The antithrombotic benefits of warfarin are countered by a narrow therapeutic index that contributes to excessive bleeding or cerebrovascular clotting and stroke in some patients. This article ...reviews the current literature describing warfarin sensitivity genotyping and compares the results of that review to the findings of our study in 189 patients at Mayo Clinic conducted between June 2001 and April 2003. For the review of the literature, we identified relevant peer-reviewed articles by searching the Web of Knowledge using key word warfarin-related adverse event . For the 189 Mayo Clinic patients initiating warfarin therapy to achieve a target international normalized ratio (INR) in the range of 2.0 to 3.5, we analyzed the CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genetic loci to study the relationship among the initial warfarin dose, steady-state dose, time to achieve steady-state dose, variations in INR, and allelic variance. Results were compared with those previously reported in the literature for 637 patients. The relationships between allelic variants and warfarin sensitivity found in our study of Mayo Clinic patients are fundamentally the same as in those reported by others. The Mayo Clinic population is predominantly white and shows considerable allelic variability in CYP2C9 and VKORC1 . Certain of these alleles are associated with increased sensitivity to warfarin. Polymorphisms in CYP2C9 and VKORC1 have a considerable effect on warfarin dose in white people. A correlation between steady-state warfarin dose and allelic variants of CYP2C9 and VKORC1 has been demonstrated by many previous reports and is reconfirmed in this report. The allelic variants found to most affect warfarin sensitivity are CYP2C9*1*1-VKORC1BB (less warfarin sensitivity than typical); CYP2C9*1*1-VKORC1AA (considerable variance in INR throughout initiation); CYP2C9*1*2-VKORC1AB (more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C9*1*2-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1AA (much more sensitivity to warfarin than typical); and CYP2C9*2*2-VKORC1AB (much more sensitivity to warfarin than typical). Although we were unable to show an association between allelic variants and initial warfarin dose or dose escalation, an association was seen between allelic variant and steady-state warfarin dose. White people show considerable variance in CYP2C9 allele types, whereas people of Asian or African descent infrequently carry CYP2C9 allelic variants. The VKORC1AA allele associated with high warfarin sensitivity predominates in those of Asian descent, whereas white people and those of African descent show diversity, carrying either the VKORC1BB , an allele associated with low warfarin sensitivity, or VKORC1AB or VKORC1AA , alleles associated with moderate and high warfarin sensitivity, respectively.
Privacy in Direct-to-Consumer Genetic Testing Park, Jason Y; Risher, Michael T; Caulfield, Timothy ...
Clinical chemistry,
05/2019, Letnik:
65, Številka:
5
Journal Article, Transcript
Recenzirano
Odprti dostop
In 2018, a suspect in the Golden State Killer murder cases was identified by use of DTC genetic testing information, 30 years after the last known crime was committed. Since the break in the Golden ...State Killer cases, >100 law enforcement investigations are now underway using DTC genetic data. The benefits for law enforcement will also hinge on how these samples are used. Since DTC genetic testing can uncover direct and indirect genetic connections between individuals, the increasing use of DTC genetic testing without consumer consent threatens to harm trust in the companies that provide this service as well as increase suspicion of law enforcement strategies. Initially, DeAngelo was not considered as a lead suspect, but upon closer scrutiny of his timeline and through interviews of some of his associates, they developed a high level of confidence that DeAngelo was likely the killer. Since genealogical DNA evidence may not have been admissible in court, the detectives went 1 step further to ensure that their suspect's DNA matched the crime scene DNA. ...there is the concern for misidentification or misinformation derived from such genetic data that may have lower quality control measures as compared to genetic data derived in the traditional forensics setting.
What Is the True Prevalence of Hypertrophic Cardiomyopathy? Baudhuin, Linnea M., PhD; Kotzer, Katrina E., MS, CGC; Kluge, Michelle L., MS, CGC ...
