Table Of ContentGenomic and Personalized
Medicine
Second Edition
Genomic and
Personalized Medicine
Volume 1
Second Edition
Edited by
Geoffrey S. Ginsburg, M.D., Ph.D.
Director, Genomic Medicine
Duke Institute for Genome Sciences & Policy
Executive Director, Center for Personalized Medicine
Duke University Health System
Professor of Medicine
Duke University School of Medicine
Durham, North Carolina 27710
and
Huntington F. Willard Ph.D.
Institute Director
Duke Institute for Genome Sciences & Policy
Nanaline H. Duke Professor of Genome Sciences
Duke University
Durham, North Carolina 27708
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Second editon 2013
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Foreword
Publicaton of this second editon of Genomic and Personalized for sequencing DNA. These spectacular advances can be
Medicine occurs roughly nine and a half years (or ~3500 days!) nicely illustrated with just a few facts and fgures, as follows.
afer the ofcial completon of the Human Genome Project in The frst human genome sequence generated by the Human
April 2003. That monumental internatonal and historic pro- Genome Project took ~6–8 years to complete and cost roughly
ject catapulted forward the felds of genetcs and genomics at $1 billion. When the Human Genome Project ended in April
a pace that only the most optmistc scientfc leaders realis- 2003, it was estmated that, theoretcally, to generate another
tcally envisioned at that tme. Indeed, it is truly stunning to human genome sequence using the then-available DNA-
consider what has been accomplished in the past nine-plus sequencing technologies would take ~3–4 months and cost
years, especially with respect to accomplishments relevant to ~$10–50 million. At the tme of publishing this second editon
genomic and personalized medicine. These advances can be of Genomic and Personalized Medicine, sequencing a human
grouped into four major areas. genome can be completed in a couple of days for <$5000.
First, armed with the high-quality reference human That ~200,000-fold reducton in cost (not to menton the pro-
genome sequence produced by the Human Genome Project, foundly more-rapid generaton tme) has truly been “game
numerous genomic studies have focused on understanding the changing” for virtually every aspect of genomics research.
rich complexites encoded by the roughly three billion leters More importantly, with a cost analogous to that of a high-
that consttute the human genomic blueprint (i.e., interpretng end radiological study or clinical laboratory test, sequencing
the human genome sequence). Our view of this landscape has human genomes will increasingly become clinically relevant
changed markedly in the past nine-plus years, including a much and will inevitably have a profound impact on the topics cov-
greater recogniton of the critcal roles that non-coding DNA and ered in virtually every chapter of this book.
epigenomics (in conjuncton with our ~20,000 protein-coding Even with these incredible advances, much work remains
genes) play in the intricate choreography of genome functon. to be done en route to implementng genomic and personal-
Second, some key large-scale initatves (e.g., the ized medicine. For starters, data analysis is now the domi-
Internatonal HapMap Project and the 1000 Genomes Project) nant botleneck in genomics – long gone are the days when
have generated deep catalogs of human genome variaton. data generaton was limitng! Meanwhile, establishing the
The growing knowledge of the architectural features of this precise genomic architecture underlying human diseases
variaton – both with respect to the physical nature (e.g., (especially complex genetc diseases) is turning out to be far
single-nucleotde, copy-number, and structural polymor- more complicated than previously appreciated. Similarly, actu-
phisms) and its frequency across diferent human popula- ally infusing genomics into the complex world of healthcare
tons – is providing a much more sophistcated view of human delivery – the actual implementaton of genomic and person-
genomic diversity. The later has important implicatons for alized medicine – is associated with myriad nuances and com-
studying the genomic basis of disease, human evoluton, and plexites that will take many years to appreciate fully and to
human populaton history and ancestry. address adequately; among the many issues to tackle is the
Third, the greater knowledge of human genomic varia- need to increase the genomic literacy of healthcare providers
ton coupled with advances in genome analysis (in partcular (something being aided by this second editon). Finally, the
genotyping) technologies has yielded more powerful strategic many societal issues associated with genomic advances seem
approaches for elucidatng the genomic basis of disease. This to grow in importance as medical uses of personal genomic
has greatly accelerated the identfcaton of mutatons respon- informaton are envisioned and developed.
