Common genetic polymorphisms and coronary heart disease

Susceptibility to coronary heart disease (CHD) is to some extent genetically determined, but despite a great deal of effort, in the past decade research has shown little progress towards identifying the genetic variants responsible. This article explores the reasons why this is so, using the ACE insertion/deletion polymorphism, which has been the most extensively studied of all genetic polymorphisms with respect to CHD risk, as an example. It is suggested that issues long recognized as important in epidemiological studies of classical risk factors, such as appropriate sample size, a requirement for high levels of statistical significance, and avoidance of excessive subgroup analysis, have tended to be under-appreciated in case-control studies of genetic polymorphisms and disease thus far. I discuss the consequences of such methodological limitations. Finally, I present a ;;checklist'' of important factors in study design and analysis in order to assist readers who may be unfamiliar with aspects of genetic methodology in the evaluation of these increasingly frequently conducted studies.