(Circulation. 2000;102:IV-103.)
© 2000 American Heart Association, Inc.
Special Anniversary Issue |
Genetics of Cardiovascular Disease
From the Department of Internal Medicine, University of Texas at Houston Medical School, Houston (D.M.M.), and Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, Mass (C.E.S.).
Correspondence to Dianna M. Milewicz, MD, PhD, Associate Professor of Medical Genetics, Department of Internal Medicine, Division of Medical Genetics, University of Texas at Houston Medical School, 6431 Fannin, Suite 1.614, Houston, TX 77030. E-mail Dianna.M.Milewicz{at}uth.tmc.edu
Key Words: genetics • cardiovascular diseases • metabolism
Fifty years ago, cardiovascular genetics simply did not exist. Genetics was a nascent field of basic research, with little apparent relevance to cardiovascular science or any other medical subspecialty. Today, cardiovascular genetics is a discipline that fully integrates high-technology laboratory investigation and clinical medicine. From this hybrid have emerged discoveries that have precisely identified the cause of heretofore "idiopathic" disorders, provided fundamental insights into disease processes, and delineated subtypes in well-defined pathologies. Insights from these discoveries uproot traditional anatomic classifications of disease and integrate cell physiology and molecular biochemistry into the study of pathology. For researchers, practitioners, and patients alike, cardiovascular genetics is having a growing impact on the definition and diagnosis of disease, the explanation of prognosis, and the expansion of treatments.
While appreciating the progress that cardiovascular genetics has achieved, one must be mindful of antecedent and seminal discoveries in the broader field of genetics that enabled the birth and growth of the molecular era. By the mid 1900s, Mendel’s theory of inheritance was proven, the segregation and assortment of chromosomes during meiosis was recognized, the linear arrangement of genes on chromosomes was appreciated, and recombination frequency was accepted as an accurate assessment for the distances between genes.1 Even the potential for assigning genetic traits to specific chromosomes through the study of human inheritance was appreciated: familial transmission of color blindness and hemophilia was correctly interpreted to indicate genes encoded on the X chromosome.2 3
Any review of the critical developments that fostered the
birth of cardiovascular genetics must acknowledge the enormous
contributions made by clinicians, patients, and families. For advances
in genetics to become relevant to clinical cardiology, the heritable
nature of cardiovascular disease needed to be recognized. This
recognition was gained through case reports, descriptions of the
familial aggregation of diseases, and epidemiological studies, which
provided compelling evidence of a genetic component to many cardiac
diseases. The significance of these contributions is perhaps best
appreciated through the Mendelian Inheritance in Man
website.4 This
catalogue meticulously details 
800 distinct inherited human
phenotypes and classifies each as autosomal-dominant or -recessive,
X-linked, or mitochondrial trait on the basis of clinical descriptions.
More than a third of these 800 entries have a cardiovascular
component.
The pace of genetic research markedly accelerated after 1950; this can be attributed largely to progress in molecular biology, statistics, and computer science. The biochemical components of DNA were deduced, and bacterial (restriction) enzymes were discovered to cleave DNA, thus enabling cloning technologies and hybridization (Southern) blotting methodologies.5 6 7 The year 1977 heralded the development of DNA sequencing; this was followed soon after by the recognition of the considerable variation in nucleotide sequences (polymorphisms) in human genomes.8 9 10 The utility of polymorphism analyses for defining the chromosome location of genes in concert with statistical approaches (calculation of logarithm of odds ratios) firmly established the feasibility of molecular genetic approaches to define the chromosome location of genes, a first step in identifying disease-causing mutations.11
The 1980s initiated a decade of genome cartography. Early
maps were based on restriction fragment length polymorphisms (RFLPs)
and, in 1987, the first genome-wide map was
published.12 These
early maps provided few landmarks in comparison with contemporary
versions, as illustrated in
Figure 1
. The subsequent identification of variable
nucleotide repeat sequences (di-, tri-, and tetra-nucleotide) and a
definition of their extensive distribution throughout the genome led to
the construction of detailed maps, which continue to underpin
contemporary strategies for the chromosomal localization of genes.
Concurrent developments of molecular technologies throughout the 1980s,
such as the notable discovery of the polymerase chain reaction (PCR)
for selective amplification of prescribed segments of DNA, enhanced the
feasibility of genetic mapping strategies. Analyses of RFLPs required
large amounts of DNA and repetitive Southern blots, and they provided
limited polymorphic content; PCR-based analyses of di-, tri-, or
tetra-nucleotide repeats were more efficient and
informative.
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Chromosome mapping formed the basis for a novel approach to finding genes that, when mutated, caused human disease. The previous discoveries of the genetic basis of diseases came from meticulous dissection of perturbed biochemical pathways or cell processes. Pinpointing the inciting flaw was laborious and often impossible. Studying the genetic basis of cardiovascular diseases compounded these challenges: human cardiac tissue samples were rarely available and, when obtained, were usually too severely diseased to be useful. Researchers studying other organ systems overcame similar problems by developing immortal, tissue-specific cell lines, but researchers have only recently gained some success in establishing lines from cardiac myocytes.13 Chromosome mapping provided an alternative approach that bypassed these difficulties. Furthermore, the genetic mapping of diseases provided a route to the cause of a disease that was independent of a theory or hypothesis of the cause of the disease. If a disease gene could be localized to a small region of the human genome, then positional cloning, or the direct isolation of a disease gene based on its chromosome location, was feasible. Although the speed of discovery of disease-causing genes using such approaches was initially slow, the rate has increased considerably, in part due to the near-completion of the sequencing of the human genome.
The following sections describe the insights gleaned from
the elucidation of the molecular basis of specific cardiovascular
disorders. Given the plethora of discoveries made during the last
decade that are highly relevant to this topic, the pathologies selected
here for review indicate solely the interest and bias of the authors.
