Fine Mapping of the Insulin-Induced Gene 2 Identifies a Variant Associated With LDL Cholesterol and Total Apolipoprotein B Levels

Abstract

Background-In a whole-genome scan, a single nucleotide polymorphism (SNP) (rs7566605) upstream of the insulin-induced gene 2 (INSIG2) was shown to influence body mass index and obesity in the Framingham Heart Study, with replication of these results in an additional 4 of 5 studies. However, other studies could not replicate the association. Because INSIG2 plays an important role in cholesterol biosynthesis, we hypothesized that human INSIG2 variants might play a role in the regulation of plasma lipid and lipoprotein levels. Methods and Results-We selected tagging SNPs spanning Ͼ100 kb of INSIG2 locus and sequenced 18 434 base pairs to discover novel SNPs. Thirty-two SNPs were genotyped in 645 individuals from the Quebec Family Study. Two SNPs (rs10490626 and rs12464355) were associated with plasma low-density lipoprotein cholesterol (LDL-C) (PϽ0.0015) and total apolipoprotein B (apoB) levels (PϽ0.014), whereas no association was found between any SNP and body mass index. We replicated the finding of rs10490626 for both LDL-C and total apoB in additional study samples, including 758 individuals from Saguenay-Lac St. Jean, Quebec (Pϭ0.040 for LDL-C, Pϭ0.044 for apoB), 3247 Europeans (Pϭ0.028 for LDL-C, Pϭ0.030 for apoB), and 1695 South Asians (Pϭ0.0036 for LDL-C, Pϭ0.034 for apoB) from the INTERHEART study (for LDL-C, the combined 2-sided Pϭ6.2ϫ10 Ϫ5 and for total apoB, Pϭ0.0011). Furthermore, we identified a variant in the human sorbin and SH 3 -domain-containing-1 gene that was associated with INSIG2 mRNA levels, and this SNP was shown to act in combination with rs10490626 to affect LDL-C (Pϭ0.022) in the Quebec Family Study and in INTERHEART South Asians (Pϭ0.019) and Europeans (Pϭ0.052). A n association between a single nucleotide polymorphism (SNP) (rs7566605) in the insulin-induced gene 2 (IN-SIG2) and body mass index (BMI) was discovered in a genome-wide scan of 86 604 SNPs in 923 individuals from the Framingham Heart Study. 1 The association was replicated in an additional 4 of 5 independent study samples composed of western Europeans and blacks. 1 A follow-up study reproduced this result in 5 of 9 samples. 2 However, subsequent studies performed by other groups could not replicate the association. [3][4][5][6][7][8][9][10][11][12][13][14] A recent meta-analysis suggested that different study designs might have contributed to these heterogeneous results. 15 Conclusion-These Clinical Perspective on p 461Although the physiologic role of INSIG2 in obesity is unclear, there is strong evidence suggesting that the gene plays a key role in both fatty acid and cholesterol biosynthesis. Double-knockout mice containing germline disruption of Received October 30, 2009; accepted August 20, 2010 20 A limitation of previous gene association studies involving INSIG2 is that they have all focused on a single SNP (ie, rs7566605) and/or on 1 trait (obesity or BMI). The inconsistency of the association with obesity among studies could be due to differential linkage disequilibrium (LD) with a causal SNP or differential corre...

Association of INSIG2 Polymorphism with Overweight and LDL in Children

“…Our study also found a protective effect on LDL (those with the minor allele, G, of SNP rs12464355 had lower levels). This finding replicates a previous report of an association between rs12464355 and LDL[ 35 ]). Our failure to identify association between SNP rs7566605 and lipid levels is consistent with previous studies [ 12 , 13 , 14 , 24 , 26 , 27 ].…”

SETDB2 Links Glucocorticoid to Lipid Metabolism through Insig2a Regulation

“…Furthermore, there are single nucleotide polymorphisms (SNPs) within the human SETDB2 locus that are associated with metabolic disease traits including glycosylated hemoglobin (HGVPM569), systolic blood pressure (HGVPM563), fasting plasma insulin (HGVPM822), and serum cholesterol (HGVPM568). Additionally, SNPs near the human INSIG2 locus have been associated with obesity and lipid metabolism (Do et al, 2010; Herbert, 2006; Hotta et al, 2008; Kaulfers et al, 2015). Also, SETDB2 is induced by Dex in other metabolic tissues such as white adipose and skeletal muscle (data not shown).…”

INSIG2 variants, dietary patterns and metabolic risk in Samoa

“…Consequently, the INSIG2 polymorphism rs9308762 has been associated with adiposity measures in the Samoan population and in a population of 1,495 Hispanics (11). Although most studies have focused on the association of INSIG2 variants with adiposity measures, others have also explored associations with related metabolic traits such as plasma lipids and glucose homeostasis (11, 17, 19, 21, 26, 28–30). Results from these studies are not consistent either.…”