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104 PA R T II / Physiologic and Pathologic Responses

greater than those associated with elevated cholesterol level, smok-
ing, or inactivity. Population studies have shown on average a 2- Table 4-3 ■ CANDIDATE GENES IMPLICATED IN RISK FOR
to 3-fold increase in CAD risk in first-degree relatives of HEART DISEASE IN HUMANS
cases, 35,61–64 and prospective studies have shown a 1.5- to 2-fold Candidate Genes
increase in CAD risk associated with a positive family history. 65–71
The observation of aggregation of CAD-associated risk factors Lipid Metabolism
(e.g., dyslipidemia, hypertension, obesity, and diabetes) in fami- Apolipoprotein(a) 74,102
lies with CAD further suggests a genetic basis for these conditions Apolipoprotein B 51
103–106
and explains, in part, the familial aggregation of CAD. 64, 72–78 Apolipoprotein E 107,108
Cholesterol ester transfer protein
Angiography studies have confirmed that family history of LDL receptor 49,50
CAD is an independent risk factor for angiographically evident Lipoprotein lipase 109
CAD. 76,79,80 Many studies of familial aggregation of CAD have Paraoxonase 110
indicated that the age of onset of a case is inversely proportional Blood Pressure Regulation
to the risk to relatives and that the risk of disease is typically sev- Angiotensinogen 111–114 112,114,115
eral times greater in relatives of females with CAD compared with Angiotensin II receptor, type 1 114–117
Angiotensin-converting enzyme inhibitor
males with CAD. 61,63 The heritability for CAD is estimated at ap- Thrombosis
proximately 56%, suggesting that more than half of the cases of Factor II (Prothrombin) 118
premature CAD (diagnosed before age 55) are caused by the con- Factor V (Factor V Leiden) 119,120
tribution of genes. Moreover, in families with CAD onset before Factor VII 49,121–124
age 46, heritability was estimated at 90% to 100%, whereas Fibrinolysis
within families of the oldest cases the heritability ranged from Fibrinogen 124–127 128
15% to 30%. 61 Plasminogen activator inhibitor-1b
Platelet function glycoprotein IIIa 129–131
Endothelial Function/Inflammatory Response
Animal Models Endothelial leukocyte adhesion molecule-1 (E-selectin) 132
Endothelial cell nitric oxide synthase 129
In the past two decades, understanding of the molecular mecha- Homocysteine Metabolism
nisms in atherogenesis has been revolutionized by studies in ge- Cystathionine -synthase 133–135
81
netically engineered animal models. These models include stud- Methylene tetrahydrofolate reductase 136–138
ies in rabbits, pigs, nonhuman primates, and rodents. Mice
deficient in apoE or the LDL receptor have advanced lesions and Adapted from Lusis, A. J. [2000]. Atherosclerosis. Nature, 407[6801], 233–241. 27
are the models most used in genetic and physiological studies. 82
These have permitted in vivo testing of hypotheses. Caveats to progression of atherosclerosis. There are also numerous studies that
such studies are the limits imposed by species differences com- have found gene associations with related disorders that are indi-
pared with humans. rectly implicated in the development and progression of CAD,
Excellent animal models exist for the study of heart disease and diabetes, 87–92 hypertension, 35,46,93,94 and obesity. 95–101 Recent
the associated conditions of diabetes, dyslipidemia, hypertension, investigations using genome scan approaches, which are unbiased
and obesity. Use of animals eliminates problems caused by genetic screens of the entire genome that can implicate novel genes, have
heterogeneity (mixed population backgrounds) and environmen- identified additional genetic loci associated with CAD, hyperten-
tal influences. Given a controlled environment, trait differences sion, and diabetes, which might provide additional insight into ge-
between animal strains are best explained by genetic factors. Gene netic factors contributing to atherosclerosis. 74,139–146 Genetic fac-
associations in animal models can result in the identification of tors have been identified that accelerate progression and clinical
candidate genes for study in human families, because conserved coronary events by influencing the response to risk factor modifi-
chromosomal segments exist between model animals and humans cation such as diet, alcohol, and use of postmenopausal hormone
(synteny). 83 replacement therapy. 108,118,123 For example, the risk of myocardial
The use of animal models is a potentially powerful way of iden- infarction is lower in men with an alcohol dehydrogenase variation
tifying genes that contribute to common forms of atherosclero- that is associated with a slower rate of ethanol metabolism, and a
84
sis. Many animal models have common variations in many traits significant interaction between this genetic variation and alcohol
relevant to atherosclerosis, and orthologous genes (i.e., those hav- intake was found. 147 Those who were homozygous for the suscep-
ing an evolutionary counterpart in other species) frequently con- tibility allele and drank at least one drink per day had the greatest
tribute to a trait in rodents and humans. 85 Mapping and identifi- reduction in risk for myocardial infarction and the highest HDL
cation of genes contributing to complex traits is easier in animals cholesterol levels. Genetic variation also plays a role in response to
than in humans. During this decade, it is likely that genome scan diet. 148–150 A recent study found that 40% of the interindividual
approaches and large-scale gene expression studies in animal mod- variation in LDL cholesterol levels in response to a diet low in sat-
els of disease will become widely used in atherosclerosis research. urated fat is a familial trait. 151
Although genetic association studies have generated a veritable
Gene Associations tidal wave of attractive candidate genes, an important caveat to
such studies exists. While these studies may provide strong and ex-
Many polymorphisms have been associated with atherosclero- citing correlations between particular genetic variations and dis-
sis 27,86 (Table 4-3). Because of methodological constraints, these ease, they must be replicated and generalized to the population
genes were historically identified as a result of their participation (by their study in large epidemiologic studies) before their clinical
in biochemical pathways implicated in the development and usefulness can be accepted and realized.