These few examples provide convincing evidence for the importance of
genetics in cardiovascular medicine today, but a similar conclusion is
also readily reached by a review of Circulation’s
content over the past 25 years
(Figure 2). The number of articles reporting hereditary
cardiovascular conditions, chromosome mapping studies, and the role of
mutations and polymorphisms in cardiovascular phenotypes is growing
exponentially. Although the number of already identified genes
contributing to cardiovascular diseases is significant
(Figure 3), research promises to implicate many more
genes in cardiovascular diseases in the next 50
years.
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SG-C,
Inborn Errors of Metabolism: Lesson Learned from Familial Hypercholesterolemia
In 1901, Sir Archibald Garrod studied a patient with black urine and suggested that genetic mutations can lead to a deficiency of a single enzyme in a metabolic pathway, thereby disrupting the normal metabolism of a product in the pathway. Garrod termed such disease processes an "inborn error of metabolism," thus setting the stage for contemporary biochemical genetics with his observations in a patient with alkaptonuria.14 In 1972, Michael S. Brown and Joseph L. Goldstein applied the concept of inborn errors of metabolism to the study of the human genetic disease familial hypercholesterolemia (FH); they postulated that the genetic defect in FH resulted from a failure of end-product repression of cholesterol synthesis. Patients with FH have greatly elevated levels of cholesterol in their blood, leading to premature heart disease early in life. In the mid 1960s and early 1970s, it was shown that FH existed clinically in a severe, homozygous form and a less severe, heterozygous form.15
Because DNA sequencing and cloning techniques were not
available at that time, Brown and
Goldstein’s16
approach was to apply the techniques of cell culture to identify the
genetic defect in FH. Initially, they used the dermal fibroblasts
explanted from normal individuals to study 3-hydroxy-methylglutaryl
coenzyme A (HMG CoA) reductase activity, the rate-limiting enzyme of
cholesterol biosynthesis. When these fibroblasts were cultured in the
presence of lipoproteins, HMG CoA reductase activity was low. When the
lipoproteins were removed from the culture media, the activity of the
enzyme rose by 
50-fold over a 24-hour period. Further studies
determined that of the 2 major cholesterol-carrying lipoproteins,
low-density lipoprotein (LDL) and high-density lipoprotein, only the
presence of LDL in the media could repress HMG CoA reductase activity.
Both the fact that the repression of HMG CoA reductase was specific for
LDL and the observation that very low concentrations of LDL could
repress enzyme activity suggested that a high-affinity receptor was
responsible for the enzyme repression.
The studies of fibroblasts from homozygous FH patients supported the observations of the mechanisms of LDL regulation of HMG CoA activity. The presence of LDL in the culture media did not repress HMG CoA reductase in FH cells; when grown in the presence of LDL, FH fibroblasts had reductase activities that were 50-fold higher than control fibroblasts. Interestingly, when FH cells were incubated with an emulsion of free cholesterol that can enter cells passively, HMG CoA reductase was repressed in both FH and control cells. These observations led Brown and Goldstein16 to hypothesize that the genetic defect in FH cells was in the high-affinity receptor responsible for repression of HMG CoA reductase by LDL. These investigators went on to demonstrate the existence of a high-affinity receptor for LDL in cultured fibroblasts. Furthermore, they showed that FH-homozygous cells lacked high-affinity receptors for LDL, providing biochemical evidence that the genetic defect causing FH was the lack of a high-affinity receptor for LDL.
Between 1972 and 1976, Brown and Goldstein16 completed work that was crucial to delineating the cellular metabolism of LDL and the feedback regulation of HMG CoA reductase; they also elucidated the defect in the high-affinity receptor for LDL in FH patients. Nine years later, in 1985, mutations in the LDL receptor gene were identified in FH patients, confirming that the genetic defect was indeed in the LDL receptor.17 18 19 20 21 This same year, the significance of this work was acknowledged by awarding the Nobel Prize in Medicine to Brown and Goldstein.
FH is an example of a single gene disorder that results in atherosclerosis and coronary artery disease, thereby contributing to the genetic basis of this common disease. Individuals heterozygous for LDL receptor mutations are common in the general population, with an estimated prevalence of 1 in 500. The risk for coronary artery disease in these heterozygotic individuals is significantly increased over that of the general population; the probability of a heterozygous male experiencing a myocardial infarction before the age of 60 is 75% versus 15% for the general population.
Subsequent studies have identified other loci influencing plasma lipid levels and increasing coronary artery disease risk, including apolipoprotein B-100, apolipoprotein E, lipoprotein(a), lipoprotein lipase, apolipoprotein CII, cholesteryl ester transfer protein, apolipoprotein AI, lecithin-cholesterol acyl transferase, and microsomal triglyceride transfer protein.22 23 24 25 26 27 The contributions of these loci, as well as yet-to-be-identified loci, to coronary artery disease have expanded and will continue to expand our knowledge of the genetic basis of this common disease.
Genetic Vascular Diseases: Heritable Disorders
of Connective Tissue
In 1896, a renowned French pediatrician named Antoine
Marfan described a young girl with unusual skeletal features, including
long, thin extremities (dolichostenomelia) and long, spider-like
fingers (arachnodactyly). Over the next 50 years, the cardiovascular
and ocular manifestations associated with such unusual skeletal
features were recognized, along with the autosomal-dominant inheritance
of the condition. The cardiovascular hallmarks of Marfan
syndrome are a dilatation of the proximal aorta and aortic
dissection associated with a degeneration of the elastic fibers in the
tunica media of the aorta. Ocular lesions are localized to the lens in
the form of congenital dislocations due to weakening of the suspensory
ligament of the lens.
