Human Genome Epidemiology A Scientific Foundation for

Using Genetic Information to Improve Health and Prevent

Disease

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Library of Congress Cataloging-in-Publication Data

Human genome epidemiology:
a scientific foundation for using genetic information to
improve health and prevent disease/
edited by Muin J. Khoury, Julian Little, Wylie Burke.
p. cm. Includes bibliographical references and index.
ISBN 0-19-514674-3
1. Genetic disorders—Epidemiology. 2. Medical genetics—Methodology.
3. Genomics.
I. Khoury, Muin J. II. Little, Julian. III. Burke, Wylie.
RB155.5.H86 2003 616'.042—dc21 2003048623

987654321
Printed in the United States of America
on acid-free paper
Preface

Advances in human genetics are expected to play a central role in medicine and
public health in the 21st century by providing genetic information for disease pre-
diction and prevention. Although human gene discoveries generate excitement and
expectations, the translation of gene discoveries into meaningful actions to improve
health and prevent disease depends on scientific information from multiple medical
and public health disciplines. The field of epidemiology plays a central role in this
effort. Epidemiology is often viewed as the scientific core of public health and in-
volves the study of the distribution and determinants of health-related states or events
in populations and the application of this study to control health problems. Epi-
demiologists determine risk factors for various diseases, identify segments of the
population with highest risk to target prevention and intervention opportunities, and
evaluate the effectiveness of health programs and services in improving the health
of the population.
In this book, we show how the epidemiologic approach will play an important
role in the continuum from gene discovery to the development and applications of
genetic tests. We call this continuum human genome epidemiology (or HuGE) to
denote an evolving field of inquiry that uses systematic applications of epidemio-
logic methods to assess the impact of human genetic variation on health and dis-
ease. Since most gene discoveries are based on studies of high-risk families or
selected population groups, once disease genes are found, well-conducted epidemi-
ologic studies are needed to quantify the population impact of gene variants on the
risk for health outcomes and to identify and measure the impact of modifiable risk
factors that interact with gene variants. Epidemiologic studies are also required to
clinically validate new genetic tests, to monitor population use of genetic tests, and
to determine the impact of genetic information on the health and well-being of

v
VI PREFACE

different populations. The results of such studies will help medical and public health
professionals integrate genetics into practice.
As more epidemiologic investigations of human genes are conducted and pub-
lished, evidence needs to be integrated from different studies. Given the large num-
bers of genes that will be examined in relation to diseases, many spurious findings
are likely to emerge. Variation in study design and execution will make it difficult
to synthesize information across studies. The increasing number of human genome
epidemiologic studies has uncovered the need for guidelines on synthesizing results,
particularly for assessing the prevalence of gene variants, gene-disease associations,
and gene-environment and gene-gene interactions, and for evaluating genetic tests.
Although none of the material presented here is novel, we have structured the
book to allow readers to proceed systematically from the fundamentals of genome
technology and discovery, to epidemiologic approaches to gene characterization, to
evaluation of genetic tests and health services. We then illustrate these concepts in
several disease-specific case studies. The book focuses on post-gene discovery (what
do you do with a gene when you find one?) with an overview of emerging analytic
methods for gene discovery. Part I describes genomic technologies and their appli-
cations, discusses evolving methods of gene discovery, and summarizes the current
status of the ethical, legal, and social issues for conducting epidemiologic studies
of the human genome (with emphasis on informed consent issues). Part II addresses
epidemiologic approaches to the study of genotypes in populations and their rela-
tion to diseases, including the assessment of gene-gene and gene-environment in-
teraction. This section also addresses issues of synthesis of these studies, including
some methodologic standards. Part III deals with the application of epidemiologic
methods to assessing genetic information for clinical and public health applications.
The section lays an epidemiologic foundation for using population level informa-
tion to assess individual risk for clinical use. We explore population-based concepts
of the usefulness of genetic tests in populations and discuss the evaluation of ge-
netic tests from a combined clinical-laboratory approach. We also explore an epi-
demiologic framework for the interface among genetics, pharmacology, and medi-
cine. Lastly, we explore the integration of genetics into controlled clinical trials and
the role of genetics in the development of clinical practice guidelines. Finally, Part
IV uses case studies to illustrate concepts discussed in the first three sections in re-
lation to specific disease examples, including gene-environment interactions (pes-
ticides and oral contraceptive use), chronic diseases (colon cancer, Alzheimer
disease, cardiovascular disease, breast cancer, and iron overload), occupational ex-
posures (berylliosis), newborn screening issues (fragile X syndrome and hearing
loss), and infectious disease (human immunodeficiency virus infection). These ex-
amples are by no means exhaustive, but they do illustrate the spectrum from single
gene disorders to complex conditions, and the need for epidemiologic research to
obtain population level information for developing health policy and practice. In-
deed, for many of the case studies, the lack of solid epidemiologic data represents
a primary barrier to developing appropriate health policies related to the use of ge-
Preface vii

netic information. Because our knowledge is rapidly evolving for each one of these
examples, most likely, the case studies will be outdated soon. Nevertheless, the ba-
sic methodologic foundation for translating gene discovery into usable clinical in-
formation will still apply.
Ultimately, a multidisciplinary approach is needed to fulfill the promise of the
Human Genome Project in improving health. At the core of these disciplines, the
epidemiologic approach will begin to fill immense gaps in our knowledge of pop-
ulation risk for various diseases in relation to genetic variation. This information is
a necessary first step in the long road from gene discovery to medical and public
health practice.

