Genetic and environmental contributions to CHD pathogenesis

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The significant changes in CHD incidence and mortality over the past 20 years can be attributed at least in part to variation in known environmental risk factors (Table 24.1). Frequency of cigarette smoking, efficacy of primary and in-hospital coronary care, treatment of plasma lipids, and the prevalence of obesity and type 2 diabetes (T2DM) have changed significantly over the past 20 years and also vary markedly between populations. These environmental factors explain, at least in part, the widely differing CHD prevalence and trends in CHD prevalence observed between populations over the past two to three decades.

Whilst environmental influences account for a significant part of individual and population susceptibility to CHD, the longevity of some individuals with multiple risk factors (e.g. smoking, hypercholesterolemia, hypertension), and the consistent and highly significant risk conferred by a positive family history of CHD, point to the importance of genetic factors in CHD pathogen-esis. Genes which control plasma lipids and lipoproteins are amongst the clearest examples of genetic risk factors for CHD (Table 24.1).

In this chapter, we discuss first the evidence from family studies that genetic influences are important in susceptibility to CHD. Secondly, we review the genetics of lipid risk factors, including the genetic basis of monogenic and complex dyslipidaemias, and their impact on CHD susceptibility. Thirdly, we review genetic studies of human CHD and its risk factors, including consideration of the role played by the metabolic syndrome, whose prevalence is increasing rapidly

Table 24.1. Known risk factors for coronary heart disease

Environmental

Mainly genetic (Primary

(modifiable)

cause not modifiable)

Combined genetic and environmental

Cigarette smoking

Lp(a)

Obesity

Physical inactivity

Monogenic

Raised LDL cholesterol, triglycerides; reduced HDL cholesterol

dyslipidemias

Dietary fat

Ethnic origin

Complex dyslipidemias (e.g. familial combined hyperlipidemia)

Lipid lowering therapies

Family history

Insulin resistance, metabolic syndrome and type 2 diabetes

Small dense low density lipoprotein

Homocysteine

Fibrinogen, PAI-1

C-reactive protein

LDL: low density lipoprotein; HDL: high density lipoprotein; PAI-1: plasminogen activator inhibitor-1.

LDL: low density lipoprotein; HDL: high density lipoprotein; PAI-1: plasminogen activator inhibitor-1.

and whose contribution to CHD prevalence and susceptibility is increasingly important. Finally, we discuss data from rodent studies which have thrown light on the genes, regulatory pathways and molecular mechanisms underlying development of dyslipidemia and atherosclerosis.

The understanding of atherosclerosis cell biology and pathophysiology has advanced dramatically over the past 10-15 years. These areas have been reviewed extensively elsewhere (Glass and Witztum, 2001; Lusis, 2000; 2003), and will not be discussed here unless of direct relevance to the genetic basis of CHD.

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