Marfan syndrome was the disease listed first in the catalog of heritable disorders of connective tissue described by Victor McKusick in the first edition of his book, Heritable Disorders of Connective Tissue, in 1956. In the fourth edition of this book, McKusick made the following prediction: "What the suspensory ligament of the lens has in common with the tunica media of the aorta is obscure. If this common factor were known, the basic defect of the Marfan syndrome might be understood."28 McKusick’s speculation proved to be correct when, in 1991, it was determined that mutations in the FBN1 gene were the cause of Marfan syndrome.29 30 31 FBN1 encodes fibrillin-1, a major protein component of extracellular matrix structures called microfibrils, which either alone or in association with the elastin in elastic fibers provide critical biomechanical properties to a wide variety of tissues. FBN1 mutations cause a dominant-negative effect on microfibril formation through the production of mutant fibrillin-1 monomer on the background of a normal fibrillin-1 monomer from the nonmutant allele. Immunohistochemical studies and pulse-chase analyses have shown that dermal fibroblasts explanted from Marfan patients have a decrease in fibrillin-1–containing microfibrils in the extracellular matrix far below the 50% level predicted by a heterozygous FBN1 mutation.32 33 34 35
Although the vast majority of FBN1 mutations cause classic Marfan syndrome, they are also responsible for some familial forms of isolated thoracic aortic aneurysms, ectopia lentis, arachnodactyly, and disproportionate tall stature, along with the severe and rare congenital disorders termed neonatal Marfan syndrome and Shprintzen-Goldberg syndrome.36 37 38 39 40 FBN1 mutations can, therefore, cause a continuum of clinical phenotypes, which at one end present as severe congenital disorders, and at the other end, have features that merge with common traits found in the general population.
The role of type III collagen in maintaining the structural integrity of the arterial walls was recognized through the identification of mutations in the gene encoding the type III collagen polypeptides (COL3A1) in patients with Ehlers Danlos syndrome type IV, an autosomal-dominant condition. Although this condition is associated with thin, translucent, and fragile skin, the life-threatening complication of this condition is spontaneous rupture or dissections of the aorta or large- to medium-sized arteries in the second to third decade of life.41 Similar to FBN1 mutations, COL3A1 mutations exert a dominant-negative effect on the formation of type III collagen as a result of the multimerization of the polypeptides encoded by COL3A1 into homotrimers of type III collagen.42
Supraventricular aortic stenosis (SVAS) is a vascular disorder that may occur as an isolated disease inherited in an autosomal-dominant fashion or as a part of a complex developmental disorder, Williams-Beuren syndrome.43 44 45 46 The typical vascular lesion in SVAS is an hourglass-shaped stenosis of the ascending aorta, which is associated with an increased volume of the medial layer with disorganization of the lamellar architecture of the media, irregular elastic fibers, and smooth muscle cell hypertrophy.47 In addition to the aorta, other major arteries, including the pulmonary, carotid, cerebral, renal, and coronary arteries, may also be stenotic in patients with SVAS.
Mutations in elastin, the major component of the elastic fiber system, cause SVAS. Surprisingly, these mutations lead to haploinsufficiency for the elastin gene, with decreased elastin production.48 49 50 51 Pathological studies of the aorta in SVAS and studies of mice with a targeted mutation of the elastin gene (ELN) suggest that elastin plays an unanticipated role in arterial morphogenesis by controlling the proliferation of smooth muscle cells and stabilizing arterial structure.52 53
Linkage Heterogeneity: Unraveling Genetic
Complexity
Late in the 1950s, a report appeared in the medical
literature that systematically detailed the clinical profiles of young
patients with asymmetric hypertrophy of the
heart.54 Throughout
the subsequent 2 decades, thousands of patients were evaluated, and
voluminous data were acquired on the pathophysiology of a disorder
labeled idiopathic hypertrophic subaortic stenosis, asymmetric septal
hypertrophy, hypertrophic obstructive cardiomyopathy or, in the
vernacular, as IHSS, ASH and HOCM, respectively. Cardiac
catheterization and, subsequently, echocardiography identified the
hallmarks of the disease, which included hypertrophy, hyperdynamic
systolic function, diastolic dysfunction and, in some, systolic
anterior motion of the mitral valve and outflow tract
obstruction.55 56
Diverse clinical outcomes were observed, ranging from severe cardiac
symptoms and sudden death to minimal symptoms and excellent
prognosis.57 Not
surprisingly, these investigations prompted speculation about the
causes of hypertrophic heart disease; suggestions were as diverse as
heightened catecholamine sensitivity to congenital anomalies of
intra-mural coronary
arteries.57 58
Clinical studies clearly demonstrated familial prevalence in hypertrophic cardiomyopathy, and genetic transmission consistent with an autosomal-dominant trait was delineated. These data prompted genetic strategies to define the causal gene. In 1989, linkage analyses in one large kindred demonstrated that a gene responsible for familial hypertrophic cardiomyopathy was located on chromosome 14q2.59 This chromosomal location was the initial clue that suggested the cardiac myosin heavy chain genes might be mutated to cause this condition. Even before the ß-cardiac myosin heavy chain gene encoded in this locus was established as the mutated gene at 14q causing familial hypertrophic cardiomyopathy, linkage studies in unrelated families demonstrated genetic heterogeneity.60 These genetic analyses demonstrated that this clinical disorder could also be caused by mutations in genes encoded on other chromosomes. Over a period of 5 years, hypertrophic cardiomyopathy disease loci were reported on chromosomes 1q, 11p, and 15q.61 62 63 Locus heterogeneity led to the hypothesis that genes mutated in hypertrophic cardiomyopathy might encode proteins of similar function. This hypothesis was proven initially by the identification of the disease genes cardiac troponin T and atropomyosin, and confirmed by the subsequent definition of disease-causing mutations in cardiac myosin binding protein-C, troponin I, cardiac actin, and the ventricular essential and regulatory myosin light chains.64 65 Hypertrophic cardiomyopathy was no longer an idiopathic pathology but a disease of sarcomere proteins.66