Atlanta, GA M.J.K.
Aberdeen, UK J.L.
Seattle, WA W.B.
This page intentionally left blank
Acknowledgments

We are grateful to the following individuals for reviewing drafts of selected book
chapters: Harry Campbell, David FitzPatrick, Seymour Garte, Scott Grosse, James
E. Haddow, Robin Harbour, Neil Holtzman, Craig Hooper, Rolv T. Lie, Zosia
Miedzybrodzka, Arno Motulsky, Thomas O'Brien, Scott Ramsey, Sonja Rasmussen,
Duncan Shaw, Michael Steel, Karen Steinberg, Donna Stroup, James Tang, Em-
manuela Taioli, Bruce Tempel, Paolo Vineis, Benjamin Wilfond, and Paula Yoon.
In addition, we thank Karen Foster, Pamela Gillis Watson, Elizabeth Fortenberry,
and Patti Seikus, with the Centers for Disease Control and Prevention editorial staff,
for their literary support to this book; thanks also to Thelma Brown, without whom
the book would have never been completed.

IX
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Contents

Contributors xv

PART I Fundamentals
1. Human Genome Epidemiology: Scope and Strategies 3
Muin J. Khoury, Julian Little, and Wylie Burke
2. Emerging Genomic Technologies and Analytic Methods for Population-
and Clinic-Based Research 17
Darrell L. Ellsworth and Christopher J. O 'Donnell
3. Approaches to Quantify the Genetic Com of and Identify Genes
for Complex Traits 38
Patricia A. Peyser and Trudy L. Burns
4. Ethical, Legal, and Social Issues in the Design and Conduct of Human
Genome Epidemiology Studies 58
Laura M. Beskow

PART II Methods and Approaches I: Assessing Disease

Associations and Interactions
5. Assessing Genotypes in Human Genome Epidemiology Studies 79
Karen Steinberg and Margaret Gallagher
6. Statistical Issues in the Design and Analysis of Gene-Disease
Association Studies 92
Duncan C. Thomas

XI
XII CONTENTS

7. Facing the Challenge of Complex Genotypes and Gene-Environment

Interaction: The Basic Epidemiologic Units in Case-Control and
Case-Only Designs 111
Lorenzo D. Botto and Muin J. Khoury
8. Inference Issues in Cohort and Case-Control Studies of Genetic Effects
and Gene-Environment Interactions 127
Montserrat Garcia-Closas, Sholom Wacholder, Neil Caporaso,
and Nathaniel Rothman
9. Applications of Human Genome Epidemiology to Environmental Health 145
Samir N. Kelada, David L. Eaton, Sophia S. Wang, Nathaniel R. Rothman,
and Muin J. Khoury
10. Reporting and Review of Human Genome Epidemiology Studies 168
Julian Little

PART III Methods and Approaches II:

Assessing Genetic Tests for Disease Prevention
11. Epidemiologic Approach to Genetic Tests: Population-Based Data for
Preventive Medicine 195
Marta Gwinn and Muin J. Khoury
12. Genetic Tests in Populations: An Evidence-Based Approach 207
Paolo Vineis
13. ACCE: A Model Process for Evaluating Data on Emerging
Genetic Tests 217
James E. Haddow and Glenn E. Palomaki
14. The Interface between Epidemiology and Pharmacogenomics 234
David L. Veenstra
15. Integrating Genetics into Randomized Controlled Trials 247
John P.A. loannidis and Joseph Lau
16. Developing Guidelines for the Clinical Use of Genetic Tests:
A U.S. Perspective 264
Linda E. Pinsky, David Atkins, Scott Ramsey, and Wylie Burke
17. Using Human Genome Epidemiologic Evidence in Developing Genetics
Services: The U.K. Experience 283
Brenda J. Wilson, Jeremy M. Grimshaw, and Neva E. Haites
Contents xiii

