© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
G-250A Substitution in Promoter of Hepatic Lipase Gene Is Associated With Dyslipidemia and Insulin Resistance in Healthy Control Subjects and in Members of Families With Familial Combined Hyperlipidemia
From the Department of Medicine (J.P., L.K., P.K., I.V., M.L.), University of Kuopio, Kuopio, Finland; the Department of Medicine (M.-R.T.), University of Helsinki, Helsinki, Finland; and the Departments of Medicine and Genetics (S.S.D.), University of Washington, Seattle.
Correspondence to Markku Laakso, MD, Professor and Chair, Department of Medicine, University of Kuopio, 70210 Kuopio, Finland. E-mail markku.laakso{at}uku.fi
Abstract—Low activity of hepatic lipase (HL) has been associated with high levels of triglycerides and high density lipoproteins, but the association of the HL promoter variants with insulin sensitivity has not been investigated. Therefore, in this study, the relationship of the G-250A promoter variant of the HL gene to the rates of insulin-stimulated glucose uptake measured by the hyperinsulinemic euglycemic clamp was investigated in 110 control subjects (82 men and 28 women, aged 50.7±7.6 [mean±SD] years, body mass index 26.1±3.6 kg/m2) and in 105 first-degree relatives (65 men and 40 women, aged 47.8±16.0 years, body mass index 26.9±5.3 kg/m2) of 34 families with familial combined hyperlipidemia (FCHL). The A-250 allele of the HL promoter was associated with low rates of insulin-stimulated whole-body nonoxidative glucose disposal in control subjects (41.1±12.7 µmol · kg-1 · min-1 in subjects with the G-250G genotype, 36.9±13.1 µmol · kg-1 · min-1 in subjects with the G-250A genotype, and 29.9±13.5 µmol · kg-1 · min-1 in subjects with the A-250A genotype; P=0.012 adjusted for age and sex) and with low rates of insulin-stimulated whole-body glucose oxidation in FCHL family members (16.7±4.2 versus 15.0±4.4 versus 14.1±4.4 µmol · kg-1 · min-1, P=0.024). In addition, the A-250 allele was associated with high levels of fasting insulin (P=0.047), very low density lipoprotein cholesterol (P=0.007), and total (P=0.009) and very low density lipoprotein (P=0.005) triglycerides in control subjects and with high levels of low density lipoprotein triglycerides (P=0.001) in FCHL family members (n=340). We conclude that the G-250A promoter variant of the HL gene is associated with dyslipidemia and insulin resistance. Mechanisms via which this polymorphism could affect insulin sensitivity remain to be elucidated.
Key Words: hepatic lipase • insulin resistance • familial combined hyperlipidemia • hypertriglyceridemia
This article has been cited by other articles:
 |
|
 |
|
  J. Healy, H. Belanger, P. Beaulieu, M. Lariviere, D. Labuda, and D. Sinnett Promoter SNPs in G1/S checkpoint regulators and their impact on the susceptibility to childhood leukemia Blood, January 15, 2007; 109(2): 683 - 692. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Belanger, P. Beaulieu, C. Moreau, D. Labuda, T. J. Hudson, and D. Sinnett Functional promoter SNPs in cell cycle checkpoint genes Hum. Mol. Genet., September 15, 2005; 14(18): 2641 - 2648. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Stefan, S. Schafer, F. Machicao, J. Machann, F. Schick, C. D. Claussen, M. Stumvoll, H.-U. Haring, and A. Fritsche Liver Fat and Insulin Resistance Are Independently Associated with the -514C>T Polymorphism of the Hepatic Lipase Gene J. Clin. Endocrinol. Metab., July 1, 2005; 90(7): 4238 - 4243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Gomez, F. Perez-Jimenez, C. Marin, J. A. Moreno, M. J. Gomez, C. Bellido, P. Perez-Martinez, F. Fuentes, J. A. Paniagua, and J. Lopez-Miranda The -514 C/T polymorphism in the hepatic lipase gene promoter is associated with insulin sensitivity in a healthy young population J. Mol. Endocrinol., April 1, 2005; 34(2): 331 - 338. