Author Affiliation: Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas.
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
Garg A. HMGA1, A Novel Locus for Type 2 Diabetes Mellitus. JAMA. 2011;305(9):938-939. doi:10.1001/jama.2011.236