PART IV Case Studies: Using Human Genome

Epidemiology Information to Improve Health
18. Paraoxonase Polymorphisms and Susceptibility to Organophosphate
Pesticides 305
Kathryn Battuello, Clement Furlong, Richard Fenske, Melissa A. Austin,
and Wylie Burke
19. Factor V Leiden, Oral Contraceptives, and Deep Vein Thrombosis 322
Jan P. Vandenbroucke, Frits R. Rosendaal, and Rogier M. Bertina
20. Methylenetetrahydrofolate Reductase Gene (MTHFR), Folate, and
Colorectal Neoplasia 333
Linda Sharp and Julian Little
21. Apolipoprotein E and Alzheimer Disease 365
Richard Mayeux
22. Immunogenetic Factors in Chronic Beryllium Disease 383
Erin C. McCanlies, Michael E. Andrew, and Ainsley Weston
23. Fragile X Syndrome: From Gene Identification to Clinical Diagnosis
and Population Screening 402
Dana C. Crawford and Stephanie L. Sherman
24. The Connexin Connection: From Epidemiology to Clinical Practice 423
Aileen Kenneson and Coleen Boyle
25. Genetic and Environmental Factors in Cardiovascular Disease 436
Molly S. Bray
26. BRCA1/2 and the Prevention of Breast Cancer 451
Jenny Chang-Claude
27. The Role of Chemokine and Chemokine Receptor Genes in
HIV-1 Infection 475
Thomas R. O'Brien
28. Hereditary Hemochromatosis 495
Giuseppina Imperatore, Rodolfo Valdez, and Wylie Burke
29. Genetic Testing of Railroad Track Workers with Carpal
Tunnel Syndrome 511
Paul A. Schulte and Geoffrey Lomax
Index 525
This page intentionally left blank
Contributors

MICHAEL E. ANDREW, PH.D. ROGIER M. BERTINA, M.D., PH.D.

Biostatistics and Epidemiology Branch Thrombosis and Haemostatis Research
National Institute for Occupational Center
Safety and Health Centers for Leiden University Medical Center
Disease Control and Prevention Leiden, Netherlands
Morgantown, West Virginia
LAURA M. BESKOW, M.P.H.
Department of Health Policy and
DAVID ATKINS, M.D., M.P.H. Administration
Center for Practice and Technology University of North Carolina at
Assessment Chapel Hill
Agency for Healthcare Research and School of Public Health
Quality Chapel Hill, North Carolina
Rockville, Maryland
LORENZO D. BOTTO, M.D.
National Center on Birth Defects and
MELISSA A. AUSTIN, PH.D. Developmental Disabilities
Institute for Public Health Genetics Centers for Disease Control and
Department of Epidemiology Prevention
University of Washington Atlanta, Georgia
Seattle, Washington
COLEEN BOYLE, PH.D.
National Center on Birth Defects and
KATHRYN BATTUELLO, J.D., M.P.H. Developmental Disabilities
Institute for Public Health Genetics Centers for Disease Control and
University of Washington Prevention
Seattle, Washington Atlanta, Georgia

XV
XVI CONTRIBUTORS

MOLLY S. BRAY, PH.D. RICHARD FENSKE, PH.D.

Human Genetics Center Department of Environmental Health
University of Texas Health Science University of Washington
Center Seattle, Washington
Houston, Texas

CLEMENT FURLONG, PH.D.

WYLIE BURKE, M.D., PH.D.. Department of Genome Sciences and
Department of Medical History and Medicine
Ethics University of Washington
University of Washington Seattle, Washington
Seattle, Washington

MARGARET GALLAGHER, PH.D.

TRUDY L. BURNS, PH.D., M.P.H. Division of Laboratory Sciences
Division of Statistical Genetics National Center for Environmental
Department of Biostatistics Health
College of Public Health Centers for Disease Control and
University of Iowa Prevention
Iowa City, Iowa Atlanta, Georgia

NEIL CAPORASO, M.D. MONTSERRAT GARCIA-CLOSAS,

Division of Cancer Epidemiology and M.D., M.P.H., DR.P.H.
Genetics Division of Cancer Epidemiology and
National Cancer Institute Genetics
National Institutes of Health National Cancer Institute
Bethesda, Maryland National Institutes of Health
Bethesda, Maryland
JENNY CHANG-CLAUDE, M.D.
German Cancer Research Centre JEREMY M. GRIMSHAW, M.B.,
Division of Clinical Epidemiology CH.B., PH.D., F.R.C.G.P.
Heidelberg, Germany Director, Clinical Epidemiology
Program
DANA C. CRAWFORD, PH.D. Ottawa Health Research Institute
Department of Genome Sciences Director, Centre for Best Practice
University of Washington Institute of Population Health
Seattle, Washington University of Ottawa
Ottawa, Canada

DAVID L. EATON, PH.D.

Department of Environmental Health MARTA GWINN, M.D., M.P.H.
Center for Ecogenetics and Office of Genomics and Disease
Environmental Health Prevention
University of Washington Centers for Disease Control and
Seattle, Washington Prevention
Atlanta, Georgia

DARRELL L. ELLSWORTH, PH.D.