A second mysterious disorder, which consisted of congenital deaf mutism, prolongation of the QT interval, and sudden death, was also reported in the late 1950s.67 Shortly thereafter, Ward68 and Romano69 described a prolongation of the QT interval and a predisposition to torsades de pointes in individuals without hearing loss or other abnormalities. Reports of the electrocardiographic and electrophysiological features of this remarkable disease were followed by an increasing recognition of the considerable arrhythmia risk in such patients.70 Repolarization abnormalities that occurred in the absence of cardiac pathology induced arrhythmias, particularly in the setting of exercise or excitement. However, the spectrum of clinical manifestations and range of QT intervals made accurate diagnosis problematic. Related investigations into the mechanism for arrhythmias in animal models led to the suggestion that an imbalance in the sympathetic cardiac innervation accounted for this disease, and both ß-adrenergic blockade and stellate ganglionectomy were considered therapeutic options.71 72
Genetic linkage studies again provided fundamental insights that ultimately led to etiological understandings of autosomal-dominant long-QT syndrome and autosomal-recessive Jervell-Lange-Nielsen syndrome. Over the past decade, 5 disease loci have been identified on chromosomes 3p, and 7q.73 74 75 76 77 Although genetic heterogeneity initially suggested considerable complexity in the molecular causes for this disorder, the identification of disease genes clarified this issue. Subunits for the voltage-gated potassium channel, rapid current delayed rectifier potassium channels, and cardiac sodium channels encoded at these loci are mutated in long-QT syndrome. Collectively, these data defined this inherited arrhythmia as a disorder of cardiac ion channels.
Genetic heterogeneity is considerable in hypertrophic cardiomyopathy and long-QT syndrome. Within each disease gene, many mutations have been identified in unrelated families. This large number of "private" mutations explains some of the variable clinical manifestations of these disorders. For example, different disease genes produce variable onsets and severities of hypertrophy, and the various mutations in any one sarcomere protein gene influence sudden death risk in hypertrophic cardiomyopathy. Mutations in different cardiac ion channel genes account for the variable clinical response to therapeutic agents in long-QT syndrome. For example, mexiletine provides beneficial effects on repolarization abnormalities caused by sodium channel gene mutations but not those due to potassium channel defects.78 Ongoing technological developments in rapid DNA sequencing will foster a continued investigation of the role that genotype has on disease phenotype, information that is likely to increase the importance of genotype data in patient management.
Recent evidence indicates that not every mutation in sarcomere protein or cardiac ion channel genes causes hypertrophic cardiomyopathy or long-QT syndrome. Distinct mutations in sarcomere protein genes can produce ventricular enlargement and dysfunction (dilated, not hypertrophic, cardiomyopathy).79 80 Distinct mutations in cardiac sodium channels cause ST segment elevations and idiopathic ventricular tachycardia (Brugada syndrome81 ) or progressive atrioventricular block (Lev or Lenegre disease82 ). These observations indicate that clinically different cardiovascular disorders share molecular etiologies and, as a corollary, that selective biophysical and/or biochemical processes are perturbed by specific mutations. Elucidation of the signaling pathways triggered by particular gene defects is an area of active investigation.
Diverse Cardiac Malformations From Single
Gene Defects
Epidemiological and pathological investigations of
human congenital heart malformations have identified multiple
teratogens, infectious agents, and factors in the maternal environment
as important etiologies for some cardiac defects. However, in most
cases, the cause of the disease remains unknown. In a posthumous
publication, Dr Helen Taussig speculated that because "common cardiac
malformations ... occur in otherwise ‘normal’ individuals ...
these malformations must be genetic in origin ... neither exposure
to toxic substances nor the parents can be held accountable for the
occurrence of (most) congenital
abnormalities."83
Recent molecular studies of congenital heart defects indicate the
prophetic nature of her observations.
Clinical studies have recognized that occurrence of a congenital heart defect in a parent or proceding sibling is the greatest risk factor for developing a cardiac malformation. Epidemiological and family studies further demonstrate variations in the precise congenital defects exhibited by related, affected individuals. For example, the Baltimore-Washington Infant Heart Study demonstrated an increased incidence of tetralogy of Fallot, transposition of the great arteries, and truncus arteriosus in the family members of individuals with ventricular septal defects.84 These observations have been interpreted to indicate that some cardiac structures share developmental pathways. Such data also suggest that clinically distinct outcomes could arise from a single genetic defect, an observation that has hindered the recognition of the genetic basis of congenital heart disease. Recent identification of single gene mutations that cause multiple cardiac malformations support these hypotheses.
Compelling evidence for an essential role of genetics in human congenital heart disease comes from investigations of the etiologies for conotruncal malformations. Cytogenetic studies of DiGeorge syndrome (aplasia/hypoplasia of the thymus and parathyroid glands in association with conotruncal defects) indicate a visible or microdeletion of chromosome 22q11 in >90% of patients.85 Refined mapping of this disease interval has fostered the identification of many genes that are deleted in patients.86 Whether haploinsufficiency of one or a few genes accounts for the pleiotropic findings in DiGeorge syndrome remains an open question.87
Human defects in laterality (heterotaxy) are associated with a wide spectrum of cardiac malformations. Recognition of the X-linked inheritance in some families led to the definition that a human gene for heterotaxy is encoded at Xq24.88 Positional cloning approaches defined mutations in zinc-finger of cerebellum (ZIC3), a transcription factor with homology to proteins involved in left-right axis formation. In women, ZIC3 mutations caused either mild or no consequences, whereas affected men had severe, complex heart malformations that frequently resulted in neonatal lethality.
