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Genetic Variation and Dietary Response

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World Review of Nutrition and Dietetics

Vol. 80

Series Editor

Artemis P. Simopoulos
The Center for Genetics, Nutrition and Health, Washington, D.C., USA

Advisory Board

Ake Bruce, Sweden Ji Di Chen, China Jean-Claude Dillon, France J.E. Dutra de Oliveira, Brazil Claudio Galli, Italy Ghafoorunissa, India Demetre Labadarios, South Africa Eleazar Lara-Pantin, Venezuela Paul J. Nestel, Australia Konstantin Pavlou, Greece A. Rerat, France V. Rogozkin, Russia Michihiro Sugano, Japan Naomi Trostler, Israel Ricardo Uauy-Dagach, Chile

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Genetic Variation and Dietary Response

Volume Editors

A.P. Simopoulos The Center for Genetics, Nutrition and Health, Washington, D.C. P.J. Nestel Baker Medical Research Institute, Prahran, Victoria

30 gures and 4 tables, 1997

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World Review of Nutrition and Dietetics

Library of Congress Cataloging-in-Publication Data Genetic variation and dietary response / volume editor, A.P. Simopoulos. (World review of nutrition and dietetics; vol. 80) Includes bibliographical references and index. 1. Chronic diseases Genetic aspects. 2. Chronic diseases Nutritional aspects. 3. Nutrition disorders Genetic aspects. 4. Lipids Metabolism Genetic aspects. 5. Lipids Metabolism Disorders Genetic aspects. I. Simopoulos, Artemis P., 1933. II. Series. [DNLM: 1. Variation (Genetics) 2. Disease Susceptibility genetics. 3. Diet adverse eects. 4. Chronic Disease. 5. Diet Therapy. W1 W0898 v.80 1997 / QH 438.5 G328 1997] QP141.A1W59 vol. 80 [RB156] 612.3 sdc21 [616.042] ISBN 3805563477 (alk. paper)

Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents and Index Medicus. Drug Dosage. The authors and the publisher have exerted every eort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant ow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Copyright 1997 by S. Karger AG, P.O. Box, CH4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Thur AG Osetdruck, Pratteln ISBN 3805563477

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Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI 1

Genetic Control of Response to Dietary Fat and Cholesterol

Peter M. Clifton, Mavis Abbey CSIRO Division of Human Nutrition, Adelaide, Australia

Introduction . . . . . . . . . . . . . . . . . Low-Density Lipoprotein Receptor Gene . Apolipoprotein B Gene . . . . . . . . . . . Apolipoprotein E . . . . . . . . . . . . . . . The AI-CIII-AIV Gene Complex . . . . . . Apolipoprotein AIV . . . . . . . . . . . . . Apolipoprotein CI . . . . . . . . . . . . . . Apolipoprotein AII . . . . . . . . . . . . . Lipoprotein Lipase . . . . . . . . . . . . . . Hepatic Lipase . . . . . . . . . . . . . . . . Cholesteryl Ester Transfer Protein . . . . . Low-Density Lipoprotein Subclass Patterns Conclusions . . . . . . . . . . . . . . . . . .

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Apolipoprotein E Polymorphism and Plasma Cholesterol Response to Dietary Change . . . . . . . . . . . . . . . . . . . . . . . .

Matti J. Tikkanen Department of Medicine, Division of Cardiology, University of Helsinki, Finland

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of Apolipoprotein E Isoforms in the Regulation of Plasma Lipid Levels: Underlying Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Apolipoprotein E Phenotype and Plasma Lipid Response to Dietary Lipid Intake Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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15 16 17 18

Genetic, Metabolic, and Dietary Inuences on the Atherogenic Lipoprotein Phenotype . . . . . . . . . . . . . . . . . .