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. F. Lewis, S. Murdoch, K. Uffelman, M. Naples, L. Szeto, A. Albers, K. Adeli, and J. D. Brunzell Hepatic Lipase mRNA, Protein, and Plasma Enzyme Activity Is Increased in the Insulin-Resistant, Fructose-Fed Syrian Golden Hamster and Is Partially Normalized by the Insulin Sensitizer Rosiglitazone Diabetes, November 1, 2004; 53(11): 2893 - 2900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Shuldiner, N. Hoppman, and T. I. Pollin Hepatic Lipase Genotype, Diabetes Risk, and Implications for Preventative Medicine J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2015 - 2018. [Full Text] [PDF]
|
|
|
|
|
|
B. Todorova, A. Kubaszek, J. Pihlajamaki, J. Lindstrom, J. Eriksson, T. T. Valle, H. Hamalainen, P. Ilanne-Parikka, S. Keinanen-Kiukaanniemi, J. Tuomilehto, et al. The G-250A Promoter Polymorphism of the Hepatic Lipase Gene Predicts the Conversion from Impaired Glucose Tolerance to Type 2 Diabetes Mellitus: The Finnish Diabetes Prevention Study J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2019 - 2023. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ueno, J. Tremblay, J. Kunes, J. Zicha, Z. Dobesova, Z. Pausova, A. Y. Deng, Y.-L. Sun, H. J. Jacob, and P. Hamet Rat model of familial combined hyperlipidemia as a result of comparative mapping Physiol Genomics, March 12, 2004; 17(1): 38 - 47. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Austin, K. L. Edwards, S. A. Monks, K. M. Koprowicz, J. D. Brunzell, A. G. Motulsky, M. C. Mahaney, and J. E. Hixson Genome-wide scan for quantitative trait loci influencing LDL size and plasma triglyceride in familial hypertriglyceridemia J. Lipid Res., November 1, 2003; 44(11): 2161 - 2168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E S. Tai, D. Corella, M. Deurenberg-Yap, J. Cutter, S. K. Chew, C. E. Tan, and J. M. Ordovas Dietary Fat Interacts with the -514C>T Polymorphism in the Hepatic Lipase Gene Promoter on Plasma Lipid Profiles in a Multiethnic Asian Population: The 1998 Singapore National Health Survey J. Nutr., November 1, 2003; 133(11): 3399 - 3408. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Soro, M. Jauhiainen, C. Ehnholm, and M.-R. Taskinen Determinants of low HDL levels in familial combined hyperlipidemia J. Lipid Res., August 1, 2003; 44(8): 1536 - 1544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Conde-Knape, A. Bensadoun, J. H. Sobel, J. S. Cohn, and N. S. Shachter Overexpression of apoC-I in apoE-null mice: severe hypertriglyceridemia due to inhibition of hepatic lipase J. Lipid Res., December 1, 2002; 43(12): 2136 - 2145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Su, S. Zhang, D. W. Nebert, L. Zhang, D. Huang, Y. Hou, L. Liao, and C. Xiao A novel allele in the promoter of the hepatic lipase is associated with increased concentration of HDL-C and decreased promoter activity J. Lipid Res., October 1, 2002; 43(10): 1595 - 1601. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jansen, A. J. M. Verhoeven, and E. J. G. Sijbrands Hepatic lipase: a pro- or anti-atherogenic protein? J. Lipid Res., September 1, 2002; 43(9): 1352 - 1362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Perret, L. Mabile, L. Martinez, F. Terce, R. Barbaras, and X. Collet Hepatic lipase: structure/function relationship, synthesis, and regulation J. Lipid Res., August 1, 2002; 43(8): 1163 - 1169. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Pihlajamaki, M. Austin, K. Edwards, and M. Laakso A Major Gene Effect on Fasting Insulin and Insulin Sensitivity in Familial Combined Hyperlipidemia Diabetes, October 1, 2001; 50(10): 2396 - 2401. [Abstract] [Full Text]
|
|
|
|
|
|
L.-L. HSIAO, F. DANGOND, T. YOSHIDA, R. HONG, R. V. JENSEN, J. MISRA, W. DILLON, K. F. LEE, K. E. CLARK, P. HAVERTY, et al. A compendium of gene expression in normal human tissues Physiol Genomics, December 21, 2001; 7(2): 97 - 104. [Abstract] [Full Text] [PDF]
|
|