sible for both rare and common diseases. For the former, we Despite these challenges, one cannot gaze at the future
now know the genomic basis for well over 3000 disorders horizon without a sense of optmism that genomics will usher
caused by defects in a single gene; for the later, impres- in improved approaches for practcing medicine. Early high-
sive advances in the use of genome-wide associaton stud- lights point towards new genomically guided strategies for
ies (GWAS) have greatly facilitated the difcult search for the selectng specifc, more appropriate medicatons for each
many variants conferring risk for complex multgenic disorders. patent, new insights about the molecular taxonomy of difer-
The fourth area of advancement is (almost) without ques- ent cancers that will lead to more robust diagnoses and more
ton the one that has also had the greatest impact on the precise treatments, and new insights about genetc variants
feld of genomics – the development of new technologies that confer increased risk to patents for disorders that are
ix
x n Foreword
increasingly preventable. Just as the inventon of the micro- genomics change medical practce. Together, these chapters
scope and the CT scanner fundamentally changed the practce provide unequivocal evidence about the current state of
of medicine, so, too, will the infusion of genomic informaton genomic and personalized medicine – that the opportunites
about individual patents. are breathtaking, that the challenges are immense, and that
The ~100 chapters in this second editon of Genomic and the potental to improve health is nearly unlimited.
Personalized Medicine elegantly showcase the depth and
breadth of this rapidly growing area of biomedicine. Once
again, Ginsburg and Willard have recruited an impressive Eric D. Green, M.D., Ph.D.
cast of genetcists and genomicists to contribute chapters Director, Natonal Human Genome Research Insttute
spanning a wide spectrum of topics – from fundamentals in Natonal Insttutes of Health
genomics research to key clinical areas that represent some Bethesda, Maryland
of the “lowest hanging fruit” in terms of opportunites to have
Preface
With the completon of the Human Genome Project and the l Detect the onset of disease earlier and before it is clini-
rapid development of our ability to understand and query the cally evident, based on newly discovered biological mark-
genome and its variaton, we must now antcipate and outline ers that arise from changes at the molecular level
the early stages of what promises to be nothing less than a l Preempt disease progression, as a result of early detecton
transformaton of medicine over the coming decades. Even in l Target medicines and their dose more precisely to achieve
just the past two years, we have already witnessed dramatc beter safety and efcacy for each patent.
diagnoses and lifesaving treatments owing to the advances in
This revoluton in genomic and personalized medicine was
whole-genome and exome sequencing and their applicatons
antcipated over three decades ago by Nobel laureate Paul
to clinical diagnostc dilemmas. Undoubtedly we will see more
Berg, who then stated so presciently:
widespread use of these and other technologies to advance
medicine and improve health, at both the personal and popu- Just as our present knowledge and practce of medicine
laton levels. These and other examples highlighted in this sec- relies on a sophistcated knowledge of human anatomy,
ond editon are the frst signs of a fundamental shif in how we physiology, and biochemistry, so will dealing with dis-
behold human physiology and pathology, how we defne the ease in the future demand a detailed understanding of
taxonomy of disease at the molecular level, how we view the the molecular anatomy, physiology, and biochemistry of
concept of what is “normal,” and how we consider individuals the human genome. … We shall need a more detailed
and their prospects for lifelong health. All of this requires that knowledge of how human genes are organized and how
we design healthcare delivery systems that are adaptable to they functon and are regulated. We shall also have to
the demands of populaton-wide epidemics and, at the same have physicians who are as conversant with the molecu-
tme, provide opportunites for personalized care that utlizes lar anatomy and physiology of chromosomes and genes
as the cardiac surgeon is with the structure and work-
genome-based informaton to consider individual susceptbil-
ings of the heart.
ity to disease and therapeutc optons.
