Abstract
In our analysis of a quantitative trait locus (QTL) for plasma triglyceride (TG) levels [logarithm of odds (LOD) = 3.7] on human chromosome 7q36, we examined 29 single nucleotide polymorphisms (SNPs) across INSIG1, a biological candidate gene in the region. Insulin-induced genes (INSIGs) are feedback mediators of cholesterol and fatty acid synthesis in animals, but their role in human lipid regulation is unclear. In our cohort, the INSIG1 promoter SNP rs2721 was associated with TG levels (P = 2 x 10(-3) in 1,560 individuals of the original linkage cohort, P = 8 x 10(-4) in 920 unrelated individuals of the replication cohort, combined P = 9.9 x 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.
Highlights
In our analysis of a quantitative trait locus (QTL) for plasma triglyceride (TG) levels [logarithm of odds (LOD) = 3.7] on human chromosome 7q36, we examined 29 single nucleotide polymorphisms (SNPs) across insulin-induced gene 1 (INSIG1), a biological candidate gene in the region
Among the 22 identified genes in this QTL, INSIG1 is the only candidate with known biological roles that are related to lipid metabolism and has been the focus of this study
We tested for INSIG1 association using 11 SNPs selected from the Hapmap database using the tagger function of Haploview [35, 36] (Fig. 1 and Table 2)
Summary
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 profile such as elevated serum TG and low HDL levels. A genome-wide linkage scan of these families identified a quantitative trait locus (QTL) on human chromosome 7q36 linked to plasma TG levels (LOD = 3.7) [10]. This region has been implicated in numerous other studies [11,12,13,14,15] and represents.
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