Holt-Oram syndrome, a rare autosomal-dominant condition, is characterized by upper limb abnormalities and cardiac defects.89 Skeletal malformations vary from subtle defects in carpal bones and thumb anomalies (triphalangism or aplasia) to phocomelia. Most patients with Holt-Oram syndrome have congenital cardiac malformations that range from simple atrial and/or ventricular septal defects to multiple complex lesions. Conduction system disease and other anomalies, including anomalous pulmonary venous return, abnormal ventricular trabeculation, and right isomerism, are often present. Despite the considerable clinical diversity in Holt-Oram syndrome phenotypes, all patients have a mutation in the gene TBX5, which encodes a transcription factor that is essential for normal heart formation.90 91
There is also evidence that human gene mutations cause nonsyndromic congenital heart disease. Clinical reports have characterized familial cardiac malformations associated with conduction system defects.92 Although secundum atrial septal defects occurred frequently in these families, ventricular septal defects, tetralogy of Fallot, subvalvular aortic stenosis, pulmonary atresia, and redundant mitral valve leaflets with fenestrations were also observed. The relationship of these structural defects to slowly progressive conduction system disease was initially unclear. Sudden death in some family members occurred years after the surgical correction of congenital defects. Electrophysiological studies have localized abnormalities to the atrioventricular node.
Clinical evidence of autosomal-dominant transmission prompted genome-wide linkage analyses, and a disease gene for cardiac malformations and conduction system disease was mapped to chromosome 5q35. This genomic location identified the gene encoding the transcription factor Nkx2.5 as a candidate for human mutations; DNA sequencing affirmed this hypothesis.93 94 Developmental biologists had defined an important role for Nkx2.5 in cardiac morphogenesis. These studies both extended this information to humans and indicated that this transcription factor must also be important for normal cardiac electrophysiology.
In addition to defining gene mutations as important etiologies for congenital heart disease, these examples suggest that mutationally altered transcription factors cause human cardiac malformations. Understanding why defects in these molecules can produce a wide array of clinical malformations will be essential for elucidating the biological function of these proteins throughout development. However, these examples indicate that insights into transcription factor biology gleaned from studies of lower vertebrate model systems will be relevant to the study of human cardiac pathologies. Given the significant incidence of cardiac malformations (5 to 8 per 1000 live births), the definition of the genetic basis for even a subset of these patients has the potential for insights into pathways that are critical for the extraordinarily complex process of cardiac development.95
The Next 50 Years
As the Human Genome Project moves toward
completion, research efforts to identify genes related to
cardiovascular diseases will move forward at a more rapid pace than
ever before. The underlying genetic etiologies for not only monogenic
cardiovascular disorders, but also for common disorders with complex
polygenic inheritance will be determined. Mapping the genetic
determinants for both rare, single-gene disorders and common disorders
will provide further insight into the molecular pathogenesis of disease
processes. This research will provide clinicians with such tangible
benefits as genetic risk profiles for cardiovascular diseases and
specific pharmacotherapy based on both the molecular pathology of the
disease and the patient’s own genetic composition.
As the door to the human genome is opened, the challenge ahead is to determine the normal biological functions of these gene products in maintaining cardiovascular cellular homeostasis. Rational approaches to pharmacotherapy and gene therapy for congenital structural cardiovascular disorders, cardiomyopathies, cardiovascular malignancies, and complex traits such as hypertension and atherosclerosis can only be achieved by elucidating such basic genetic regulatory mechanisms. Moreover, it is likely that such novel therapeutic modalities will ultimately inform the future management of common sporadic nonfamilial cardiovascular diseases.
Such unprecedented advances in genetic knowledge are not without social and ethical implications. The new genetics raise problems of confidentiality, stigmatization, and insurability. Furthermore, genetic information providing "presymptomatic" diagnosis of diseases may lead to individuals altering their expectations and behavior based on the dangers encoded within their cells. Dealing with the complexity of these issues will be perhaps the greatest challenge facing clinicians in the future.
References
1.
McKusick
VA. The morbid anatomy of the human genome: a review of gene mapping in
clinical medicine (1). Medicine (Baltimore). 1986;65:I–33.
2.
Wilson
ED. The sex chromosomes. Arch Mikrosk Anat
Entwick-Lungsmech. 1911;77:249–271.
3.
Becker
PE. Eine neue X-chromosomale muskeldystrophie. Acta Psychiatr
Neuro Scand. 1995;193:427.
4.
McKusick-Nathans
Institute for Genetic Medicine, ed. Online Mendelian Inheritance in
Man. Baltimore and Bethesda, Md: Johns Hopkins University and National
Center for Biotechnology; 2000. Available at:
www.ncbi.nlm.nih.gov/omim
5.
Watson
JD, Cick FHC. Molecular structure of nucleic acids: a structure for
deoxyribose nucleic acid. Nature. 1953;171:964–967.
6.
Weinberg
RA. The molecules of life. Sci Am. 1985;253:48–57.
7.
Southern
EM. Detection of specific sequences among DNA fragments separated by
gel electrophoresis. J Mol Biol. 1975;98:503–517.
8.
Sanger
F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating
inhibitors. Proc Natl Acad Sci
U S A. 1977;74:5463–5467.
9.
Gilbert
W. DNA sequencing and gene structure. Science. 1981;214:1305–1312.
10.
Botstein
D, White RL, Skolnick M, et al. Construction of a genetic
linkage map in man using restriction fragment length polymorphisms.
Am J Hum Genet. 1980;32:314–331.
11.
Ott J.
A computer program for linkage analysis of general human pedigrees.
Am J Hum Genet. 1976;28:528–529.