As is evident throughout these volumes, we have now That tme has come. This book is intended to lay out the
entered the era of “big data.” Genome-based data, infor- foundatons of this new science, to outline the early oppor-
maton, knowledge, and eventually wisdom will make pos- tunites for the practce of medicine to incorporate genome-
sible the kind of healthcare that has been dreamed of since based analysis into healthcare, and to antcipate the many
the advent of disease-based medicine early in the 20th cen- conditons to which genomic and personalized medicine will
tury. A system of healthcare that harnesses the full breadth apply in the years ahead. The chapters in these volumes are
of genome-based informaton, along with electronic medical designed to be read either sequentally – introducing the sci-
records that capture imaging and clinical data, paired with entfc underpinnings of this paradigm shif, exploring aspects
geospatal databases capturing environmental informaton, of translatonal medicine and genomics that will be critcal for
will empower healthcare providers – and patents – to make bringing about the full integraton of genomics into medical
medical care as individualized as possible. This newfound care, and presentng practcal aspects of the frst applicatons
informaton and knowledge will also allow each of us as con- of genomic and personalized medicine in the context of spe-
sumers of healthcare to take more control of our futures and cifc medical conditons – or one-at-a-tme for those interested
to develop a more strategic and a prospectve approach to in partcular disorders or approaches.
health. We stand at the dawn of a profound change in science These volumes also describe a feld with many challenges
and medicine’s predictve nature and in our understanding of for society at large, in additon to those associated with health-
the biological underpinnings of health and disease. Even in care systems rife with inefciencies and heterogeneous in their
this early light, we can see the outlines of a coming ability to: ability to deliver the basics of healthcare, and the diversity of
the populatons they serve. There are “grand challenges” for
l Predict individual susceptbility to disease, based on the visionary science and the clinical care highlighted in these
genetc, genomic and other factors pages. Such challenges include the potental for these innova-
l Provide more useful tools and individualized programs tons to exaggerate existng health disparites, informaton
for disease preventon, based on knowledge of one’s technology systems that have been described as a “tower of
susceptbility Babel,” an unprepared healthcare work force, and economic
xi
xii n Preface
incentves that are inadequately aligned for the various stake- adopters and members of a global community of key opinion
holders to fully embrace genomic and personalized medicine. leaders who will make this happen.
Nonetheless, we are optmistc that the appropriate delivery Our intended audience is broad, ranging from medical stu-
models and economic incentves will be developed in a trust- dents (and even the intrepid undergraduate eager to explore
worthy framework that will be embraced by societes around this new era of personalized and prospectve medicine) to resi-
the globe. dents and fellows to practtoners in any of the healthcare pro-
The paradigm shif of personalized medicine will depend fessions – physicians in any of the medical specialtes, surgeons,
on contributons from a broad stakeholder community: sci- nurses, genetc (and genomic) counselors, and laboratory direc-
entsts, clinicians, patents, policy-makers, payers, and regu- tors – and, fnally, to members of the genomic and personalized
lators, as well as leaders in industry and in government. This medicine research communites, both public and private, who
book is intended to help each of these key consttuencies gain will, we trust, help write future editons of this text.
a common understanding of a complex and evolving feld, In tmes of transformaton, we are all students. We hope
such that they can partcipate efectvely in the breadth of that this book will help usher in this new era of genomic and
issues and challenges, and debate the opportunites that lie personalized medicine and will provide a useful and thorough
ahead. Furthermore, we believe that a collectve and global introducton to the science and practce of this new approach
approach to genomic and personalized medicine – one of the to human health.
most complex scientfc and clinical undertakings in the history
of healthcare – is undoubtedly what is required. Our interna- Geofrey S. Ginsburg, M.D., Ph.D.
tonal collectve of contributors to this work refects the early Huntngton F. Willard, Ph.D.
