CYP2C19 loss-of-function alleles and efficacy of clopidogrel, this study of stable patients establishes a potential link with reduced bleeding complications. CLINICAL TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov number, NCT00050817.


Subject(s)
Aryl Hydrocarbon Hydroxylases/genetics , Atherosclerosis/genetics , Hemorrhage/genetics , Ischemia/genetics , Polymorphism, Genetic/genetics , Thrombosis/genetics , Atherosclerosis/drug therapy , Clopidogrel , Cytochrome P-450 CYP2C19 , Female , Genotype , Heterozygote , Humans , Ischemia/drug therapy , Kaplan-Meier Estimate , Male , Middle Aged , Myocardial Infarction/genetics , Platelet Aggregation Inhibitors/metabolism , Platelet Aggregation Inhibitors/therapeutic use , Stroke/genetics , Thrombosis/drug therapy , Ticlopidine/analogs & derivatives , Ticlopidine/metabolism , Ticlopidine/therapeutic use
2.
Pharmacogenomics ; 12(7): 939-51, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21787188

ABSTRACT

One approach to delivering cost-effective healthcare requires the identification of patients as individuals or subpopulations that are more likely to respond to an appropriate dose and/or schedule of a therapeutic agent, or as subpopulations that are less likely to develop an adverse event (i.e., personalized or stratified medicine). Biomarkers that identify therapeutically relevant variations in human biology are often only uncovered in the later stage of drug development. In this article, the Industry Pharmacogenomics Working Group provides, for regulatory consideration, its perspective on the rationale for the conduct of what is commonly referred to as the prospective-retrospective analysis (PRA) of biomarkers. Reflecting on published proposals and materials presented by the US FDA, a decision tree for generating robust scientific data from samples collected from an already conducted trial to allow PRA is presented. The primary utility of the PRA is to define a process that provides robust scientific evidence for decision-making in situations where it is not necessary, nor practical or ethical to conduct a new prospective clinical study.


Subject(s)
Biomarkers, Pharmacological , Pharmacogenetics/standards , Clinical Trials as Topic , Decision Making , Humans , Industry , Precision Medicine , Prospective Studies , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins p21(ras) , Retrospective Studies , Treatment Outcome , United States , United States Food and Drug Administration , ras Proteins/genetics
3.
Am J Hum Genet ; 87(1): 60-74, 2010 Jul 09.
Article in English | MEDLINE | ID: mdl-20598273

ABSTRACT

The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET. In a study of 690 European- and 192 Chinese-descent probands and their parents or controls, we demonstrate the ubiquity of a >4-fold susceptibility from a C-->T allele (rs2435357: p = 3.9 x 10(-43) in European ancestry; p = 1.1 x 10(-21) in Chinese samples) that probably arose once within the intronic RET enhancer MCS+9.7. With in vitro assays, we now show that the T variant disrupts a SOX10 binding site within MCS+9.7 that compromises RET transactivation. The T allele, with a control frequency of 20%-30%/47% and case frequency of 54%-62%/88% in European/Chinese-ancestry individuals, is involved in all forms of HSCR. It is marginally associated with proband gender (p = 0.13) and significantly so with length of aganglionosis (p = 7.6 x 10(-5)) and familiality (p = 6.2 x 10(-4)). The enhancer variant is more frequent in the common forms of male, short-segment, and simplex families whereas multiple, rare, coding mutations are the norm in the less common and more severe forms of female, long-segment, and multiplex families. The T variant also increases penetrance in patients with rare RET coding mutations. Thus, both rare and common mutations, individually and together, make contributions to the risk of HSCR. The distribution of RET variants in diverse HSCR patients suggests a "cellular-recessive" genetic model where both RET alleles' function is compromised. The RET allelic series, and its genotype-phenotype correlations, shows that success in variant identification in complex disorders may strongly depend on which patients are studied.


