Insulin-induced gene 2 (insig-2) protein is known to play important roles in cholesterol and TAG metabolism both in vivo and in vitro. One particularly interesting single nucleotide polymorphism (SNP), rs7566605, located 10 kb upstream of INSIG2 was reported to have the strongest association with obesity among 86 604 SNP, while the relationship with dyslipidaemia is uncertain. Eight hundred and eighty-five Japanese Americans (347 men and 538 women) and 378 Japanese (182 men and 196 women) were enrolled, and the rs7566605 SNP, which is consistent with either G or C, was determined. We investigated the association between the rs7566605 SNP and the prevalence of hypercholesterolaemia or hypertriacylglycerolaemia, or obesity parameters, as assessed by BMI, waist girth and percentage body fat. There were no significant differences in BMI, waist girth and percentage body fat according to the genotype in each of the four groups, which was divided by population and sex. The prevalence of hypercholesterolaemia was significantly different between the genotypes in Japanese American female subjects (GG, 62·2 %; GC, 57·1 %; CC, 42·1 %; P¼ 0·021), but not in the other subjects. In Japanese American women, the subjects with the CC genotype had a 0·43-fold decreased risk (95 % CI 0·24, 0·80) for hypercholesterolaemia compared with the GG genotype after adjustment for age, percentage body fat, smoking status and hormone replacement therapy. The CC genotype of the rs7566605 SNP is suggested to be a protective genetic factor against the progression of hypercholesterolaemia on a high-fat diet, especially in Japanese female subjects.INSIG2: Polymorphisms: Dyslipidaemia: Obesity: High-fat diet Insulin-induced gene insig proteins, including insig-1 and insig-2, play many important roles in regulating cholesterol or TAG synthesis, mainly in the liver. 3-Hydroxy-3-methylglutaryl (HMG)-CoA reductase, a rate-limiting enzyme in cholesterol synthesis, catalyses the reduction of HMG-CoA to mevalonate (1) . Overexpression of insig proteins can activate the degradation of HMG-CoA reductase in Chinese hamster ovary cells in vitro (2) . The knockdown of insig-2 by RNA interference suppresses the degradation of HMG-CoA reductase in SV-589 cells (3) . In addition, insig-2-overexpressing mice exhibit lower plasma TAG levels compared with wild-type mice, independent of food intake, body weight and fat weight (4) , which suggests the association between insig-2 and TAG metabolism. Taken together, it is suggested that insig-2 is strongly related to cholesterol and TAG metabolism through the level of insig-2 expression.Recently, an interesting single nucleotide polymorphism (SNP), rs7566605, which is located 10 kb upstream of INSIG2, was found to be associated with obesity, as assessed by BMI (5) . This polymorphism was identified from a genomewide association scan of 86 604 SNP in the Framingham Heart Study offspring cohort. In the report, the relationship with obesity was confirmed in four out of five additional cohorts (5) . Moreover, Lyon et al. id...