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Open Access Research article

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

Melissa C Smart-Halajko1*, Alyson Kelley-Hedgepeth2, Maria Claudia Montefusco2, Jackie A Cooper1, Alan Kopin2, Jeanne M McCaffery3, Ashok Balasubramanyam4, Henry J Pownall4, David M Nathan5, Inga Peter6, Philippa J Talmud1, Gordon S Huggins2* and the Look AHEAD Study

Author Affiliations

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

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BMC Medical Genetics 2011, 12:89  doi:10.1186/1471-2350-12-89

Published: 29 June 2011



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.


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.


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.


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.