Gene and Drug Discovery Center JAMES E. HADDOW, M.D.
Windber Research Institute Foundation for Blood Research
Windber, Pennsylvania Scarborough, Maine
Contributors xvii

NEVA E. HAITES, PH.D., M.B., JOSEPH LAU, M.D.

CH.B., F.R.C.PATH., F.R.C.P. Division of Clinical Care Research
(EDIN), F.R.C.P. (LOND). Department of Medicine
Department of Medical Genetics Tufts University School of Medicine
University of Aberdeen New England Medical Center
Aberdeen, Scotland Boston, Massachusetts

GIUSEPPINA IMPERATORE, M.D., JULIAN LITTLE, PH.D.

PH.D. Epidemiology Group
Division of Diabetes Translation Department of Medicine and
National Center for Chronic Disease Therapeutics
Prevention and Health Promotion University of Aberdeen
Centers for Disease Control and Aberdeen, Scotland
Prevention
Atlanta, Georgia
GEOFFREY LOMAX, DR.P.H.,
M.P.H.
JOHN P.A. IOANNIDIS, M.D. Occupational Health Branch
Department of Hygiene and California Department of Health
Epidemiology Services
University of loannina School of Public Health Institute
Medicine, Greece University of California
Department of Medicine Berkeley, California
Tufts University School of Medicine
New England Medical Center RICHARD MAYEUX, M.D., M.SC.
Boston, Massachusetts The Taub Institute for Research on
Alzheimer's Disease and the Aging
Brain and
SAMIR N. KELADA, M.P.H. The Gertrude H. Sergievsky Center
Department of Environmental Health
College of Physicians and Surgeons
University of Washington
Columbia University
School of Public Health and
New York, New York
Community Medicine
Seattle, Washington
ERIN C. MCCANLIES, PH.D.
Biostatistics and Epidemiology Branch
AILEEN KENNESON, PH.D. National Institute of Occupational
National Center on Birth Defects Safety and Health
and Developmental Disabilities Centers for Disease Control and
Centers for Disease Control and Prevention
Prevention Morgantown, West Virginia
Atlanta, Georgia

THOMAS R. O'BRIEN, M.D., M.P.H.

MUIN J. KHOURY, M.D., PH.D. Viral Epidemiology Branch
Office of Genomics and Disease Division of Cancer Epidemiology and
Prevention Genetics
Centers for Disease Control and National Cancer Institute
Prevention National Institutes of Health
Atlanta, Georgia Bethesda, Maryland
XV111 CONTRIBUTORS

CHRISTOPHER J. O'DONNELL, M.D. PAUL A. SCHULTE, PH.D.

M.P.H. Education and Information Division
Cardiology Division, Department of National Institute for Occupational
Medicine Safety and Health
Massachusetts General Hospital Centers for Disease Control and
Harvard Medical School Prevention
Boston, Massachusetts Cincinnati, Ohio

GLENN E. PALOMAKI, B.A. LINDA SHARP, M.SC.

Foundation for Blood Research Epidemiology Group
Scarborough, Maine Department of Medicine and
Therapeutics
University of Aberdeen
PATRICIA A. PEYSER, PH.D. Aberdeen, Scotland
Department of Epidemiology
School of Public Health
University of Michigan STEPHANIE L. SHERMAN, PH.D.
Ann Arbor, Michigan Department of Human Genetics
Emory University School of Medicine
Atlanta, Georgia
LINDA E. PINSKY, M.D.
Department of Medicine
KAREN STEINBERG, PH.D.
University of Washington
Division of Laboratory Sciences
Seattle, Washington
National Center for Environmental
Health
Centers for Disease Control and
SCOTT RAMSEY, M.D., PH.D.
Prevention
Department of Medicine
Atlanta, Georgia
University of Washington
Fred Hutchinson Cancer Research
Center DUNCAN C. THOMAS, PH.D.
Seattle, Washington Department of Preventive Medicine
Keck School of Medicine
Los Angeles, California
FRITS R. ROSENDAAL, M.D., PH.D.
Department of Clinical Epidemiology
Leiden University Medical Center RODOLFO VALDEZ, PH.D.
Thrombosis and Haemostatis Research Division of Diabetes Translation
Center National Center for Chronic Disease
Leiden University Medical Center Prevention and Health Promotion
Leiden, Netherlands Centers for Disease Control and
Prevention
Atlanta, Georgia
NATHANIEL ROTHMAN, M.D.,
M.P.H., M.H.A.
Division of Cancer Epidemiology and JAN P. VANDENBROUCKE, M.D.,
Genetics PH.D.
National Cancer Institute Department of Clinical Epidemiology
National Institutes of Health Leiden University Medical Center
Bethesda, Maryland Leiden, Netherlands