Candidate gene case-control association studies: advantages and potential pitfalls

There is increasing information on the importance of genetic polymorphisms in human genes. Polymorphisms occur on average once every 500-1000 base pai rs in the human genome and are useful in the identification of genes involv ed in human disease. Some genetic polymorphisms have functionally significa nt effects on the gene product and are the most useful type of polymorphism in disease association studies while others are simply useful markers. The re are two main approaches using polymorphisms in the identification of gen es involved in polygenic diseases. The first involves examining inheritance patterns for genetic polymorphisms in family studies and the second case-c ontrol studies which compare genotype frequencies for candidate disease gen es in unrelated individuals with the disease and healthy controls. Use of f amily studies is generally the preferred approach but this is only feasible if the genetic component of the disease is relatively strong, DNA samples are available from other family members and the disease is relatively easy to diagnose and is not stigmatized. Population case-control studies are use ful both as an alternative and an adjunct to family studies. When performin g case-control studies factors such as study design, methods for recruitmen t of cases and controls, functional significance of polymorphisms chosen fo r study and statistical analysis of data require close attention to ensure chat only genuine associations are detected. To illustrate some potential p roblems in the design and interpretation of association studies, some speci fic examples of association studies on drug response and on disease suscept ibility involving receptor genes, cytochrome P450 and other xenobiotic meta bolizing enzyme genes and immune system genes including TNF-alpha, IL-10 an d the IL-4 receptor are discussed.