The single nucleotide polymorphism upstream of insulin-induced gene 2 (INSIG2) is associated with the prevalence of hypercholesterolaemia, but not with obesity, in Japanese American women

Abstract

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...

INSIG1 influences obesity-related hypertriglyceridemia in humans

“…To determine whether there was an interaction between INSIG1 and INSIG2 , as suggested from mouse knockout studies, we fi rst examined the relationship between the family specifi c LOD scores for TG at the two loci ( 40 ). Second, we genotyped two SNPs in INSIG2 (rs7566605 and rs2422166) that had been reported to be associated with BMI and LDL-C in other studies (41)(42)(43) and tested for both main effects and interaction effects using the measured genotype analysis in SOLAR. Third, we examined the impact of INSIG1 variants conditional on INSIG2 variants.…”

“…Interestingly, while INSIG1 is involved in the feedback regulation of lipid synthesis, INSIG2 has been shown to be associated with obesity and adipocyte metabolism in a number of recent studies (41)(42)(43). However, no study to date has addressed whether these two genes work cooperatively in humans to affect lipid levels, as has been shown in mice ( 26 ).…”

“…However, at this point, the specifi c proteins mediating this effect (binding to the T allele, reducing expression of INSIG1 , and thereby elevating plasma TG levels) P < 0.0001). Based on these results, we selected two SNPs in INSIG2 (rs2422166 and rs7566605) that have been repeatedly shown to be associated with BMI and LDL-C in other studies (41)(42)(43). Gene-gene interaction analysis was performed on the two INSIG2 SNPs and rs2721 of INSIG1 .…”

Possible role for ENPP1 polymorphism in obesity but not for INSIG2 and PLIN variants

“…They subsequently obtained the same result in four other cohorts while in a fifth sample, the confidence interval for the OR for obesity was not significant. It is intriguing, then, that most studies initiated afterward in different population samples found no evidence to support the claim by Herbert et al Indeed, rs7566605 was significantly associated with BMI in a Chinese subpopulation and with morbid obesity in a Japanese population, while 10 other reports were negative [23][24][25][26][27][28][29][30][31]33]. Lyon et al [46], in a large multi-ethnic study, did find an association in five cohorts but could not confirm the association in three other cohorts, while the combined analysis was also significant.…”

“…elevated body mass index (BMI), a polymorphic variant upstream of the INSIG2 gene (insulin-induced gene 2) on chromosome 2 was identified for the first time [18], although mouse and human linkage studies had already identified INSIG2 as an obesity QTL [19,20]. Despite successful replication by Herbert et al of their finding in four out of five samples from different populations [18], subsequent studies have yielded only negative results [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35].…”