Ronald M. Krauss Ernest Orlando Lawrence Berkeley National Laboratory, University of California, Berkeley, Calif., USA

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physicochemical and Metabolic Heterogeneity of Low- and Intermediate-Density Lipoproteins . . . . . . . . . . . . . . . . . . . . . . . . The Small, Dense Low-Density Lipoprotein Phenotype . . . . . . . . . . . . . . . Low-Density Lipoprotein Heterogeneity and the Risk of Coronary Artery Disease . In vitro Studies of the Atherogenic Properties of Low-Density Lipoprotein Subfractions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eects of Lipid-Lowering Therapies on Low-Density Lipoprotein Subfractions . . Diet and Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hormonal Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacologic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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22 23 26 28 31 32 32 35 36 37

The Adipsin-Acylation-Stimulating Protein Pathway and Microenvironmental Metabolic Regulation . . . . . . . . . . . . . .

Allan D. Sniderman, Katherine Cianone

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McGill Unit for the Prevention of Cardiovascular Disease, Royal Victoria Hospital, Montreal, Canada

Introduction and Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular Identity of Acylation-Stimulating Protein . . . . . . . . . . . . . . . . Generation of Acylation-Stimulating Protein from C3, Adipsin, and Factor B . . Mechanism of Acylation-Stimulating Protein Action . . . . . . . . . . . . . . . . Evidence for a Specic Cell Membrane Receptor for Acylation-Stimulating Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evidence for Activation of Protein Kinase C as the Acylation-Stimulating Protein Signal Transduction Pathway . . . . . . . . . . . . . . . . . . . . Eect of Acylation-Stimulating Protein on the Activation of Diacylglycerol Acyltransferase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eect of Acylation-Stimulating Protein on Specic Membrane Transport of Glucose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Adipsin-Acylation-Stimulating Protein Pathway in Adipocytes . . . . . . . .

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45 46 47 48 49 50 51 51 53

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The Microenvironmental Model of Chylomicron Clearance and Adipocyte Activation Lipoprotein Lipase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparison of Very-Low-Density Lipoprotein and Chylomicron Metabolism in Adipose Tissue and their Abilities to Activate the Acylation-Stimulating Protein Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physiologic Roles of Acylation-Stimulating Protein in Determining the Triglyceride Balance in Adipocytes . . . . . . . . . . . . . . . . . . . . . . . . . In vivo Regulation by Acylation-Stimulating Protein of Plasma Triglyceride Clearance in the Postprandial State . . . . . . . . . . . . . . . . . . . . . . . Role of Acylation-Stimulating Protein in Regulation of Fatty Acid Eux from Adipocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acylation-Stimulating Protein Eects on Basal Fasting Adipocyte Fatty Acid Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Insulin-Mediated Inhibition of Adipocyte Fatty Acid Release . . . . . . . Catecholamine-Mediated Adipocyte Fatty Acid Release . . . . . . . . . . Pathophysiologic Abnormalities of the Adipsin-Acylation-Stimulating Protein Pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dyslipoproteinemias: HyperapoB/Familial Combined Hyperlipidemia . . . . . . In vivo Observations in Patients with HyperapoB . . . . . . . . . . . . . . . In vitro Observations of Cellular Deciencies in Triglyceride Synthesis in Hypertriglyceridemic Patients . . . . . . . . . . . . . . . . . . . . . . . . . In vitro Observations in Patients with HyperapoB . . . . . . . . . . . . . . . Pathophysiology of HyperapoB due to Decient or Defective AcylationStimulating Protein Receptors . . . . . . . . . . . . . . . . . . . . . . . . . Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acylation-Stimulating-Protein Ecient Obesity: Gynoid Obesity . . . . . . . Acylation-Stimulating-Protein Inecient Obesity: Android (Omental) Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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58 61 61 61 62 64 65 65 65 67 67 68 69 72 72 74 76

Mechanisms Controlling Lipemic Responses to Dietary Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Rampratap S. Kushwaha, Henry C. McGill, Jr. Department of Physiology and Medicine, Southwest Foundation for Biomedical Research, San Antonio, Tex., USA

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Introduction . . . . . . . . . . . . . . . . . . . . . . . Overview of Cholesterol and Lipoprotein Metabolism Basic Metabolic Pathways . . . . . . . . . . . . . Eects of Dietary Cholesterol . . . . . . . . . . . Eects of Dietary Fatty Acids . . . . . . . . . . . Human Studies . . . . . . . . . . . . . . . . . . . . . .

