Personalized Medicine

Human Genome Sequencing in Health and Disease

by Claudia Gonzaga-Jauregui

Claudia Gonzaga-Jauregui, James R. Lupski, and Richard A. Gibbs

Annual Review of Medicine
Vol. 63: 35-61 (Volume publication date February 2012)
DOI: 10.1146/annurev-med-051010-162644

Treatment for tobacco dependence: a potential application for stratified medicine?

by Alistair Brock

Alistair J Brock, Andrea Takeda, Caroline Brennan & Robert T Walton. Personalized Medicine. 2011; 8(5):571–579.

Tobacco addiction is a leading preventable cause of death worldwide and places a heavy social and financial burden on... more Tobacco addiction is a leading preventable cause of death worldwide and places a heavy social and financial burden on society. Therefore, ways of helping people to overcome nicotine dependence are a key element of strategies aimed at improving public health. Current treatments are only partially effective and there is a need to develop more efficient approaches to help smokers to stop. There exists a substantial genetic variability in smoking behavior and the likelihood of cessation – tailoring treatment according to an individual’s genetic profile is now technologically feasible and could lead to more successful cessation attempts. Here we review studies of the genetic effects on smoking cessation in randomized controlled trials of pharmacological therapy and discuss the potential value of a personalized approach to help people stop smoking.

CYP2C19 Genotype, Clopidogrel Metabolism, Platelet Function, and Cardiovascular Events: A Systematic Review and Meta-analysis

by Michael V Holmes

Co-authored with  Pablo Perel, Tina Shah, Aroon Hingorani and Juan P. Casas

Context The US Food and Drug Administration recently recommended that CYP2C19 genotyping be considered prior to... more Context The US Food and Drug Administration recently recommended that CYP2C19 genotyping be considered prior to prescribing clopidogrel, but the American Heart Association and American College of Cardiologists have argued evidence is insufficient to support CYP2C19 genotype testing.

Objective To appraise evidence on the association of CYP2C19 genotype and clopidogrel response through systematic review and meta-analysis.

Data Sources PubMed and EMBASE from their inception to October 2011.

Study Selection Studies that reported clopidogrel metabolism, platelet reactivity or clinically relevant outcomes (cardiovascular disease [CVD] events and bleeding), and information on CYP2C19 genotype were included.

Data Extraction We extracted information on study design, genotyping, and disease outcomes and investigated sources of bias.

Results We retrieved 32 studies of 42 016 patients reporting 3545 CVD events, 579 stent thromboses, and 1413 bleeding events. Six studies were randomized trials (“effect-modification” design) and the remaining 26 reported individuals exposed to clopidogrel (“treatment-only” design). In treatment-only analysis, individuals with 1 or more CYP2C19 alleles associated with lower enzyme activity had lower levels of active clopidogrel metabolites, less platelet inhibition, lower risk of bleeding (relative risk [RR], 0.84; 95% CI, 0.75-0.94; absolute risk reduction of 5-8 events per 1000 individuals), and higher risk of CVD events (RR, 1.18; 95% CI, 1.09-1.28; absolute risk increase of 8-12 events per 1000 individuals). However, there was evidence of small-study bias (Harbord test P = .001). When analyses were restricted to studies with 200 or more events, the point estimate was attenuated (RR, 0.97; 95% CI, 0.86-1.09). In effect-modification studies, CYP2C19 genotype was not associated with modification of the effect of clopidogrel on CVD end points or bleeding (P > .05 for interaction for both). Other limitations included selective outcome reporting and potential for genotype misclassification due to problems with the * allele nomenclature for cytochrome enzymes.

Conclusion Although there was an association between the CYP2C19 genotype and clopidogrel responsiveness, overall there was no significant association of genotype with cardiovascular events.

Putting genomics into practice

by Michael V Holmes

Co-authored with Casas JP, Hingorani AD.

Variation in the human genome has long been considered to
contribute to individual differences in disease... more Variation in the human genome has long been considered to
contribute to individual differences in disease susceptibility and
drug response. But a key question for clinical practice is whether
knowledge of a patient’s genotype could be useful for stratify-
ing disease risk or guiding treatment. In the linked systematic
review Bauer and colleagues report a systematic review and
meta-analysis of studies examining the association of variation
in the CYP2C19 gene and atherothrombotic events during treat-
ment with clopidogrel.

Fulfilling the promise of personalized medicine? Systematic review and field synopsis of pharmacogenetic studies

by Michael V Holmes

Co-authored with Shah T, Vickery C, Smeeth L, Hingorani AD, Casas JP.

