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March 2, 2011

HMGA1, A Novel Locus for Type 2 Diabetes Mellitus

Author Affiliations

Author Affiliation: Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas.

JAMA. 2011;305(9):938-939. doi:10.1001/jama.2011.236

Both genetic and environmental factors contribute to the pathogenesis of type 2 diabetes mellitus (DM). Linkage analysis and genome-wide association studies have revealed 34 common variants (also called single-nucleotide polymorphisms) associated with type 2 DM.1 Most of the loci are associated with either abnormal insulin processing or secretion, suggesting that most of the risk of type 2 DM in the population is due to beta cell dysfunction. However, some type 2 DM loci, such as peroxisome proliferator-activated receptor gamma (PPARG) and Kruppel-like factor 14 (KLF14), indicate defective insulin action or insulin resistance as a contributor.1 In addition, some genes (eg, glucokinase [hexokinase 4] regulator, insulin-like growth factor 1 [IGF1 ], and the fat mass and obesity associated gene) are associated with fasting insulin, insulin resistance, and obesity and may also contribute to type 2 DM.1 Most of the identified variants have modest effect sizes (1.1-1.3), and all of the type 2 DM–associated variants can explain only 10% to 15% of the heritability. Thus, there is a need to identify additional novel loci for type 2 DM. One approach is to conduct large-scale meta-analyses or association analyses with common variants.2 Another is to find rare variants in candidate genes selected for their known role in biological processes related to the disease.3,4

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