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VII

Cholesterol Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cholesterol Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Apolipoprotein B Kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . Apolipoprotein Polymorphism . . . . . . . . . . . . . . . . . . . . . . . . Bile Acid Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Animal Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cholesterol-Resistant Rabbits . . . . . . . . . . . . . . . . . . . . . . . . . Rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inbred Mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Marsupials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nonhuman Primates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Squirrel Monkeys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cynomolgus Monkeys . . . . . . . . . . . . . . . . . . . . . . . . . . . . Rhesus Monkeys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . African Green Monkeys . . . . . . . . . . . . . . . . . . . . . . . . . . . Baboons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . High- and Low-Low-Density-Lipoprotein-Responding Phenotypes . High- and Low-High-Density-Lipoprotein-1-Responding Phenotypes Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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90 91 92 94 96 96 97 98 99 99 100 100 101 101 101 103 103 105 109 113

Genetics of Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . 126

P.J. Kelly, P.N. Sambrook, N.A. Morrison, T. Nguyen, J.A. Eisman Bone and Mineral Research Division, Garvan Institute of Medical Research, and Departments of Endocrinology, Gerontology and Rheumatology, St. Vincents Hospital, Sydney and University of New South Wales, Australia

Introduction . . . . . . . . . . . . . . . . . . . . . . . Genetics of Osteoporosis Candidate Traits . . . . . . Genetic Epidemiology of Bone Mineral Density . . . Family Studies of Bone Mass . . . . . . . . . . . Twin Studies of Bone Mass . . . . . . . . . . . . Twin Studies of Bone Density Changes with Age Mechanisms of Genetic Eects on Bone Density . . . Genetic Disorders of Bone Collagen Synthesis . . . . Vitamin D Receptor Gene . . . . . . . . . . . . . . . . Vitamin D Receptor Gene Alleles, Calcium Intake and Genetics and Fractures . . . . . . . . . . . . . . . . . Ethnic Factors . . . . . . . . . . . . . . . . . . . . . . Other Genetic Inuences . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . .

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Gene-Nutrient Interactions in Single-Gene Defects and Polygenic Diseases: Methodologic Considerations . . . . . . . . . 145
Antonio Velazquez Department of Nutritional Genetics, Instituto de Investigaciones Biomedicas, UNAM and Instituto Nacional de Pediatra, Mexico, Mexico

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 Single-Gene Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 Common (Polygenic-Multifactorial) Diseases . . . . . . . . . . . . . . . . . . . . . . 154

Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

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Preface

The subject of Volume 63 in the series World Review of Nutrition and Dietetics was Genetic Variation and Nutrition. Published in 1990, it comprised the papers presented at the international conference on Genetic Variation and Nutrition held in June 1989 in Washington, DC. While volume 63 provided the reader an opportunity to consider the important advances in molecular biology as they impact on genetics, nutrition and public health, the present volume on Genetic Variation and Dietary Response focuses on genetics and nutrition, and their interaction in the development of chronic diseases. Coronary artery disease, hypertension, diabetes, cancer and other chronic diseases tend to aggregate in families, and the risk for relatives is much higher than that in the general population. Families share both genes and environment and similarity may result from either. Much research has been carried out to dene the contribution of each and their interaction in the development of the individual. Broadly dened, heritability is the proportion of the total variance that can be explained by genes. Studies in the United States have shown that 50% of the variance in plasma cholesterol concentration, 3050% of the variability in low-density lipoprotein (LDL) particle size, and 3060% of the variance in blood pressure are genetically determined; between 15% and 50% of the variance in brinogen, an independent risk factor for coronary artery disease, is genetically determined: 15% was found in the United Kingdom, while 51% is the gure among the Hawaiian population, indicating signicant dierences between populations. In Australians, 75% of the variance in bone density is genetically determined. Calculations of heritability are relevant only to the specic population and environment from which information is gathered. Heritability may vary between populations if they dier in the prevalence of the types of genes aecting the disease entity under consideration. Populations therefore should not copy each others dietary recommendations

