Evidence for the genetic basis of CHD

Family history of the disease is one of the strongest and most consistent risk factors for CHD. Relative risk estimates of between 1.5 and 5 have been derived from a range of family and population studies (Hawe et al., 2003; Lusis, 2003). At least a part of the risk of family history is conferred by the monogenic dyslipidaemias, including familial hypercholesterolemia (FH) (Goldstein et al., 1973), which carry a high penetrance of CHD. However, since the frequency of the FH heterozygous state, and of other monogenic dyslipidaemias, is only at most around 1 in 500, these cannot account for more than a small proportion of all cases.

Although the risk conferred by family history is consistent, such family studies cannot distinguish reliably shared environmental from inherited influences. More informative are twin and adoption studies, which confirm definitively the part played by inherited factors. A 26-year follow-up of 21000 Swedish twins showed a relative hazard of 8.1 for coronary disease in a male monozygotic twin dying of CHD before age 55 years compared to monozygotic twins not dying of CHD, and a relative hazard of 3.8 for dizygotic twins. Among female twins, the relative hazard for the mono-zygotic twin dying under age 65 years was 15.0 compared to 2.6 for a dizygotic twin. Heritability after 36 years follow-up was estimated to be 0.57 in male twins and 0.38 in female twins (Zdravkovic et al., 2002). Such a high heritability is supported by the adoption study of Sorensen et al. (Sorensen et al., 1988) who found a relative risk of death in adoptees of 4.5 for death from vascular disease before age 50 years of a biological parent, compared to a relative risk of 3.0 for death of an adoptive parent. These results and similar data from other studies provide clear evidence for the existence of CHD susceptibility genes and provide the justification for the large number of studies seeking their identification.

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