BACKGROUND: Studies of the genetic basis of drug response could help clarify mechanisms of drug action/metabolism, and... more BACKGROUND: Studies of the genetic basis of drug response could help clarify mechanisms of drug action/metabolism, and facilitate development of genotype-based predictive tests of efficacy or toxicity (pharmacogenetics).
OBJECTIVES:
We conducted a systematic review and field synopsis of pharmacogenetic studies to quantify the scope and quality of available evidence in this field in order to inform future research.
DATA SOURCES:
Original research articles were identified in Medline, reference lists from 24 meta-analyses/systematic reviews/review articles and U.S. Food and Drug Administration website of approved pharmacogenetic tests. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTION CRITERIA: We included any study in which either intended or adverse response to drug therapy was examined in relation to genetic variation in the germline or cancer cells in humans. STUDY APPRAISAL AND SYNTHESIS METHODS: Study characteristics and data reported in abstracts were recorded. We further analysed full text from a random 10% subset of articles spanning the different subclasses of study.
RESULTS:
From 102,264 Medline hits and 1,641 articles from other sources, we identified 1,668 primary research articles (1987 to 2007, inclusive). A high proportion of remaining articles were reviews/commentaries (ratio of reviews to primary research approximately 25 ratio 1). The majority of studies (81.8%) were set in Europe and North America focussing on cancer, cardiovascular disease and neurology/psychiatry. There was predominantly a candidate gene approach using common alleles, which despite small sample sizes (median 93 [IQR 40-222]) with no trend to an increase over time, generated a high proportion (74.5%) of nominally significant (p<0.05) reported associations suggesting the possibility of significance-chasing bias. Despite 136 examples of gene/drug interventions being the subject of >or=4 studies, only 31 meta-analyses were identified. The majority (69.4%) of end-points were continuous and likely surrogate rather than hard (binary) clinical end-points. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: The high expectation but limited translation of pharmacogenetic research thus far may be explained by the preponderance of reviews over primary research, small sample sizes, a mainly candidate gene approach, surrogate markers, an excess of nominally positive to truly positive associations and paucity of meta-analyses. Recommendations based on these findings should inform future study design to help realise the goal of personalised medicines. SYSTEMATIC REVIEW REGISTRATION NUMBER: Not Registered.

The Human Microbiome Project, Personalized Medicine and the Birth of Pharmacomicrobiomics

by Mariam Rizkallah

Pharmacomicrobiomics website:
Abstract / Publisher's site/ Pre-Print PDF (Our full text version without the journal copyediting or formatting) - Corresponding author: Ramy Aziz, PhD

After the completion of the human genome sequence, international efforts have been directed to the characterization of... more After the completion of the human genome sequence, international efforts have been directed to the characterization of the genomes of human-associated resident microbes. The Human Microbiome Project was launched in 2007 with the aim of sequencing the resident microbiota from different sites of the human body. In this paper, we introduce the Human Microbiome Project, the role of the human microbiome in health and disease, and the implications of the microbiome variations in personalized medicine and in pharmacomicrobiomics, which we define as the effect of microbiome variations on drug disposition, action, and toxicity.

Whole-Genome Sequencing for Optimized Patient Management

by Claudia Gonzaga-Jauregui

Bainbridge MN, Wiszniewski W, Murdock DR, Friedman J, Gonzaga-Jauregui C, Newsham I, Reid JG, Fink JK, Morgan MB, Gingras MC, Muzny DM, Hoang LD, Yousaf S, Lupski JR, Gibbs RA.

Sci Transl Med. 2011 Jun 15;3(87):87re3.

Pharmacogenomics of the RNA world: structural RNA polymorphisms in drug therapy

by Ryan Smith

The use of pharmacogenomic biomarkers can enhance treatment outcomes. Regulatory polymorphisms are promising... more The use of pharmacogenomic biomarkers can enhance treatment outcomes. Regulatory polymorphisms are promising biomarkers that have proven difficult to uncover. They come in two flavors: those that affect transcription (regulatory single-nucleotide polymorphisms (rSNPs)) and those that affect RNA functions such as splicing, turnover, and translation (termed structural RNA SNPs (srSNPs)). This review focuses on the role of srSNPs in drug metabolism, transport, and response. An understanding of the nature and diversity of srSNPs and rSNPs enables clinical scientists to evaluate genetic biomarkers.

Clinical evaluation incorporating a personal genome

by Ryan Whaley

Genetic discrimination: genealogy of an American problem

by Janet Childerhose

User-centric hospital websites: A case for trust and personalization

by Linda Gallant

Gallant, L.M., Irizarry, C., & Kreps, G. (2007). User-centric hospital websites: A case for trust and personalization. e-Service Journal, 5(2), 5-26.

Employing a user-centered design approach, hospital Web sites were investigated to understand what content and... more Employing a user-centered design approach, hospital Web sites were investigated to understand what content and interactivity users preferred. The findings show that trust, credibility, usefulness, and personalization are vital factors for people in the adoption of hospital Web site usage. A mixed method of usability testing and in-depth interviewing was used to develop a participatory design framework. With a high fidelity prototype of a
hospital Web site, 30 participants matching the institution’s patient demographics took part in usability testing and in-depth interviewing. The results have implications for designing future hospital, healthcare, and medical Web sites.

Putting the personal in personalized medicine

by Nathaniel Comfort

Exploring the nature of the medical individual. Beginning with the ancient concept of diathesis, I trace how... more Exploring the nature of the medical individual. Beginning with the ancient concept of diathesis, I trace how constitution, heredity, and idiosyncrasy have developed in medicine, on down to contemporary personalized medicine. I show how racial distinctions have always been a part of efforts to understand medical idiosyncrasy and polymorphism, and question the current dogma that race is an intermediate step on the way to a medical approach that treats each patient as genetically unique. In short, science cannot by itself eliminate the notion of race; so long as race exists in our culture, it will imprint itself on our science.

Likelihood ratios for genome medicine

by Rong Chen