for the prevention of coronary artery disease, and cancer, or any other disease for that matter. Using the tools of molecular biology and genetics, research is dening the mechanisms by which genes inuence nutrient absorption, metabolism and excretion, taste perception, and degree of satiation, and the mechanisms by which nutrients inuence gene expression. Furthermore, advances in molecular and recombinant DNA technology have led to exquisite studies in the eld of genetics and the recognition in a much more specic way, through DNA sequencing, how unique each one of us is, and the extent to which genetic variation occurs. The importance of the eects of genetic variation has been extensively studied and applied by pharmacologists in drug development and evaluation of drug metabolism and adverse reactions to drugs. In the past two decades, physicians, geneticists, and nutritionists have begun to study the eects of genetic variation and gene-nutrient interactions in the management of chronic diseases. It was therefore considered appropriate to dedicate a volume of World Review of Nutrition and Dietetics to the subject of Genetic Variation and Dietary Response. In planning this volume with Paul J. Nestel, MD (Australia), leaders in their eld were identied and we are very pleased to have their contributions. Practically all chronic conditions and diseases are genetically determined. Genes dene susceptibility to disease, and environmental factors (nutrition being an environmental factor of major importance) determine who among the susceptible individuals will develop disease. The role of genetics in cardiovascular disease and the response to diet is the area that has been investigated most extensively, particularly the genes and their variants or polymorphisms involved in lipid metabolism. This area of research began with studies that showed variability in plasma cholesterol response to dietary lipids, and the identication of high and low cholesterol responders among humans and animals. Hyperresponsiveness to dietary cholesterol may be due to a variant of one gene, interactions among a number of genes or to inuences of other diseases such as diabetes, obesity or hypothyroidism. Studies on genetic variants of apolipoproteins (apo) such as apoE in various populations, apoAIV, cholesteryl ester transfer protein, and LDL subclass patterns, to name just a few, have shown the contribution of genetic variation or polymorphism to dietary response in terms of lipid levels. For example, studies of the apoAIV polymorphism showed that there are clinically signicant major dierences in dietary response between the two phenotypes apoAIV-1/1 and apoAIV1/2. Following 900 mg/day of dietary cholesterol, individuals with phenotype apoAIV-1/1 showed a signicant increase in plasma cholesterol levels while those with the apoAIV-1/2 phenotype showed only a small (0.03 mmol/l) rise in plasma cholesterol level. The latter individuals account for 13% of

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the US population indicating that universal dietary recommendations to lower dietary cholesterol would not be appropriate for those with phenotype apoAIV-1/2. The volume begins with the chapter Genetic Control of Response to Dietary Fat and Cholesterol by Drs. Clifton and Abbey. The authors provide an overview on the status of the genetic variants involved in lipid metabolism and comment on their clinical usefulness. In Apolipoprotein E Polymorphism and Plasma Cholesterol Response to Dietary Change, Dr. Tikkanen reviews the studies and discusses the reasons for the dierent responses to dietary fat and cholesterol in persons with apoE polymorphism in various ethnic groups. The eect of the apoE phenotype on diet-induced lowering of plasma LDL cholesterol has been extensively studied. In general, the data indicate that apoE phenotype modulates the LDL-cholesterol-lowering response to diet and that male subjects carrying the apoE4 allele are the most responsive to a low-fat diet. Genetic variation at the apoE locus results from three common alleles in the population E4, E3 and E2. Population studies have shown that plasma cholesterol, LDL cholesterol, and apoB are highest in subjects carrying the apoE4 isoform, intermediate in those with the apoE3 isoform, and lowest in those with the apoE2 isoform. It has been suggested that apoE allelic variation may account for as much as 14% of the variation in total and LDL cholesterol in the general population. The frequencies of apo E4, E3 and E2 in the Caucasian population is approximately 15%, 76.9% and 8% respectively. Compared to Caucasians (15%), extremely high frequencies of the apoE4 allele have been found in African and Asian populations such as New Guineans (35%) and Nigerians (30%). Among European populations, northern countries have higher frequencies (Finland 22.7%; Sweden 20.3%) than southern countries (Italy 9.4%) which suggests that apoE4 may in part account for the dierences in cardiovascular disease prevalence in the two European regions. The relationship between LDL cholesterol levels and apoE genetic variation is not independent of environmental and ethnic factors. The association of the apoE4 isoform with elevated serum cholesterol levels is greater in populations consuming diets rich in saturated fat and cholesterol than in other populations. Recent data indicate that the higher LDL cholesterol levels observed in subjects carrying the apoE4 isoform are manifested primarily in the presence of an atherogenic diet characteristic of certain societies, and that the response to saturated fat and cholesterol diers among individuals with dierent apoE phenotypes. In the chapter Genetic, Metabolic, and Dietary Inuences on the Atherogenic Lipoprotein Phenotype, Dr. Krauss reviews the physicochemical and metabolic heterogeneity of LDL; intermediate density lipoprotein (IDL), the small, dense LDL phenotype; and the risk of coronary heart disease. In