Letter.
12.
Donis-Keller
H, Green P, Helms C, et al. A genetic linkage map of the human genome.
Cell. 1987;51:319–337.
13.
Claycomb
WC, Lanson NA Jr, Stallworth BS, et al. HL-1 cells: a cardiac muscle
cell line that contracts and retains phenotypic characteristics of the
adult cardiomyocyte. Proc Natl Acad Sci
U S A. 1998;95:2979–2984.
14.
Garrod
AE. Inborn Errors of Metabolism. London: Oxford
University Press; 1923.
15.
Fredrickson
DS, Levy RI. In: Stanbury JB, Wyngaarden JB, Fredrickson DS,
eds. The Metabolic Basis of Inherited Disease. New
York: McGraw-Hill; 1972:545–614.
16.
Brown
MS, Goldstein JL. A receptor-mediated pathway for cholesterol
homeostasis. Science. 1986;232:34–47.
17.
Schneider
WJ, Goldstein JL, Brown MS. Purification of the LDL receptor.
Methods Enzymol. 1985;109:405–417.
18.
Russell
DW, Yamamoto T, Schneider WJ, et al. cDNA cloning of the bovine low
density lipoprotein receptor: feedback regulation of a receptor mRNA.
Proc Natl Acad Sci
U S A. 1983;80:7501–7505.
19.
Lehrman
MA, Schneider WJ, Sudhof TC, et al. Mutation in LDL receptor: Alu-Alu
recombination deletes exons encoding transmembrane and cytoplasmic
domains. Science. 1985;227:140–146.
20.
Lehrman
MA, Goldstein JL, Brown MS, et al. Internalization-defective LDL
receptors produced by genes with nonsense and frameshift mutations that
truncate the cytoplasmic domain. Cell. 1985;41:735–743.
21.
Hobbs
HH, Russell DW, Brown MS, et al. The LDL receptor locus in familial
hypercholesterolemia: mutational analysis of a membrane protein.
Annu Rev Genet. 1990;24:133–170.
22.
Jukema
JW, van Boven AJ, Groenemeijer B, et al. The Asp9 Asn mutation in the
lipoprotein lipase gene is associated with increased progression of
coronary atherosclerosis: REGRESS Study Group, Interuniversity
Cardiology Institute, Utrecht, The Netherlands: Regression Growth
Evaluation Statin Study. Circulation. 1996;94:1913–1918.
23.
Kuivenhoven
JA, Jukema JW, Zwinderman AH, et al. The role of a common variant of
the cholesteryl ester transfer protein gene in the progression of
coronary atherosclerosis: the Regression Growth Evaluation Statin Study
Group. N Engl J Med. 1998;338:86–93.
24.
Soria
LF, Ludwig EH, Clarke HR, et al. Association between a specific
apolipoprotein B mutation and familial defective apolipoprotein B-100.
Proc Natl Acad Sci
U S A. 1989;86:587–591.
25.
Walden
CC, Hegele RA. Apolipoprotein E in hyperlipidemia. Ann Intern
Med. 1994;120:1026–1036.
26.
Stein
JH, Rosenson RS. Lipoprotein Lp(a) excess and coronary heart disease.
Arch Intern Med. 1997;157:1170–1176.
27.
Ozturk
IC, Killeen AA. An overview of genetic factors influencing plasma lipid
levels and coronary artery disease risk. Arch Pathol Lab
Med. 1999;123:1219–1222.
28.
McKusick
VA. Heritable Disorders of Connective Tissue, 4th ed.
Saint Louis: Mosby; 1972.
29.
Dietz
HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a
recurrent de novo missense mutation in the fibrillin gene.
Nature. 1991;352:337–339.
30.
Lee B,
Godfrey M, Vitale E, et al. Linkage of Marfan syndrome and a
phenotypically related disorder to two different fibrillin genes.
Nature. 1991;352:330–334.
31.
Dietz
HC, Pyeritz RE. Mutations in the human gene for fibrillin-1 (FBN1) in
the Marfan syndrome and related disorders. Hum Mol
Genet. 1995;4:1799–1809.
32.
Hollister
DW, Godfrey M, Sakai LY, et al. Immunohistologic abnormalities of the
microfibrillar-fiber system in the Marfan syndrome. N Engl
J Med. 1990;323:152–159.
33.
Milewicz
DM, Pyeritz RE, Crawford ES, et al. Marfan syndrome: defective
synthesis, secretion, and extracellular matrix formation of fibrillin
by cultured dermal fibroblasts. J Clin Invest. 1992;89:79–86.
34.
Aoyama
T, Francke U, Dietz HC, et al. Quantitative differences in biosynthesis
and extracellular deposition of fibrillin in cultured fibroblasts
distinguish five groups of Marfan syndrome patients and suggest
distinct pathogenetic mechanisms. J Clin Invest. 1994;94:130–137.
35.
Eldadah
ZA, Brenn T, Furthmayr H, et al. Expression of a mutant human fibrillin
allele upon a normal human or murine genetic background recapitulates a
Marfan cellular phenotype. J Clin Invest. 1995;95:874–880.
36.
Francke
U, Berg MA, Tynan K, et al. A Gly1127Ser mutation in an EGF-like domain
of the fibrillin-1 gene is a risk factor for ascending aortic aneurysm
and dissection. Am J Hum Genet. 1995;56:1287–1296.
37.
Kainulainen
K, Karttunen L, Puhakka L, et al. Mutations in the fibrillin gene
responsible for dominant ectopia lentis and neonatal Marfan syndrome.
Nat Genet. 1994;6:64–69.
38.
Milewicz
DM, Grossfield J, Cao SN, et al. A mutation in FBN1 disrupts
profibrillin processing and results in isolated skeletal features of
the Marfan syndrome. J Clin Invest. 1995;95:2373–2378.
