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

Abstract

There is increasing information on the importance of genetic polymorphisms in human genes. Polymorphisms occur on average once every 500±1000 base pairs in the human genome and are useful in the identi®cation of genes involved in human disease. Some genetic polymorphisms have functionally signi®cant effects on the gene product and are the most useful type of polymorphism in disease association studies while others are simply useful markers. There are two main approaches using polymorphisms in the identi®cation of genes involved in polygenic diseases. The ®rst involves examining inheritance patterns for genetic polymorphisms in family studies and the second case-control studies which compare genotype frequencies for candidate disease genes in unrelated individuals with the disease and healthy controls. Use of family 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 useful both as an alternative and an adjunct to family studies. When performing case-control studies factors such as study design, methods for recruitment of cases and controls, functional signi®cance of polymorphisms chosen for study and statistical analysis of data require close attention to ensure that only genuine associations are detected. To illustrate some potential problems in the design and interpretation of association studies, some speci®c examples of association studies on drug response and on disease susceptibility involving receptor genes, cytochrome P450 and other xenobiotic metabolizing enzyme genes and immune system genes including TNF-a, IL-10 and the IL-4 receptor are discussed.

Role of genetic polymorphisms in tumour angiogenesis

“…Other variants, even if not functional, can be associated with phenotype because of linkage to closely situated functional polymorphisms. It is now recognized that specific combinations of polymorphisms in a gene (haplotypes) might be of greater significance than individual polymorphisms, not only for a more efficient capture and analysis of common genetic variation (Johnson et al, 2001), but also from a functional view point (Daly and Day, 2001). The numbers of patients and appropriately matched controls, needed to demonstrate a specific relative risk with adequate power and acceptable type I error risk in a case -control study would depend on the frequency of the polymorphism in the population.…”

“…Studying rare polymorphisms (55% rare allele frequency) requires thousands of patients to prove small associations (odds ratio of 1.5 or lower), which may be of little biological interest because of the rarity of the polymorphism in the general population. A detailed discussion of these and related issues can be found in several recent reviews (Daly and Day, 2001;Risch, 2000;Weinberg and Umbach, 2000).…”

Association studies of genetic polymorphisms in central obesity: a critical review

“…This approach, however, is most prone to identify gene variants that prove to be spuriously associated with disease. 115 The nature of spurious association is the failure to replicate the data and the inability to provide evidence for genetic linkage. 62 An important difficulty with this study design is the choice of controls, which are often identified and ascertained after collection of the disease group.…”

Human Genetic Susceptibility to Tuberculosis and Other Mycobacterial Diseases

“…Well-designed association studies (16,17) can still establish the relevance of many candidate genes in the disease process. It appears likely from the genes identified thus far that a number of genes, all conferring a moderate increase in risk, will be involved in the overall susceptibility of a population to TB.…”