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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2319.)
© 2008 American Heart Association, Inc.

Clinical and Population Studies

ANGPTL4 E40K and T266M

Effects on Plasma Triglyceride and HDL Levels, Postprandial Responses, and CHD Risk

Philippa J. Talmud; Melissa Smart; Edward Presswood; Jackie A. Cooper; Viviane Nicaud; Fotios Drenos; Jutta Palmen; Michael G. Marmot; S. Matthijs Boekholdt; Nicholas J. Wareham; Kay-Tee Khaw; Meena Kumari; Steve E. Humphries on behalf of the EARSII Consortium and the HIFMECH Consortium

From the Division of Cardiovascular Genetics, Department of Medicine (P.J.T., M.S., E.P., J.A.C., F.D., J.P., S.E.H.), University College London Medical School, UK; INSERM, UMR S 525 (V.N.), Paris, France; Université Pierre et Marie Curie-Paris6 (V.N.), UMR S 525, Paris, France; the Department of Epidemiology and Public Health (M.G.M., M.K.), University College London, UK; the Department of Cardiology (S.M.B.), Academic Medical Center, Amsterdam, The Netherlands; MRC Epidemiology Unit (M.N.W.), Institute of Metabolic Science, Cambridge, UK; and the Department of Public Health and Primary Care (K.-T.K.), University of Cambridge, UK.

Correspondence to Philippa J. Talmud, Division of Cardiovascular Genetics, Department of Medicine, University College London Medical School, 5 University St, London WC1E 6JF, United Kingdom. E-mail p.talmud{at}ucl.ac.uk

Background— Angiopoietin-like 4 is a dual-function protein: an inhibitor of LPL, influencing plasma triglycerides (TGs), with angiogenic properties. We examined the association of common ANGPTL4 variants with CHD traits and risk in 5 studies (13 527 individuals).

Methods and Results— The effects on plasma lipids of 6 tagging SNPs and the recently identified E40K were examined in a study of 2772 men. Only T266M (rs1044250, MAF=30%) and E40K (MAF=2%) were significantly associated with TG-lowering (–10.4%, P<0.004 and –20.4%, P<0.0001), respectively. T266M no longer showed significant associations when K40 carriers (K40+) were excluded (P=0.2). Combining data from 5 studies confirmed the TG-lowering effect of K40+ (weighted mean difference: –0.12 [95% CI –0.18, –0.05] mmol/L TG P=0.0001). Surprisingly, in the 3 prospective studies, the combined OR for CHD was 1.48 (1.11 to 1.96, P=0.007), independent of TG. In individuals with a paternal history of MI (n=332) T266M, but not E40K, showed effects on postprandial AUC TG and glucose (P=0.009 and P=0.017, respectively) compared to controls (n=370).

Conclusion— Although associated with an atheroprotective lipid profile, E40K was associated with increased CHD risk, suggesting Angptl4 influences parameters beyond lipid levels. T266M showed effects only under conditions of postprandial stress. The functionality of these potential "loss-of-function" variants needs validation.

Examination 7 ANGPTL4 SNPs on the pooled data from 5 studies (>13 500 individuals) showed only E40K with consistent TG-lowering and HDL-raising effects, yet associated with increased CHD risk, independent of TG levels. T266M showed effects on postprandial responses. Functional studies on these 2 "loss of function" SNPs are necessary.

Key Words: ANGPTL4 • LPL • inhibition • angiogenesis • E40K • T266M • postprandial responses

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