Methods for the study of the genetic determinants of diabetes and its complications.

Diabetes and its complications have a multifactorial etiology that includes both environmental and genetic factors. This makes the aim of finding susceptibility genes difficult because of the contribution of multiple genes, the wide variety of environmental factors that are involved, the lack of a clear mode of inheritance, and the presence of genetic heterogeneity. Despite these problems, the recent advances in biotechnology offer the opportunity to dissect the genetics background of complex diseases. As in the case of other disorders, there are two major approaches to study the molecular genetics of diabetes: association studies and linkage studies in families. Association studies aim to identify susceptibility alleles through several approaches, the simplest of which is to compare unrelated cases and controls. While this study design is relatively easy, false positive results are common due to unrecognized differences between cases and controls. An alternative is to use family-based association studies such as the transmission disequillibrium test. While this approach requires more recruitment efforts, the chances of false positive results are minimized. In contrast to association studies, linkage studies are not targeted to single candidate genes, but rather investigate the cosegregation between large chromosomal regions and the disease. Linkage analysis can be performed by either non-parametric or parametric methods. Non-parametric studies are relatively easy to conduct and do not require previous knowledge of the mode of inheritance. However, they cannot detect genetic heterogeneity (i.e. the presence of multiple genes that contribute to diabetes in different families). In contrast, parametric methods require large pedigrees and the assumption of a model of genetic inheritance, but they can detect genetic heterogeneity. Several new diabetes loci and genes have already been identified through the strategies outlined above, and many more are expected to be found in the next few years with the completion of the Human Genome Project.