Smith, Edward M., Zhang, Y., Baye, T. M., Gawrieh, S., Cole, R., Blangero, J., Carless, Melanie A., Curran, Joanne E., Dyer, T. D., Abraham, L. J., Moses, E. K. (Eric Keith), Kissebah, Ahmed, Martin, L. J. (Lisa J.) and Olivier, M. (Michael) (2010) INSIG1 influences obesity-related hypertriglyceridemia in humans. Journal of Lipid Research, Vol.51 . pp. 701-708. doi:10.1194/jlr.M001404 ISSN 0022-2275.

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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 × 10−3 in 1,560 individuals of the original linkage cohort, P = 8 × 10−4 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.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history > QH426 Genetics R Medicine > RC Internal medicine
Divisions:	Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) > Biological Sciences ( -2010)
Library of Congress Subject Headings (LCSH):	Hypertriglyceridemia -- Genetic aspects, Triglycerides, Gene expression
Journal or Publication Title:	Journal of Lipid Research
Publisher:	American Society for Biochemistry and Molecular Biology, Inc.
ISSN:	0022-2275
Official Date:	April 2010
Dates:	Date Event April 2010 Published
Volume:	Vol.51
Page Range:	pp. 701-708
DOI:	10.1194/jlr.M001404
Status:	Peer Reviewed
Access rights to Published version:	Restricted or Subscription Access
Funder:	National Institutes of Health (U.S.) (NIH)
Grant number:	HL74168 (NIH)

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