ANGPTL4 variants E40K and T266M are associated with lower fasting triglyceride levels in Non-Hispanic White Americans from the Look AHEAD Clinical Trial

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• 作者：Melissa C Smart-Halajko (1)
  Alyson Kelley-Hedgepeth (2)
  Claudia Maria Montefusco (2)
  Jackie A Cooper (1)
  Alan Kopin (2)
  Jeanne M McCaffrey (3)
  Ashok Balasubramanyam (4)
  Henry J Pownall (4)
  David M Nathan (5)
  Inga Peter (6)
  Philippa J Talmud (1)
  Gordon S Huggins (2)
  
• 刊名：BMC Medical Genetics
• 出版年：2011
• 出版时间：December 2011
• 年：2011
• 卷：12
• 期：1
• 全文大小：227KB
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  4. Pi-Sunyer X, Blackburn G, Brancati FL, Bray GA, Bright R, Clark JM, Curtis JM, Espeland MA, Foreyt JP, Graves K, / et al.: Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. / Diabetes Care 2007,30(6):1374-383. CrossRef
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  11. Romeo S, Pennacchio LA, Fu Y, Boerwinkle E, Tybjaerg-Hansen A, Hobbs HH, Cohen JC: Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. / Nat Genet 2007,39(4):513-16. CrossRef
  12. Talmud PJ, Smart M, Presswood E, Cooper JA, Nicaud V, Drenos F, Palmen J, Marmot MG, Boekholdt SM, Wareham NJ, / et al.: ANGPTL4 E40K and T266M: effects on plasma triglyceride and HDL levels, postprandial responses, and CHD risk. / Arterioscler Thromb Vasc Biol 2008,28(12):2319-325. CrossRef
  13. Bray G, Gregg E, Haffner S, Pi-Sunyer XF, WagenKnecht LE, Walkup M, Wing R: Baseline characteristics of the randomised cohort from the Look AHEAD (Action for Health in Diabetes) study. / Diab Vasc Dis Res 2006,3(3):202-15. CrossRef
  14. Ryan DH, Espeland MA, Foster GD, Haffner SM, Hubbard VS, Johnson KC, Kahn SE, Knowler WC, Yanovski SZ: Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes. / Control Clin Trials 2003,24(5):610-28. CrossRef
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  19. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2350/12/89/prepub
  
• 作者单位：Melissa C Smart-Halajko (1)
  Alyson Kelley-Hedgepeth (2)
  Claudia Maria Montefusco (2)
  Jackie A Cooper (1)
  Alan Kopin (2)
  Jeanne M McCaffrey (3)
  Ashok Balasubramanyam (4)
  Henry J Pownall (4)
  David M Nathan (5)
  Inga Peter (6)
  Philippa J Talmud (1)
  Gordon S Huggins (2)
  
  1. Division of Cardiovascular Genetics, British Heart Foundation Laboratories, Department of Medicine, Royal Free and UCL Medical School, London, UK
  2. MCRI Center for Translational Genomics, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA, USA
  3. Weight Control and Diabetes Research Center, Department of Psychiatry and Human behavior, The Miriam Hospital and Brown Medical School, Providence, RI, USA
  4. Baylor College of Medicine, Houston, TX, USA
  5. Diabetes Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  6. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, USA
  
• ISSN：1471-2350

文摘

Background Elevated triglyceride levels are a risk factor for cardiovascular disease. Angiopoietin-like protein 4 (Angptl4) is a metabolic factor that raises plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). In non-diabetic individuals, the ANGPTL4 coding variant E40K has been associated with lower plasma triglyceride levels while the T266M variant has been associated with more modest effects on triglyceride metabolism. The objective of this study was to determine whether ANGPTL4 E40K and T266M are associated with triglyceride levels in the setting of obesity and T2D, and whether modification of triglyceride levels by these genetic variants is altered by a lifestyle intervention designed to treat T2D. Methods The association of ANGPTL4 E40K and T266M with fasting triglyceride levels was investigated in 2,601 participants from the Look AHEAD Clinical Trial, all of whom had T2D and were at least overweight. Further, we tested for an interaction between genotype and treatment effects on triglyceride levels. Results Among non-Hispanic White Look AHEAD participants, ANGPTL4 K40 carriers had mean triglyceride levels of 1.61 ± 0.62 mmol/L, 0.33 mmol/L lower than E40 homozygotes (p = 0.001). Individuals homozygous for the minor M266 allele (MAF 30%) had triglyceride levels of 1.75 ± 0.58 mmol/L, 0.24 mmol/L lower than T266 homozygotes (p = 0.002). The association of the M266 with triglycerides remained significant even after removing K40 carriers from the analysis (p = 0.002). There was no interaction between the weight loss intervention and genotype on triglyceride levels. Conclusions This is the first study to demonstrate that the ANGPTL4 E40K and T266M variants are associated with lower triglyceride levels in the setting of T2D. In addition, our findings demonstrate that ANGPTL4 genotype status does not alter triglyceride response to a lifestyle intervention in the Look AHEAD study.