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addition, Dr. Krauss discusses the in vitro studies of atherogenic properties of LDL subfractions and the eects of lipid-lowering therapies on LDL subfractions including diet and exercise, hormonal factors and pharmacologic agents. Estimates of heritability of LDL particle size have ranged from about 3050% indicating the importance of genetic and environmental inuences. In addition to age and gender, abdominal adiposity, oral contraceptive use and the hypertriglyceridemia of AIDS inuence LDL particle size and density distribution. Variation in dietary fat and carbohydrate strongly inuence expression of the small, dense LDL phenotype, and contribute to variations in LDL particle size distribution observed among individuals and population groups. The plasma lipoprotein prole accompanying a predominance of small, dense LDL particles (specically LDL3) is associated with an up to threefold increased risk of coronary artery disease. The next chapter by Drs. Sniderman and Cianone is on the AdipsinAcylation-Stimulating Protein Pathway and Microenvironmental Metabolic Regulation. The tight linkage of chylomicron triglyceride hydrolysis in the capillary space to adipocyte triglyceride synthesis in the subendothelial space constitutes what the authors term microenvironmental metabolic regulation. Dysfunction or dysregulation of this pathway results in a variety of clinical disorders of lipoprotein and adipose tissue metabolism. Dysfunction of the pathway produces a characteristic dyslipoproteinemia, hyperapoB, whereas hyperfunction is characteristic of gynoid obesity, but whether this is a primary abnormality or a secondary adaptation remains to be determined. The authors hypothesize that the pathophysiology of the dyslipoproteinemia in android obesity corresponds closely to that for hyperapoB due to a defective acylationstimulating protein (ASP) response. Furthermore, it is their hypothesis that dysfunction of the ASP pathway may be an important element in the pathogenesis of a number of dyslipoproteinemias associated with coronary heart disease. Hypertriglyceridemia with a normal apoB is not associated with increased cardiovasular risk, whereas hypertriglyceridemia with an elevated apoB is. This bears on treatment, since brates which decrease triglycerides substantially reduce apoB only modestly, while the reverse holds for HMG CoA reductase inhibitors. In Mechanisms Controlling Lipemic Responses to Dietary Lipids, Drs. Kushwaha and McGill, Jr. review the metabolic and molecular mechanisms of high and low plasma cholesterol responses to dietary cholesterol and fat in human studies and animal models. The authors also evaluate these studies to determine whether any markers in animal models can be applied to humans. They conclude, The mechanisms regulating responsiveness to diet, and the underlying genetic variations, seem to dier among species and even among strains of the same species. In humans, the metabolic variable most often associated with a

