Type 2 diabetes mellitus is a common chronic disease that develops in most populations late in middle age. The Pima Indians of Arizona have a very high prevalence of this disease and, in contrast to many populations, the disease often presents at an earlier age. As a result of the long-term epidemiologic studies, the familial nature of the disease is well-documented, and segregation analysis suggests that genetic determinants may influence age of onset. Genetic determinants of type 2 diabetes mellitus and its risk factors are being sought using techniques of genetic linkage analysis. Lymphoblast cell lines have been established from informative pedigrees. DNA is available from other families in nuclear pellets extracted from blood specimens obtained in the epidemiologic studies. An autosomal genome-wide linkage study, using 516 genetic markers, has been completed for 1338 individuals in 112 pedigrees potentially informative for linkage studies of diabetes. The results of these analyses identified strong evidence for a locus influencing both obesity and diabetes on chromosome 11q. Evidence for an additional locus influencing diabetes and insulin secretory function was found on chromosome 1q. Efforts to identify the causative polymorphism or polymorphisms in both of these regions are currently underway using both a systematic analysis of linkage disequilibrium and analyses of candidate genes. Methods for statistical analyses of these studies are also being developed and evaluated. Several regions that appear to be in linkage disequilibrium with obesity-susceptibility alleles on chromosome 11 have been identified and several candidate genes have been analyzed. In collaboration with the Sanger Centre a dense (5 kb) linkage disequilibrium map of chromosome 1q is being generated for Pimas and for several other populations that have shown linkage to this region.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK069028-16
Application #
6984159
Study Section
(PECR)
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2004
Total Cost
Indirect Cost
Name
U.S. National Inst Diabetes/Digst/Kidney
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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Muller, Yunhua Li; Hanson, Robert L; Zimmerman, Collin et al. (2007) Variants in the Ca V 2.3 (alpha 1E) subunit of voltage-activated Ca2+ channels are associated with insulin resistance and type 2 diabetes in Pima Indians. Diabetes 56:3089-94
Ma, Lijun; Hanson, Robert L; Que, Lorem N et al. (2007) Variants in ARHGEF11, a candidate gene for the linkage to type 2 diabetes on chromosome 1q, are nominally associated with insulin resistance and type 2 diabetes in Pima Indians. Diabetes 56:1454-9

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