Acknowledgments
We wish to express our appreciaton and grattude to our Needless to say, without their eforts, this project could never
many colleagues, especially in the Duke Insttute for Genome have come to fruiton. We also thank Dr Eric Green, Director
Sciences & Policy and in the Duke Medicine community, who of the Natonal Human Genome Research Insttute, for provid-
have shared their knowledge and ideas about genomic and ing a foreword for this book and for his enthusiastc support of
personalized medicine and who, by doing so, have contnued the concept of genomic and personalized medicine.
to provide inspiraton for this project. We partcularly thank It gives us pleasure to give special thanks to Rita
our editors at Academic Press/Elsevier, Christne Minihane Chambers and to Stephanie Mactas and Alexandra Young,
and Graham Nisbet, who have encouraged us to develop and whose organizatonal and editorial eforts kept us on track and
evolve the concepts of genomic and personalized medicine saw this project through to completon.
from the frst editon to this one. Lastly, we thank our families for their patence and under-
We acknowledge and especially thank the nearly 170 standing for the many hours we spent creatng this, the second
authors of the 101 chapters that comprise these volumes. editon of Genomic and Personalized Medicine.
xiii
Abbreviatons
αDG Alpha-dystroglycan ACS Acute coronary syndrome
α-MSH α-melanocyte stmulatng hormone ACT A rtemisinin-based combinaton
β1-AR β1-adrenergic receptor therapies
μTAS Micro total analysis system ACTH Adrenocortcotropic hormone
2D-PAGE T wo-dimensional polyacrylamide gel ACTN1 Alpha actnin
electrophoresis AD Alzheimer disease
3C Chromatn conformaton capture ADAM33 ADAM metallopeptdase domain 33
5C C hromosome conformaton capture ADAR-1 RNA-specifc adenosine deaminase 1
carbon copy ADCC A ntbody-dependent cell-mediated
6-MMP 6-Methylmercaptopurine cytotoxicity
6MP 6-Mercaptopurine ADEPT A ntbody-directed enzyme prodrug
6-MTIMP 6-Methyl-thioinosine-monophosphate therapy
6-TGN 6-Thioguanine nucleosides ADH Alcohol dehydrogenase
6-TIMP 6-Thioinosinemonophosphate ADH3 A utosomal dominant
17q21 C hromosome 17q21.31 duplicaton hypercholesterolemia
syndrome ADHD Atenton defcit hyperactvity disorder
a.a. Amino acid ADI-R Revised autsm diagnostc interview
AAA Abdominal aortc aneurysm ADME A bsorpton, distributon, metabolism,
AABB American Associaton of Blood Banks and excreton
AAH Atypical adenomatous hyperplasia ADOS Autsm diagnostc observaton schedule
ABC Actvated B cell ADP Adenosine diphosphate
ABC ATP-binding cassete ADR Adverse drug reacton
ABC DLBCL A ctvated B-cell-like difuse large B-cell AE Alternatve expression
lymphoma AED Antepileptc drugs
ABCB1 A TP-binding cassete, sub-family B, AF Atrial fbrillaton
member 1 AFAP Atenuated FAP
ABI Ankle brachial index AFib Atrial fbrillaton
Abl A belson murine leukemia viral AFLP A mplifed fragment length
oncogene homolog polymorphism
ABVD A driamycin, bleomycin, vinblastne, and AFP Alpha-fetoprotein
dacarbazine AGEN-BP A sian Genetc Epidemiology Network
ACA Ant-centromere antbodies blood pressure
ACC American College of Cardiology Agr Accessory gene regulator
ACCE A nalytcal validity, clinical validity, AGT Angiotensin I
clinical utlity, and ethical, legal, and AGTR1 Angiotensin receptor 1
social implicatons AHA American Heart Associaton
ACE Angiotensin-convertng enzyme AHIC A merican Health Informaton
ACEi A ngiotensin-convertng enzyme Community
inhibitors AhpC Alkyl hydroperoxide reductase
ACF Aberrant crypt focus AHR Aryl hydrocarbon receptor
