Genetic prediction of coronary heart disease: lessons from Canada

Before it can find clinical application, a panel of genetic tests to predict coronary heart disease (CHD) risk will need to be shown to be more effective than either a determination of family history or the assessment of intermediate phenotypes, such as plasma lipoproteins, diabetes and blood pressure. Our studies in Canadian Hutterites and Oji-Cree indicate that a single genetic factor has a small effect on an intermediate phenotype of CHD. Also, the total contribution of genetic factors, while substantial, is usually the aggregate of many small effects. Furthermore, the environment plays a capacious role in modulating the expression of the genetic susceptibility to CHD. This is seen in examples of strong monogenic determinants of CHD, such as in early CHD in Newfoundlanders that results from APOA1 Q[-2]X, and in early onset diabetes in Oji-Cree that is determined by HNF-1 alpha S319. The Oji-Cree HNF-1 alpha S3 19 example also indicates that future diagnostic tests will have to account for population-specific genetic determinants of CHD risk. Studies in Canadian Inuit suggest that a prudent environment can override an apparently high level of genetic susceptibility to CHD. These anecdotes imply that environment might be an even greater determinant of the common polygenic forms of CHD. The complexity of CHD will produce a delay in implementing routine genetic testing. This might provide more time for health care providers and society to consider the possible implications--medical, ethical and legal--and limitations of the genetic prediction of CHD.