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high cholesterolemic response to dietary lipids is high LDL apoB production. LDL apoB secretion from the liver is regulated postranslationally, and a number of factors aecting hepatic cholesterol metabolism aect this process. Kelly et al. in the Genetics of Osteoporosis present the latest information of the vitamin D receptor (VDR) gene, VDR gene alleles, their relationship to calcium intake and bone mineral density and ethnic dierences in VDR gene frequencies and dietary response. The authors state, Genetic mechanisms and factors determining bone turnover and bone density have important implications for our understanding of the pathophysiology and treatment of osteoporosis. Identication of those individuals genetically at risk for osteoporosis opens up opportunities to inuence lifetime fracture risk at various stages throughout life, for example, by maximising peak bone mass in adolescence by dietary calcium supplementation or by targeting oestrogen replacement therapy more eectively at menopause. Whether VDR gene allelic dierences are associated with response to treatment for the other therapies used to treat osteoporosis also requires investigation. The functional signicance of these VDR gene alleles in relation to the vitamin D endocrine system and bone metabolism also remains to be determined although, as noted, studies suggest signicant dierences in responsiveness to stimulation with calcitriol according to allelic status, and interactions between calcium intake and VDR genotype. In particular, further studies are necessary to identify the molecular and physiological mechanisms of the VDR gene eect in order to dene optimal interventions to improve and maintain bone density and ultimately reduce the overall fracture incidence. The question of gene-environment interaction in this regard provides an interface between nutrition and genetics. Further work must examine whether, in the longer term, preventative strategies, such as calcium supplementation, can be targeted to those most likely to respond, as determined by VDR allelotype. In the nal chapter, Gene-Nutrient Interactions in Single-Gene Defects ` and Polygenic Diseases: Methodologic Considerations, Dr. Velazquez discusses the methods that must be used to specicallly dene gene-nutrient ` interactions. Dr. Velazquez makes the point that a valid risk estimate requires that the population of controls represents the genetic background of the cases as closely as possible. With the recent availability of a comprehensive human genetic map, sibpair analysis has been applied to a whole-genome scan, and excess allele sharing has been found at a locus on chromosome 11q, pointing to a previously unidentied causal factor in insulin-dependent diabetes. One often cannot tell whether two relatives inherited a chromosomal region identical-by-descent, but only whether they have the same alleles at genetic markers in the region, i.e. are identical-by-state. Approaches have been developed to cope with this important practical diculty. Using these methods, the

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angiotensinogen gene has been shown to be linked to essential hypertension in multiplex families, although the gene explains only a minority of the phenotype. Allele-sharing methods can also be applied to quantitative traits, based on the notion that the phenotype between two relatives should be correlated with the number of alleles shared at a trait-causing locus. It has been used, for example, to relate bone density in postmenopausal women with allele sharing in the region of the VDR gene. Dr. Velazquez concludes, Perhaps the most ` transcendent goals of the human genome project will be to map, isolate and characterize the genes involved in complex, common traits. Once this is done, it will be feasible to describe the phenotypes of the same genotype in many dierent environments, something that in turn will nally make it possible to dene norms of reaction in humans, something up to now possible only in animals and plants. This in turn will allow us to better understand the naturenurture question with regard to nutrition, dene the limits of nutritional individuality and provide us with powerful tools to treat and prevent nutritional disorders in a more rational way, according to that individuality. It is evident that the health of the individual and the population in general are the result of interaction between genetic and environmental factors, nutrition being an environmental factor of major importance. Knowledge of genetic susceptibility to disease will help identify those at higher risk for disease, as well as their response to diet. The prospect of targeting specic dietary treatment to those predicted to gain the most therapeutic benet clearly has important clinical and economic consequences, particularly in diseases of high prevalence. In this volume, the reader is given the opportunity to consider the important advances in molecular biology and physiology as they impact on genenutrient interactions and response to diet. It is clear that for the prevention and control of chronic diseases, precise genetic information and the response to a specic dietary regimen should lead to a better form of prevention for those at risk for a disease, without involving the whole population in recommending dietary restrictions. This book should be of particular interest to physicians, nutritionists, dietitians, geneticists, physiologists, molecular biologists, food technologists and policy makers. Artemis P. Simopoulos, MD

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