aCGH A rray comparatve genomic AHRQ A gency for Healthcare Research and
hybridizaton Quality
ACL Anterior cruciate ligament AI Allelic imbalance
ACO Accountable care organizaton AIDS Acquired Immune Defciency Syndrome
ACR Acute cellular rejecton AIH Autoimmune hepatts
ACR American College of Rheumatology AIMs Ancestry informatve markers
xv
xvi n Abbreviatons
Akt-v A kt murine thymoma viral oncogene ASR Analyte-specifc reagent
homolog AT Angiotensin
AKT Protein kinase B (PKB) ATG16L1 Autophagy-related 16-like 1
AKI Acute kidney injury ATM Ataxia telangectasia mutated
ALD Alcoholic liver disease ATP Adenosine triphosphate
ALK Anaplastc lymphoma kinase AUC Area under the curve
ALL Acute lymphoblastc leukemia AV Atrioventricular
ALM Acral lentginous melanoma B1-AR β1-adrenergic receptor
ALOX5 5'-Lipoxygenase B2M Beta-2-microglobulin
ALPS A utoimmune lymphoproliferatve BA Biliary atresia
syndrome BAC Bacterial artfcial chromosome
ALS Amyotrophic lateral sclerosis BACE1 β-site APP-cleaving enzyme 1
ALT Alanine aminotransferase BAL Bronchoalveolar lavage
AMA American Medical Associaton BALF Bronchoalveolar lavage fuid
AMA1 Apical membrane antgen 1 BAV Bicuspid aortc valve
AMCP Academy of Managed Care Pharmacy BBB Blood–brain barrier
AML Acute myeloid leukemia BBS Bardet–Biedl syndrome
AMP Associaton of Molecular Pathologists BCA Barcode assay
AMP Adenosine monophosphate BCG Bacille Calmete–Guérin (vaccine)
AMPK A denosine monophosphate-actvated BCL B-cell lymphoma
protein kinase BCL-2 B-cell lymphoma 2
AMR Antbody-mediated rejecton BCNE Blood-culture-negatve endocardits
AMT Accurate mass tags BCNU Bis-chloroethylnitrosourea
ANA Antnuclear antbodies BD Bipolar disorder
ANG-1 Angiopoietn 1 BDNF Brain-derived neurotrophic factor
ANG-2 Angiopoietn 2 BEST β-blocker Evaluaton of Survival Trial
ANKRD1 Ankyrin repeat domain 1 BFRM Bayesian factor regression modeling
ANN Artfcial neural network BIO Biotechnology Industry Organizaton
ANP Atrial natriuretc peptde BLA Biologic License Applicaton
APACHE II Acute Physiology and Chronic Health BLIMP1 B -lymphocyte-induced maturaton
Evaluaton II score protein 1
APC Drotrecogin-α (actvated protein C) BMC Bone marrow cell
APD Acton potental duraton BMI Body mass index
ApiAP2 Apicomplexan AP2 transcripton factor BMP4 Bone morphogenic protein 4
APOC3 Apolipoprotein C3 (gene) BNP Brain natriuretc peptde
APOE Apolipoprotein E (gene) BNP B-type natriuretc peptde
APP Beta-amyloid precursor protein bp Basepair
AR Adrenergic receptor BP Blood pressure
AR Androgen receptor BPDE Benzo(a)pyrenediol epoxide
ARB Angiotensin receptor blocker BRCA1 Breast cancer 1, early onset
ARH A utosomal recessive BRCA1 Breast cancer 2, early onset
hypercholesterolemia BRD Biospecimen Research Database
ARI Acute respiratory infectons C2 Complement component 2
ARMD Age-related macular degeneraton C3PR Cancer Central Clinical Patent Registry
ARRA A merican Recovery and C4A and B Complement component 4A and 4B
Reinvestment Act caAERS C ancer Adverse Events Reportng System
ARS Axenfeld–Rieger’s syndrome CABG Coronary artery bypass grafing
ARV Antretroviral caBIG® Cancer Biomedical Informatcs Grid
ARVC A rrhythmogenic right ventricular CAC Coronary artery calcium
cardiomyopathy caCORE C ancer Common Ontologic
ASCO American Society of Clinical Oncology Representaton Environment
ASCVD Atherosclerotc vascular disease CAD Coronary artery disease
ASD Atrial septal defect CADASIL C erebral autosomal dominant
ASD Autsm spectrum disorders arteriopathy with subcortcal infarcts
ASO Antsense oligonucleotde and leukoencephalopathy
