INSIG1 influences obesity-related hypertriglyceridemia in humans

Abstract

Increased plasma triglyceride (TG) levels are an important cardiovascular risk factor and are strongly associated with atherosclerotic heart disease ( 1, 2 ). Plasma TG levels vary widely between individuals, and both genetic and environmental factors have been shown to contribute to elevated plasma TG concentrations ( 3-7 ). Elevated plasma TG levels are often observed in obese and diabetic individuals and in individuals affected by the metabolic syndrome, a common chronic disorder associated with obesity, insulin resistance, hypertension, and alterations in plasma lipid profi le such as elevated serum TG and low HDL levels. This characteristic pattern is similar to lipid abnormalities reported in familial combined hyperlipidemia ( 8 ).The Metabolic Risk Complications of Obesity Genes (MRC-OB) project was established in 1994 to identify the genetic determinants of the metabolic syndrome and its metabolic abnormalities ( 9 ). As part of the project, basic anthropomorphic phenotypes, plasma lipid measures, and fasting glucose and insulin levels were ascertained for 2,209 individuals from 507 families. A genome-wide linkage scan of these families identifi ed a quantitative trait locus (QTL) on human chromosome 7q36 linked to plasma TG levels (LOD = 3.7) ( 10 ). This region has also been implicated in numerous other studies (11)(12)(13)(14)(15) ؊ 4 in 920 unrelated individuals of the replication cohort, combined P = 9.9 × 10 ؊ 6 ). Individuals homozygous for the T allele had 9% higher TG levels and 2-fold lower expression of INSIG1 in surgical liver biopsy samples when compared with individuals homozygous for the G allele. Also, the T allele showed additional binding of nuclear proteins from HepG2 liver cells in gel shift assays. Finally, the variant rs7566605 in INSIG2 , the only homolog of INSIG1 , enhances the effect of rs2721 ( P = 0.00117). The variant rs2721 alone explains 5.4% of the observed linkage in our cohort, suggesting that additional, yet-undiscovered genes and sequence variants in the QTL interval also contribute to alterations in TG levels in humans. -Smith,

Four SNPs of insulin-induced gene 1 associated with growth and carcass traits in Qinchuan cattle in China

“…In previous studies, Smith et al (2010) reported that Insig-1 influences obesity-related hypertriglyceridemia in humans, and overexpression of Insig-1 has been shown to reduce high levels of TG in both liver and plasma of Zucker diabetic fatty rats (Takaishi et al, 2004). In addition, single knockout of Insig-1 in mice leads to increased total content of both cholesterol and TG in mouse liver (Engelking et al, 2005).…”

A novel method, the Variant Impact On Linkage Effect Test (VIOLET), leads to improved identification of causal variants in linkage regions

“…Indeed, our research team had not considered rs39179 (minor allele frequency 2.6% in our cohort; present in 25 of the 258 families and explained 0.7% of the variation in triglycerides) a promising candidate and rather focused on other SNPs. 17,18 Our results suggest that either rs39179 or SNPs in strong linkage disequilibrium (LD) with rs39179 may be causal. Using SNAP, 36 a single ungenotyped SNP (rs10276884) in strong LD with rs39179 was identified.…”

“…16 Although this region has been densely genotyped, MGA yielded associations that explained little of the observed linkage. 17,18 Using VIOLET, a single SNP (rs39179) accounting for 24% of the LOD score was identified (but it did not reach the traditional CLA threshold). This SNP was only nominally associated in MGA (P ¼ 0.04) and was ranked eighty-ninth in the P-value ranking.…”

“…16 After dense single-nucleotide polymorphism (SNP) genotyping, associations were found, but only a modest portion of the linkage was explained. 17,18 Simulated data set -GAW17-simulated data set. GAW17 used the 1000 Genomes 19 exome sequence data 14,15 to generate a data set with 697 individuals in 8 pedigrees.…”

“…16 From the initial cohort, 1235 individuals from 258 families contributing to the linkage were selected for dense genotyping (Table 1) of 1048 tag SNPs using an Affymetrix MegAllele custom-designed array (Affymetrix, Santa Clara, CA, USA). 17,18,21 Additionally, 354 SNPs from chromosome 14 were available for analysis. Chromosome 14 SNPs were used to determine VIOLET's specificity.…”