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C HAP TE R 4 / Genetics 103

into disease pathogenesis (see Table 4-2). Studies of familial hy-
Table 4-2 ■ GENETIC CHANGES RELEVANT TO HEART percholesterolemia helped unravel the pathways that regulate
DISEASE* plasma cholesterol metabolism, knowledge of which was impor-
tant for the development of cholesterol-lowering interventions. In
Trait Mendelian Characteristics
contrast to the mendelian disorders, dissecting the genetic contri-
c LDL/VLDL Familial hypercholesterolemia S LDL receptor bution of common, complex forms of CAD has proven more dif-
levels gene defects resulting in a dominant disorder resulting in ficult. Studies of candidate genes have suggested a number of
very high LDL cholesterol levels and early CAD 24 genes influencing the traits relevant to atherosclerosis, but our un-
Familial defective apoB-100 S Dominant disorder caused
by apoB mutations that affect binding to LDL derstanding remains incomplete (see Table 4-2). Large-scale se-
24
receptor ; less severe than FH quencing is now underway to identify polymorphisms for many
24
T HDL ApoAI deficiency (apoAI) ; in the homozygous state, null other candidate genes for hypertension, diabetes, and other traits
cholesterol mutations of apoAI result in the virtual absence of HDL relevant to atherosclerosis. In an attempt to identify further ath-
45
levels and early CAD erosclerosis genes, whole-genome scans (a method of fingerprint-
Tangier disease (ABC1 transporter) 32,33 . This recessive
disorder results in the inability of cells to export choles- ing the entire genome in attempts to identify genes shared in af-
terol and phospholipids, resulting in very low levels of fected individuals more often than with their relatives) for loci
HDL associated with diabetes, hyperlipidemia, low high-density
24
Coagulation Various genetic disorders of genetic hemostasis : unlike lipoprotein (HDL) levels, and hypertension have been per-
rare disorders of lipid metabolism where atherosclerotic 46
disease is a primary manifestation, disorders of hemosta- formed, but few loci with significant evidence of linkage have
sis usually present either as increased risk of bleeding or been found, emphasizing the complexity of these traits.
as thrombosis (usually venous), with no outstanding As a result of the genome projects and large-scale sequencing,
effect on atherogenesis literally millions of gene variations are being identified and cata-
Elevated Homocystinuria (cystathionine -synthase): recessive logued. Given the rapid development of DNA chip technology, it
homocysteine metabolic disorder resulting in very high levels of homo-
cysteine and severe occlusive vascular disease 19 will soon be possible to genotype large numbers of such polymor-
Diabetes, type 2 MODY1 (hepatocyte nuclear factor 4a), MODY2 phisms in many thousands of individuals. However, appropriate
(glucokinase), and MODY3 (hepatocyte nuclear factor methods to analyze such data are evolving. 47,48
24
1a) : MODY1, 2, and 3 are characterized by the devel-
opment of non-insulin-dependent diabetes mellitus in
young adults
Hypertension Glucorticoid-remediable aldosteronism: a dominant EVIDENCE FOR A GENETIC BASIS
disorder with early-onset hypertension and stroke OF CORONARY ARTERY DISEASE
(hybrid gene from cross-over of 11-b-hydroxylase and
aldosterone synthase) 34
Liddle syndrome (epithelial sodium: dominant disorder Significant amounts of research support a genetic basis for coro-
with hypertension and metabolic alkalosis channel) 34 nary heart disease and its risk factors. The methods of investiga-
35
Mineralocorticoid receptor : early-onset hypertension tion include family and twin studies, animal models, and gene as-
associated with pregnancy sociation studies. Although, historically, single gene mutation was
Common Genetic Variations Contributing to Heart Disease the first to be described as a class, only rarely is susceptibility to
and Its Risk Factors atherosclerosis the result of a single gene mutation. The most fa-
24
LDL/VLDL ApoE : three common missense alleles explain 5% of
variance in cholesterol levels miliar single gene mutation is familial hypercholesterolemia,
36
HDL levels Hepatic lipase : promoter polymorphism which is caused by disruptive mutations of the LDL receptor or
36
ApoAI-CIII-AIV cluster : multiple polymorphisms apolipoprotein B. 49–51
Cholesteryl ester transfer: common null mutations
(Japanese); protein 24 missense polymorphisms
37
Lipoprotein lipase : missense polymorphisms Twin Studies
17
Lipoprotein(a) Apolipoprotein(a) : many alleles explain 90% variance
Homocysteine Methylene tetrahydrofolate: missense polymorphism Twins have been useful in studying the genetic contribution to many
reductase 24 common diseases. A higher concordance of a trait found in monozy-
24
Coagulation Fibrinogen B : promoter polymorphism gotic twins (who share all of their genes) compared with dizygotic
Plasminogen activator: promoter polymorphism inhibitor
type 1 24 twins (who share only half of their genes) suggests a genetic compo-
6,52
24
Factor VIII : missense polymorphism nent. Several large twin registries, including the Danish Twin
34
Blood pressure Angiotensinogen : missense and promoter polymorphisms Registry, which includes approximately 8,000 unselected twin pairs,
34
2-Adrenergic receptor : missense polymorphism observed a significant difference in concordance of CAD deaths in
34
Alpha-adducin : missense polymorphism monozygotic twins compared with dizygotic twins in men and
CAD Angiotensin-converting insertion—deletion polymorphism 53–59
enzyme 38 women. A common observation in twin studies was the de-
Serum paraoxonase 39,40 : missense polymorphism affecting layed age of onset of CAD in women versus men.
enzymatic activity
Hemachromatosis: missense polymorphism-associated gene 41
Endothelial nitric oxide: missense polymorphism synthase 42 Familial Aggregation
43
Factor XIII : missense polymorphism
A genetic epidemiologic study analyzing data regarding 19 tradi-
tional risk factors from cases with myocardial infarction before age
*Only genes exhibiting evidence of linkage or association in two or more studies are 60
cited. 55 compared with matched controls suggested that the highest
Adapted from Lusis, A. J. [2000]. Atherosclerosis. Nature, 407[6801], 233–241. 27 odds ratio was associated with a family history of a first-degree rel-
ative with CAD before age 55. The risk increased 7.1-fold if the
CAD was diagnosed before age 55. These risks were substantially