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Functional Variants of the HMGA1 Gene and Type 2 Diabetes Mellitus
Study Questions:
Is variation in a gene (HMGA1) resulting in reduced insulin receptor (INSR) expression associated with type 2 diabetes mellitus (T2DM)?
Methods:
The study analyzed high-mobility group A1 (HMGA1) gene variants in patients with T2DM and controls from three populations of white European ancestry. Genomic DNA was either directly sequenced or analyzed for specific HMGA1 mutations. Messenger RNA and protein expression for HMGA1 and INSR were measured in both peripheral lymphomonocytes and cultured Epstein-Barr virus–transformed lymphoblasts from patients with T2DM and controls.
Results:
The most frequent functional HMGA1 variant was present in 7-8% of patients with T2DM in all three populations, which was significantly higher than the control groups (0-4.7%). Other functional HMGA1 gene variants were also higher in patients with T2DM compared to controls. The most common variant was associated with reduced expression of HMGA1 and INSR in transformed cell lines from patients with the variant, and these changes were corrected by transfection with HMGA1 complementary DNA.
Conclusions:
Compared with healthy controls, the presence of functional HMGA1 gene variants in individuals of white European ancestry was associated with T2DM.
Perspective:
Previous genome-wide association studies have demonstrated associations of T2DM with multiple DNA variants. Generally, the effects have been small and explain only a small percentage of the genetic contribution to T2DM. The current case-control study provides support for a potentially important locus that may predispose individuals to T2DM. Because a mechanism with biologic plausibility is also apparent, this genetic information could have prognostic and therapeutic implications for patients with diabetes. Additional studies are needed to validate the clinical utility of this information.
Keywords: Mutation, Case-Control Studies, Genome-Wide Association Study, Diabetes Mellitus, Type 2, European Continental Ancestry Group
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