Key result
INSIG1 rs2721 T allele homozygosity is linked to ~9% higher triglyceride levels versus G homozygotes.
Why the study?
The role of INSIG1 in human lipid regulation and its influence on plasma triglyceride levels in obesity-related hypertriglyceridemia is unclear.
Is the INSIG1 promoter SNP rs2721 associated with plasma triglyceride levels in humans?
Cohort (n=2,480)
Is the INSIG1 promoter SNP rs2721 associated with plasma triglyceride levels in humans?
The INSIG1 promoter SNP rs2721 is associated with elevated plasma triglyceride levels and reduced hepatic INSIG1 expression, highlighting a genetic contributor to human lipid regulation.
rs2721-TG association is hypothesis-generating; leaves open INSIG1's role in human lipid regulation pending replication.
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.
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Smith et al. (2009) conducted a cohort in obesity-related hypertriglyceridemia (n=2,480). INSIG1 promoter SNP rs2721 T allele vs. INSIG1 promoter SNP rs2721 G allele was evaluated on plasma triglyceride (TG) levels (p=9.9 x 10(-6)). Individuals homozygous for the INSIG1 promoter SNP rs2721 T allele had 9% higher triglyceride levels and 2-fold lower INSIG1 expression in liver samples compared with G allele homozygotes.
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