Subject(s)
Hirschsprung Disease/genetics , Proto-Oncogene Proteins c-ret/genetics , Asian People , Base Sequence , Case-Control Studies , Enhancer Elements, Genetic , Female , Gene Frequency , Genome-Wide Association Study , Haplotypes , Hirschsprung Disease/ethnology , Hirschsprung Disease/physiopathology , Humans , Male , Mutation , Penetrance , Polymorphism, Single Nucleotide , Protein Binding , Proto-Oncogene Proteins c-ret/metabolism , SOXE Transcription Factors/metabolism , Sex Factors , Transcriptional Activation , White People
4.
Depress Anxiety ; 27(5): 417-25, 2010 May.
Article in English | MEDLINE | ID: mdl-20455246

ABSTRACT

BACKGROUND: Antagonism of corticotropin-releasing factor (CRF) receptors has been hypothesized as a potential target for the development of novel anxiolytics. This study was designed to determine the safety and efficacy of pexacerfont, a selective CRF-1 receptor antagonist, in the treatment of generalized anxiety disorder (GAD). METHOD: This was a multicenter, randomized, double-blind, placebo-controlled and active comparator trial. Two hundred and sixty patients were randomly assigned to pexacerfont 100 mg/day (after a 1 week loading dose of 300 mg/day), placebo or escitalopram 20 mg/day in a 2:2:1 ratio. The primary outcome was the mean change from baseline to end point (week 8) in the Hamilton Anxiety Scale total score. RESULTS: Pexacerfont 100 mg/day did not separate from placebo on the primary outcome measure. The half-powered active comparator arm, escitalopram 20 mg/day, demonstrated efficacy with significant separation from placebo at weeks 1, 2, 3, 6, and 8 (P<.02). Response rates for pexacerfont, placebo, and escitalopram were 42, 42, and 53%, respectively. Genetic and psychometric rating scale data was obtained in 175 randomized subjects. There was a significant association between a single nucleotide polymorphism (SNP) of the gene encoding plexin A2 (PLXNA2-2016) with the HAM-A psychic subscale score for the entire cohort at baseline (FDR-adjusted P=.015). CONCLUSIONS: Pexacerfont did not demonstrate efficacy compared to placebo for the treatment of GAD. Whether these findings are generalizable to this class of agents remains to be determined. Our preliminary genetic finding of an association between a SNP for the gene encoding plexin A2 and an anxiety phenotype in this study merits further exploration. The trial was registered at clinicaltrials.gov (NCT00481325) before enrollment.


Subject(s)
Anti-Anxiety Agents/therapeutic use , Anxiety Disorders/drug therapy , Citalopram/therapeutic use , Pyrazoles/therapeutic use , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Receptors, Corticotropin-Releasing Hormone/genetics , Triazines/therapeutic use , Adolescent , Adult , Aged , Anxiety Disorders/diagnosis , Anxiety Disorders/psychology , Diagnostic and Statistical Manual of Mental Disorders , Double-Blind Method , Female , Humans , Male , Middle Aged , Pharmacogenetics/methods , Phenotype , Polymorphism, Single Nucleotide/genetics , Psychometrics , Severity of Illness Index , Young Adult
5.
Nature ; 434(7035): 857-63, 2005 Apr 14.
Article in English | MEDLINE | ID: mdl-15829955

ABSTRACT

The identification of common variants that contribute to the genesis of human inherited disorders remains a significant challenge. Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations in the receptor tyrosine kinase RET contribute to risk in combination with mutations at other genes. We have used family-based association studies to identify a disease interval, and integrated this with comparative and functional genomic analysis to prioritize conserved and functional elements within which mutations can be sought. We now show that a common non-coding RET variant within a conserved enhancer-like sequence in intron 1 is significantly associated with HSCR susceptibility and makes a 20-fold greater contribution to risk than rare alleles do. This mutation reduces in vitro enhancer activity markedly, has low penetrance, has different genetic effects in males and females, and explains several features of the complex inheritance pattern of HSCR. Thus, common low-penetrance variants, identified by association studies, can underlie both common and rare diseases.


Subject(s)
Enhancer Elements, Genetic/genetics , Genetic Predisposition to Disease/genetics , Hirschsprung Disease/genetics , Mutation/genetics , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases/genetics , Sex Characteristics , Animals , Female , Gene Frequency , Genomics , Haplotypes , Humans , Linkage Disequilibrium/genetics , Male , Mice , Molecular Sequence Data , Polymorphism, Single Nucleotide/genetics , Proto-Oncogene Proteins c-ret
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