In T1DM, the application of genomewide scans has identified over 18 putative loci of statistical significance, but, for now, only linkage to HLA loci seems incontestable. Albeit much excitement has recently been generated by the results of genomewide scans, for many polygenic disorders, including T1DM, careful and rigorous replication as well as association studies in many populations must be conducted before any attempts are made by positional cloning or the candidate gene approach to identify potentially elusive sequence variations that could influence genetic susceptibility. One example of controversy in this field is a publication of studies with opposing results (48,184,185).
It is noteworthy acknowledging that familial association of different autoimmune diseases in the same pedigree (172), association of different autoimmune disorders including T1DM in the same individual (186,187), and common clinical parameters of different autoimmune diseases (6,188) might share similar pathophysiologic mechanisms leading to autoimmunity. Colocalization and overlapping of candidate loci in autoimmune disease, such as T1DM, imply that common biological pathways may be involved in the immunopathogenesis of at least a subgroup of autoimmune diabetes and other clinically diversified autoimmune disorders. The latter example may resemble what occurs as a result of mutations of the autoimmune regulator gene (AIRE) (189-191), which forms the basis for genetic dysregulation in autoimmune polyen-docrine syndrome type 1 (APS-I), a non-MHC-linked disorder that is also associated with autoimmune impairment of pancreatic ß-cells.
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