title: ANGPTL4 E40K and T266M: effects on plasma triglyceride and HDL levels, postprandial responses, and CHD risk.
abstract: 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).
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Cardiovascular Genetics, Department of Medicine, University College London Medical School, 5 University St, London WC1E 6JF, United Kingdom. p.talmud@ucl.ac.uk
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: Melissa
authors.initials: M
authors.lastname: Smart
authors.forename: Edward
authors.initials: E
authors.lastname: Presswood
authors.forename: Jackie A
authors.initials: JA
authors.lastname: Cooper
authors.forename: Viviane
authors.initials: V
authors.lastname: Nicaud
authors.forename: Fotios
authors.initials: F
authors.lastname: Drenos
authors.forename: Jutta
authors.initials: J
authors.lastname: Palmen
authors.forename: Michael G
authors.initials: MG
authors.lastname: Marmot
authors.forename: S Matthijs
authors.initials: SM
authors.lastname: Boekholdt
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
mesh_terms: D000328:Adult; D000368:Aged; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D003327:Coronary Disease / Q000097:blood / Q000209:etiology* / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019518:Postprandial Period / Q000235:genetics / Q000502:physiology; D011446:Prospective Studies; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood*
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D008075:Lipoproteins, HDL; D014280:Triglycerides