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OBJECTIVE - Type 1 diabetes arises from the actions of multiple genetic and environmental risk factors. Considerable success at identifying common genetic variants that contribute to type 1 diabetes risk has come from genetic association (primarily case-control) studies. However, such studies have limited power to detect genes containing multiple rare variants that contribute significantly to disease risk.
RESEARCH DESIGN AND METHODS- The Type 1 Diabetes Genetics Consortium (TlDGC) has assembled a collection of 2,496 multiplex type 1 diabetic families from nine geographical regions containing 2,658 affected sib-pairs (ASPs). We describe the results of a genome-wide scan for linkage to type 1 diabetes in the TlDGC family collection.
RESULTS- Significant evidence of linkage to type 1 diabetes was confirmed at the HLA region on chromosome 6p21.3 (logarithm of odds [LOD] = 213.2). There was further evidence of linkage to type 1 diabetes on 6q that could not be accounted for by the major linkage signal at the HLA class II loci on chromosome 6p21. Suggestive evidence of linkage (LOD ≤2.2) was observed near CTLA4 on chromosome 2q32.3 (TLOD = 3.28) and near INS (LOD = 3.16) on chromosome llpl5.5. Some evidence for linkage was also detected at two regions on chromosome 19 (LOD = 2.84 and 2.54).
CONCLUSIONS - Five non-HLA chromosome regions showed some evidence of linkage to type 1 diabetes. A number of previously proposed type 1 diabetes susceptibility loci, based on smaller ASP numbers, showed limited or no evidence of linkage to disease. Low-frequency susceptibility variants or clusters of loci with common alleles could contribute to the linkage signals observed. Diabetes 58:1018-1022, 2009
Type 1 diabetes develops when the insulin-secreting ß-cells in the pancreas are depleted by an autoimmune process of unknown origin. Diagnosis occurs when sufficient ß-cell mass is lost that blood glucose levels cannot be maintained in the physiologic range. Although insulin treatment for type 1 diabetes is life saving, development of effective preventive therapies could be enhanced by improved prediction and a better understanding of the underlying disease mechanism, particularly events occurring during the extended preclinical period. Such considerations have motivated studies directed toward identifying the genetic risk factors that contribute to the disorder that might provide novel insights into disease etiology and targets for preventive therapy.
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