ANGPTL4 E40K and T266M: effects on plasma triglyceride and HDL levels, postprandial responses, and CHD risk.
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.
Talmud
Philippa J
PJ
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
Smart
Melissa
M
Presswood
Edward
E
Cooper
Jackie A
JA
Nicaud
Viviane
V
Drenos
Fotios
F
Palmen
Jutta
J
Marmot
Michael G
MG
Boekholdt
S Matthijs
SM
Wareham
Nicholas J
NJ
Khaw
Kay-Tee
KT
Kumari
Meena
M
Humphries
Steve E
SE
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*
C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D008075:Lipoproteins, HDL; D014280:Triglycerides