39.
Putnam
EA, Cho M, Zinn AB, et al. Delineation of the Marfan phenotype
associated with mutations in exons 23–32 of the FBN1 gene.
Am J Med Genet. 1996;62:233–242.
40.
Sood
S, Eldadah ZA, Krause WL, et al. Mutation in fibrillin-1 and the
Marfanoid-craniosynostosis (Shprintzen- Goldberg) syndrome. Nat
Genet. 1996;12:209–211.
41.
Pepin
M, Schwarze U, Superti-Furga A, et al. Clinical and genetic features of
Ehlers-Danlos syndrome type IV, the vascular type. N Engl
J Med. 2000;342:673–680.
42.
Milewicz
DM, Witz AM, Smith AC, et al. Parental somatic and germ-line mosaicism
for a multiexon deletion with unusual endpoints in a type III collagen
(COL3A1) allele produces Ehlers-Danlos syndrome type IV in the
heterozygous offspring. Am J Hum Genet. 1993;53:62–70.
43.
Wren
C, Oslizlok P, Bull C. Natural history of supravalvular aortic stenosis
and pulmonary artery stenosis. J Am Coll Cardiol. 1990;15:1625–1630.
44.
Morris
CA, Leonard CO, Dilts C, et al. Adults with Williams syndrome.
Am J Med Genet Suppl. 1990;6:102–107.
45.
Joyce
CA, Zorich B, Pike SJ, et al. Williams-Beuren syndrome: phenotypic
variability and deletions of chromosomes 7, 11, and 22 in a series of
52 patients. J Med Genet. 1996;33:986–992.
46.
Zalzstein
E, Moes CA, Musewe NN, et al. Spectrum of cardiovascular anomalies in
Williams-Beuren syndrome. Pediatr Cardiol. 1991;12:219–223.
47.
Peterson
TA, Todd DB, Edwards JE. Supravalvular aortic stenosis. J
Thorac Cardiovasc Surg. 1965;50:734–741.
48.
Curran
ME, Atkinson DL, Ewart AK, et al. The elastin gene is disrupted by a
translocation associated with supravalvular aortic stenosis.
Cell. 1993;73:159–168.
49.
Li DY,
Toland AE, Boak BB, et al. Elastin point mutations cause an obstructive
vascular disease, supravalvular aortic stenosis. Hum Mol
Genet. 1997;6:1021–1028.
50.
Olson
TM, Michels VV, Urban Z, et al. A 30 kb deletion within the elastin
gene results in familial supravalvular aortic stenosis. Hum Mol
Genet. 1995;4:1677–1679.
51.
Urban
Z, Michels VV, Thibodeau SN, et al. Isolated supravalvular aortic
stenosis: functional haploinsufficiency of the elastin gene as a result
of nonsense-mediated decay. Hum Genet. 2000;106:577–588.
52.
Li DY,
Brooke B, Davis EC, et al. Elastin is an essential determinant of
arterial morphogenesis. Nature. 1998;393:276–280.
53.
Li DY,
Faury G, Taylor DG, et al. Novel arterial pathology in mice and humans
hemizygous for elastin. J Clin Invest. 1998;102:1783–1787.
54.
Teare
D. Asymmetrical hypertrophy of the heart in young patients. Br
Heart J. 1958;20:1–8.
55.
Maron
BJ, Epstein SE. Hypertrophic cardiomyopathy: recent observations
regarding the specificity of three hallmarks of the disease: asymmetric
septal hypertrophy, septal disorganization and systolic anterior motion
of the anterior mitral leaflet. Am J Cardiol. 1980;45:141–154.
56.
Spirito
P, Chiarella F, Carratino L, et al. Clinical course and prognosis of
hypertrophic cardiomyopathy in an outpatient population. N
Engl J Med. 1989;320:749–755.
57.
Goodwin
JF. Prospects and predictions for the cardiomyopathies.
Circulation. 1974;50:210–219.
58.
Maron
BJ, Wolfson JK, Epstein SE, et al. Intramural ("small vessel")
coronary artery disease in hypertrophic cardiomyopathy. J
Am Coll Cardiol. 1986;8:545–557.
59.
Jarcho
JA, McKenna W, Pare JA, et al. Mapping a gene for familial hypertrophic
cardiomyopathy to chromosome 14q1. N Engl J
Med. 1989;321:1372–1378.
60.
Solomon
SD, Jarcho JA, McKenna W, et al. Familial hypertrophic cardiomyopathy
is a genetically heterogeneous disease. J Clin
Invest. 1990;86:993–999.
61.
Watkins
H, MacRae C, Thierfelder L, et al. A disease locus for familial
hypertrophic cardiomyopathy maps to chromosome 1q3. Nat
Genet. 1993;3:333–337.
62.
Carrier
L, Hengstenberg C, Beckmann JS, et al. Mapping of a novel gene for
familial hypertrophic cardiomyopathy to chromosome 11. Nat
Genet. 1993;4:311–313.
63.
Thierfelder
L, MacRae C, Watkins H, et al. A familial hypertrophic cardiomyopathy
locus maps to chromosome 15q2. Proc Natl Acad Sci
U S A. 1993;90:6270–6274.
64.
Wigle
ED, Rakowski H, Kimball BP, et al. Hypertrophic cardiomyopathy:
clinical spectrum and treatment. Circulation. 1995;92:1680–1692.
65.
Marian
AJ, Roberts R. Recent advances in the molecular genetics of
hypertrophic cardiomyopathy. Circulation. 1995;92:1336–1347.
66.
Spirito
P, Seidman CE, McKenna WJ, et al. The management of hypertrophic
cardiomyopathy. N Engl J Med. 1997;336:775–785.
67.
