Insulin-induced gene 2 (INSIG2) plays an important role in the regulation of cholesterol and fatty acids synthesis. A polymorphism, rs7566605, located 10 kilobases upstream of the INSIG2 gene, was identified in a genomewide association study of obesity. We conducted an association study of 12 INSIG2 tag-single nucleotide polymorphisms with longitudinal measures of body size (body mass index and waist circumference) and lipid metabolism (plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides levels). We investigated their interaction with age in 4304 Coronary Artery Risk Development in Young Adults participants (49.5% blacks, 50.5% whites) followed prospectively for 20 years. rs7566605 was not associated with variation in body size or lipid metabolism at any age in either racial group. However, rs1352083 and rs10185316 were associated with age-related decline in high-density lipoprotein cholesterol in whites (P = .0005 and .04, respectively). A similar trend was observed in blacks who consistently maintained a body mass index less than 25 kg/m2 over the study period. These data support a role of INSIG2 sequence variation in the regulation of cholesterol metabolism. © 2010 Elsevier Inc. All rights reserved.