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ETHICAL AND SOCIAL ISSUES POSED BY GENETIC STUDIES OF CARDIOVASCULAR DISEASE* JOHN B. GRAHAMS In the first part of this paper, I shall attempt to describe the genetics of cardiovascular disease and outline the types of genetic studies which are under way or in prospect. My purpose is to prepare the reader for a subsequent analysis of the ethical and social issues related to these studies and how these issues are likely to impinge on cardiology and cardiologists. The human diseases of interest both to cardiologists and geneticists appear to me to include (1) congenital malformations of the heart and great vessels; (2) atherosclerosis, including aneurysms of the great vessels ; (3) thrombosis, embolism, and infarction; (4) hereditary diseases with cardiovascular complications, that is, hyperlipidemias, diabetes, Marian's syndrome, etc.; and (5) hypertension. From the geneticist's vantage point, hereditary disorders of the cardiovascular system are seen to be inherited by one or another of three mechanisms. Some defects result from genetic change at a single locus (monogenic inheritance); others are related to aberrations in chromosomal number or structure which are visible with a miscroscope; still others are due to accidental possession of a specific collection of genes which predispose their possessor to cardiovascular disease (polygenic inheritance). Monogenic Inheritance and Cardiovascular Disease More than 1,800 human disorders are thought to be inherited as monogenic traits [I]. Man is diploid, having two genes at each locus. When possession of a single abnormal gene causes a defect—the case in Marfan's syndrome—the abnormal trait is regarded as "dominant"; *A position paper prepared for the Committee on Ethics of the American Heart Association . Research was supported in part by a grant from the National Heart and Lung Institute (HL-06350). tDistinguished professor of pathology, University of North Carolina, Chapel Hill, North Carolina 27514. 260 J John B. Graham · Genetic Studies of Cardiovascular Disease when two abnormal genes are required to produce the disorder—as in cystic fibrosis—the defect is regarded as "recessive." Many monogenic syndromes have as one of their features some form of congenital heart disease, but it is not necessarily always the same lesion in every person having a specific syndrome. Following is a list of monogenic syndromes (modified from [2]) which are often accompanied by heart disease. Each of the syndromes is rare, but together they are responsible for about 2 percent of the cases of congenital heart disease. Autosomal Dominant Acrocephalosyndactyly (Apert) Cardiac arrythmia, brachydactyly (Tabatznik) Cardiac arrythmia, prolonged Q-T, without deafness (Romano-Ward) Craniofacial dysostosis (Crouzon) Deafness, M. L, freckles (Forney) Ehlers-Danlos Lymphedema (Milroy and Meige) Marfan Neurofibromatosis (von Recklinghausen) Osteogenesis imperfecta Hemorrhagic telangiectasia (Osler-Rendu-Weber) Treacher Collins Tuberous sclerosis Ullrich-Noonan Von Hippel-Lindau X-linked Dermal hypoplasia, focal (Goetz) Incontinentia pigmenti Mucopolysacchyridosis II (Hunter) Muscular dystrophy (Duchenne and Dreifuss) Autosomal Recessive Acrocephalopolysyndactyly II (Carpenter) Alkaptonuria Bird-headed dwarfism (Seckel) Chrondrodystrophia calcificans (Conradi) Cockayne Cutis laxa Cystic fibrosis Dysautonomia (Riley-Day) Ellis-van Creveld Fanconi pancytopenia Friedreich's ataxia Glycogenoses Ila, Illa, IV Homocystinuria Jervell and Lange-Neilsen Perspectives in Biology and Medicine · Winter 1977 \ 261 Lawrence-Moon-Biedl Mucolipidosis III Mucopolysaccharidoses III, IV, V, VI Osteogenesis imperfecta Progeria Pseudoxanthoma elasticum Refsum Smith-Lemli-Opitz TAR (thrombocytopenia, absent radius) Weil-Marchesani Werner Chromosomal Abnormalities and Cardiac Defects Another type of genetic abnormality which may have a profound effect on the heart is cytological abnormality of a chromosome. Chromosomal aberrations such as aneuploidy, deletion, inversion, and translocation—cytologic changes which result in "genetic imbalance" but are not sufficiently severe to be lethal—are very frequently associated with cardiac malformation. The underlying theory is that malformation occurs when genetic "balance" is upset either by removal of genetic information (deletion or unbalanced translocation) or by addition of genetic information (21 trisomy). Since differentiation and development of the heart and great vessels (and brain) are very complex embryological processes occurring over a considerable length of time in utero, they are dependent upon the exact timing and sequence of activity of numerous fetal genes. It is not surprising, therefore, that cardiac malformation (and/or mental retardation) frequently occurs when the genome is grossly disturbed, as when there is a chromosomal change large enough to be visible...


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