Jervell
A, Lange-Nielsen F. Congenital deaf mutism, functional heart disease
with prolongation of the QT interval, and sudden death. Am
Heart J. 1957;54:59–68.
68.
Ward
OC. A new familial cardiac syndrome in children. J Ir Med
Assoc.. 1964;54:103–106.
69.
Romano
C. Congential cardiac arrhythmia. Lancet. 1965;1:658–659.
70.
Schwartz
PJ. Idiopathic long QT syndrome: progress and questions. Am
Heart J. 1985;109:399–411.
71.
Abildskov
JA. Neural mechanisms involved in the regulation of ventricular
repolarization. Eur Heart J. 1985;6(suppl
D):31–39.
72.
Schwartz
PJ, Locati EH, Moss AJ, et al. Left cardiac sympathetic denervation in
the therapy of congenital long QT syndrome: a worldwide report.
Circulation. 1991;84:503–511.
73.
Wang
Q, Shen J, Splawski I, et al. SCN5A mutations associated with an
inherited cardiac arrhythmia, long QT syndrome. Cell. 1995;80:805–811.
74.
Schott
JJ, Charpentier F, Peltier S, et al. Mapping of a gene for long QT
syndrome to chromosome 4q25–27. Am J Hum Genet. 1995;57:1114–1122.
75.
Keating
M, Atkinson D, Dunn C, et al. Linkage of a cardiac arrhythmia, the long
QT syndrome, and the Harvey ras-1 gene. Science. 1991;252:704–706.
76.
Splawski
I, Tristani-Firouzi M, Lehmann MH, et al. Mutations in the hminK gene
cause long QT syndrome and suppress IKs function. Nat
Genet. 1997;17:338–340.
77.
Curran
ME, Splawski I, Timothy KW, et al. A molecular basis for cardiac
arrhythmia: HERG mutations cause long QT syndrome.
Cell. 1995;80:795–803.
78.
Schwartz
PJ, Priori SG, Locati EH, et al. Long QT syndrome patients with
mutations of the SCN5A and HERG genes have differential responses to
Na+ channel blockade and to increases in heart rate: implications for
gene-specific therapy. Circulation. 1995;92:3381–3386.
79.
Olson
TM, Michels VV, Thibodeau SN, et al. Actin mutations in dilated
cardiomyopathy, a heritable form of heart failure.
Science. 1998;280:750–752.
80.
Kamisago
M, Sharma SD, DePalma SR, et al. Sarcomere protein gene mutations cause
dilated cardiomyopathy. N Engl J Med. In
press.
81.
Vatta
M, Li H, Towbin JA. Molecular biology of arrhythmic syndromes.
Curr Opin Cardiol. 2000;15:12–22.
82.
Schott
JJ, Alshinawi C, Kyndt F, et al. Cardiac conduction defects associated
with mutations in SCN5A. Nat Genet. 1999;23:20–21.
83.
Taussig
HB. Evolutionary origin of cardiac malformations. J Am
Coll Cardiol. 1988;12:1079–1086.
84.
Correa-Villansenon
A, Wilson PD, Loffredo CA, et al. Risk factor analysis. In: Ferencz C,
Rubin JD, Loffredo CA, et al, eds. Epidemiology of Congenital
Heart Disease: The Baltimore-Washington Infant Heart Study
1981–1989. Mont Kisco, NY: Futura;
1993:233–245.
85.
Driscoll
DA, Salvin J, Sellinger B, et al. Prevalence of 22q11 microdeletions in
DiGeorge and velocardiofacial syndromes: implications for genetic
counselling and prenatal diagnosis. J Med Genet. 1993;30:813–817.
86.
Emanuel
BS, Budarf ML, Sambler PJ. The genetic basis of conotruncal cardiac
defects: the chromosome 22q11.2 deletions. In: Harvey RP, Rosenthal N,
eds. Heart Development. New York, NY: Academic
Press; 1998:463–473.
87.
Yamagishi
H, Garg V, Matsuoka R, et al. A molecular pathway revealing a genetic
basis for human cardiac and craniofacial defects.
Science. 1999;283:1158–1161.
88.
Gebbia
M, Ferrero GB, Pilia G, et al. X-linked situs abnormalities result from
mutations in ZIC3. Nat Genet. 1997;17:305–308.
89.
Basson
CT, Cowley GS, Solomon SD, et al. The clinical and genetic spectrum of
the Holt-Oram syndrome (heart-hand syndrome) [published erratum
appears in N Engl J Med.. 1994;330:1627].
N Engl J Med.
1994;330:885–891.
90.
Basson
CT, Huang T, Lin RC, et al. Different TBX5 interactions in heart and
limb defined by Holt-Oram syndrome mutations. Proc Natl Acad
Sci U S A. 1999;96:2919–2924.
91.
Li QY,
Newbury-Ecob RA, Terrett JA, et al. Holt-Oram syndrome is caused by
mutations in TBX5, a member of the Brachyury (T) gene family.
Nat Genet. 1997;15:21–29.
92.
Benson
DW, Sharkey A, Fatkin D, et al. Reduced penetrance, variable
expressivity, and genetic heterogeneity of familial atrial septal
defects. Circulation. 1998;97:2043–2048.
93.
Schott
JJ, Benson DW, Basson CT, et al. Congenital heart disease caused by
mutations in the transcription factor NKX2–5.
Science. 1998;281:108–111.
94.
Benson
DW, Silberbach GM, Kavanaugh-McHugh A, et al. Mutations in the cardiac
transcription factor NKX2.5 affect diverse cardiac developmental
pathways. J Clin Invest. 1999;104:1567–1573.
95.
Hoffman
JI. Congenital heart disease: incidence and inheritance.
Pediatr Clin North Am. 1990;37:25–43.
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