Journal of the American College of Cardiology,
10/2015, Letnik:
66, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Technological advances have allowed us to more comprehensively and efficiently interrogate human genomes, and there are a number of large-scale efforts, such as the Exome Sequencing Project and Exome ...Aggregation Consortium, which have been publishing genomic data and variant frequencies from very large populations stratified by ethnicity. Utilizing our criteria for variant classification, which is largely on the basis of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology 2015 guidelines for variant interpretation (4) and utilizes databases and resources listed in the preceding text, only 6 of these variants could be confidently classified as likely pathogenic or pathogenic (i.e., 6 of 3,600, or approximately 1:600 HCM gene carrier frequency).
Genetic-guided P2Y12 inhibitor selection has been proposed to reduce ischemic events by identifying CYP2C19 loss-of-function (LOF) carriers at increased risk with clopidogrel treatment after ...percutaneous coronary intervention (PCI). A prespecified analysis of TAILOR-PCI (Tailored Antiplatelet Therapy Following PCI) evaluated the effect of genetic-guided P2Y12 inhibitor therapy on cumulative ischemic and bleeding events.
Here, the authors detail a prespecified analysis of cumulative endpoints. The primary endpoint was cumulative incidence rate of ischemic events at 12 months. Cumulative incidence of major and minor bleeding was a secondary endpoint. Cox proportional hazards models as adapted by Wei, Lin, and Weissfeld were used to estimate the effect of this strategy on all observed events.
The TAILOR-PCI trial was a prospective trial including 5,302 post-PCI patients with acute and stable coronary artery disease (CAD) who were randomized to genetic-guided P2Y12 inhibitor or conventional clopidogrel therapy. In the genetic-guided group, LOF carriers were prescribed ticagrelor, whereas noncarriers received clopidogrel. TAILOR-PCI’s primary analysis was time to first event in LOF carriers.
Among 5,276 patients (median age 62 years; 25% women; 82% acute CAD; 18% stable CAD), 1,849 were LOF carriers (903 genetic-guided; 946 conventional therapy). The cumulative primary endpoint was significantly reduced in the genetic-guided group compared with the conventional therapy (HR: 0.61; 95% CI: 0.41-0.89; P = 0.011) with no significant difference in cumulative incidence of major or minor bleeding (HR: 1.36; 95% CI: 0.67-2.76; P = 0.39).
Among CYP2C19 LOF carriers undergoing PCI, a genetic-guided strategy resulted in a statistically significant reduction in cumulative ischemic events without a significant difference in bleeding. (Tailored Antiplatelet Therapy Following PCI TAILOR-PCI; NCT01742117)
Display omitted
Long QT syndrome (LQTS) is a cardiac channelopathy associated with syncope, seizures, and sudden death. Approximately 75% of LQTS is due to mutations in genes encoding for 3 cardiac ion channel ...α-subunits (LQT1 to LQT3). However, traditional mutational analyses have limited detection capabilities for atypical mutations such as large gene rearrangements. We set out to determine the prevalence and spectrum of large deletions/duplications in the major LQTS-susceptibility genes in unrelated patients who were mutation negative after point mutation analysis of LQT1- to LQT12-susceptibility genes. Forty-two unrelated, clinically strong LQTS patients were analyzed using multiplex ligation-dependent probe amplification, a quantitative fluorescent technique for detecting multiple exon deletions and duplications. The SALSA multiplex ligation-dependent probe amplification LQTS kit from MRC-Holland was used to analyze the 3 major LQTS-associated genes, KCNQ1 , KCNH2 , and SCN5A , and the 2 minor genes, KCNE1 and KCNE2 . Overall, 2 gene rearrangements were found in 2 of 42 unrelated patients (4.8%, confidence interval 1.7 to 11). A deletion of KCNQ1 exon 3 was identified in a 10-year-old Caucasian boy with a corrected QT duration of 660 ms, a personal history of exercise-induced syncope, and a family history of syncope. A deletion of KCNQ1 exon 7 was identified in a 17-year-old Caucasian girl with a corrected QT duration of 480 ms, a personal history of exercise-induced syncope, and a family history of sudden cardiac death. In conclusion, because nearly 5% of patients with genetically elusive LQTS had large genomic rearrangements involving the canonical LQTS-susceptibility genes, reflex genetic testing to investigate genomic rearrangements may be of clinical value.
