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INSIG1 influences obesity-related hypertriglyceridemia in humans

By Edward M. Smith, Y. Zhang, T. M. Baye, S. Gawrieh, R. Cole, J. Blangero, Melanie A. Carless, Joanne E. Curran, T. D. Dyer, L. J. Abraham, E. K. (Eric Keith) Moses, Ahmed Kissebah, L. J. (Lisa J.) Martin and M. (Michael) Olivier


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. \ud \u

Topics: QH426, RC
Publisher: American Society for Biochemistry and Molecular Biology, Inc.
Year: 2010
OAI identifier:

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  8. (1991). An in vitro transcription analysis of early responses of the human immunodeficiency virus type 1 long terminal repeat to different transcriptional activators.
  9. (1997). Cloning, human chromosomal assignment, and adipose and hepatic expression of the CL-6/INSIG1 gene. doi
  10. (2005). Combining probability from independent tests: the weighted Z-method is superior to Fisher's approach. doi
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  12. (2002). Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. doi
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  14. (2005). Efficiency and power in genetic association studies. doi
  15. environmental influences on serum lipid levels in twins. doi
  16. (2000). Evidence for a gene influencing the TG/HDL-C ratio on chromosome 7q32.3-qter: a genome-wide scan in the Framingham study. doi
  17. (1997). Familial resemblance of plasma lipids, lipoproteins and postheparin lipoprotein and hepatic lipases in the HERITAGE Family Study. Arterioscler Thromb Vasc Biol. doi
  18. (2008). Feedback regulation of cholesterol synthesis: sterolaccelerated ubiquitination and degradation of HMG CoA reductase. doi
  19. (2004). Genetic determinants of obesity-related lipid traits.
  20. (2003). Genome-wide scan on plasma triglyceride and high density lipoprotein cholesterol levels, accounting for the effects of correlated quantitative phenotypes. doi
  21. (2009). Genomic Convergence of GenomewideInvestigations for Complex Traits. Ann Hum Genet.2009 Jul 9. [Epub ahead of print]. b y g u e s t , o n N o v e m b e r , w w w . j l r . o r g D o w n l o a d e d f r o m
  22. (2005). Haploview: analysis and visualization of LD and haplotype maps. doi
  23. (2002). High-throughput genotyping of single nucleotide polymorphisms using new biplex invader technology. doi
  24. (2008). Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in doi
  25. (2008). INSIG2 gene rs7566605 polymorphism is associated with severe obesity in Japanese. doi
  26. (1981). Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein-B kinetics in man: normolipemic subjects, familial hypertriglyceridemia and familial combined hyperlipidemia. doi
  27. (1989). Introduction to Quantitative Genetics. doi
  28. (1999). Isolated low HDL cholesterol: an insulin-resistant state only in the presence of fasting hypertriglyceridemia. doi
  29. (1999). Loci on chromosome 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans.
  30. (1998). Multipoint quantitative-trait linkage analysis in general pedigrees. doi
  31. (1993). Novel delayed-early and highly insulin-induced growth response genes. Identification of HRS, a potential regulator of alternative pre-mRNA splicing.
  32. (2003). Overexpression of sterol regulatory element-binding protein-1a in mouse adipose tissue produces adipocyte hypertrophy, increased fatty acid secretion, and fatty liver. doi
  33. (2002). Pbx1 inactivation disrupts pancreas development and in Ipf1-deficient mice promotes diabetes mellitus. doi
  34. (1997). PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescencebased resequencing. doi
  35. (1999). Prevalence of high plasma triglyceride combined with low HDL-C levels and its association with smoking, hypertension, obesity, diabetes, sedentariness and LDL-C levels in the Canadian population. Canadian Heart Health Surveys Research Group.
  36. (2006). Protein sensors for membrane sterols. doi
  37. (2000). Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. doi
  38. (1987). Risk factors for coronary heart disease in adult female twins. Genetic heritability and shared environmental influences.
  39. (2005). Schoenheimer effect explained--feedback regulation of cholesterol synthesis in mice mediated by Insig proteins. doi
  40. (2002). SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. doi
  41. (2007). Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Oxysterols block transport by binding to Insig. doi
  42. (2005). The Invader assay for SNP genotyping. Mutat Res. 573: 103-110. b y g u e s t , o n N o v e m b e r , w w w . j l r . o r g D o w n l o a d e d f r o m doi
  43. (2008). The single nucleotide polymorphism upstream of insulin-induced gene 2 ( INSIG2) is associated with the prevalence of hypercholesterolaemia, but not with obesity, in Japanese American women. doi
  44. (2001). Triglycerides: risk factor or fellow traveler? doi
  45. (2002). Two independent apolipoprotein A5 haplotypes influence human plasma triglyceride levels. doi

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