"Big Data" in Laboratory Medicine Tolan, Nicole V; Parnas, M Laura; Baudhuin, Linnea M ...
Clinical chemistry (Baltimore, Md.)
61, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Linnea Baudhuin: "Big data" is a broad term that relates to data sets that are so large, diverse, and/or complex that traditional data processing applications are inadequate to analyze, capture, ...curate, share, visualize, and store. ...big data" requires innovative bioinformatics solutions for processing, to make the data meaningful, and to derive usable information. ...I think that it's appropriate to use "big data" to describe the information that we get from our large numbers of patients, samples, and analytes in the clinical laboratory.
To evaluate perceptions toward pharmacogenetic testing of patients undergoing percutaneous coronary intervention (PCI) who are prescribed dual antiplatelet therapy (DAPT) and whether geographical ...differences in these perceptions exist.
TAILOR-PCI is the largest genotype-based cardiovascular clinical trial randomizing participants to conventional DAPT or prospective genotyping-guided DAPT. Enrolled patients completed surveys before and 6 months after randomization.
A total of 1327 patients completed baseline surveys of whom 28, 29, and 43% were from Korea, Canada and the USA, respectively. Most patients (77%) valued identifying pharmacogenetic variants; however, fewer Koreans (44%) as compared with Canadians (91%) and USA (89%) patients identified pharmacogenetics as being important (P<0.001). After adjusting for age, sex, and country, those who were confident in their ability to understand genetic information were significantly more likely to value identifying pharmacogenetic variants (odds ratio: 30.0; 95% confidence interval: 20.5-43.8). Only 21% of Koreans, as opposed to 86 and 77% of patients in Canada and USA, respectively, were confident in their ability to understand genetic information (P<0.001).
Although genetically mediated clopidogrel resistance is more prevalent amongst Asians, Koreans undergoing PCI identified pharmacogenetic variants as less important to their healthcare, likely related to their lack of confidence in their ability to understand genetic information. To enable successful implementation of pharmacogenetic testing on a global scale, the possibility of international population differences in perceptions should be considered.
Loss-of-function CYP2C19 variants are associated with increased cumulative ischemic outcomes warranting CYP2C19 genotyping prior to clopidogrel administration. TAILOR-PCI was an international, ...multicenter (40 sites), prospective, randomized trial comparing rapid point of care (POC) genotype-guided vs. conventional anti-platelet therapy. The performance of buccal-based rapid CYP2C19 genotyping performed by non-laboratory-trained staff in TAILOR-PCI was assessed. Pre-trial training and evaluation involved rapid genotyping of 373 oral samples, with 99.5% (371/373) concordance with Sanger sequencing. During TAILOR-PCI, 5302 patients undergoing PCI were randomized to POC rapid CYP2C19 *2, *3, and *17 genotyping versus no genotyping. At 12 months post-PCI, TaqMan genotyping determined 99.1% (2,364/2,385) concordance with the POC results, with 90.7-98.8% sensitivity and 99.2-99.6% specificity. In conclusion, non-laboratory personnel can be successfully trained for on-site instrument operation and POC rapid genotyping with analytical accuracy and precision across multiple international centers, thereby supporting POC genotyping in patient-care settings, such as the cardiac catheterization laboratory.Clinical Trial Registration: https://www.clinicalTrials.gov (Identifier: NCT01742117).
In this new edition of the theme issue, the editors have highlighted some of the most exciting developments in the field. Because of the limitation of space within the issue, this selection is by no ...means exhaustive but, rather, is meant to be a sampler of some of the advances that will likely impact clinical practice. ...in a Reflections article, Dennis Lo has provided a personal view on some of the emerging developments in the field, especially as they relate to the study of the circulating DNA fragmentation, referred to as fragmentomics (6). ...we are particularly excited to have an interview of George Church, one of the pioneers of genome editing in this issue (15).
PDF
