Activated factor XII levels and factor XII 46C>T genotype in relation to coronary artery calcification in patients with type 1 diabetes and healthy subjects.
The relationship of activated factor XII (FXIIa) and FXII 46C>T genotype to coronary atherosclerosis and endothelial function was examined in 192 randomly sampled subjects from the general population and 190 type 1 diabetic subjects (mean age 38+/-4 years). Coronary artery calcification (CAC) was measured using Electron beam CT. von Willebrand factor (vWF), a marker of endothelial function, and FXIIa were measured by ELISA. Endothelial nitric oxide production was quantified as the forearm blood flow response to intra-brachial infusion of bradykinin and N(G) monomethyl-L-arginine (L-NMMA). A higher FXIIa was independently associated with higher triglycerides (P<0.001), BMI (P=0.001), alcohol consumption (P=0.003) and vWF (P<0.001) in non-diabetic subjects and with insulin dose (P=0.009), total cholesterol (P=0.02) and alcohol (P<0.001) in diabetic subjects. Diabetic subjects had lower FXIIa (1.55 ng/ml) than non-diabetic subjects (1.92 ng/ml, P<0.001). Higher FXIIa was associated with lower response to bradykinin (P=0.048) and to L-NMMA (P=0.029). FXIIa was positively associated with CAC (odds ratio=1.57 for every 1 ng/ml higher FXIIa, P=0.005) but not independently of other risk factors (odds ratio=1.1 on adjustment). 46C>T genotype explained 18% of the variance in FXIIa (P<0.001) but was not associated with CAC (P=0.6). We conclude that plasma FXIIa is under strong genetic control but also reflects plasma triglycerides and endothelial activation or dysfunction. FXIIa appears unlikely to be directly atherogenic but may be a useful marker of coronary atherosclerosis because of its association with these other factors. Type 1 diabetes is associated with lower levels of FXIIa despite a greater prevalence of atherosclerosis.
Colhoun
Helen M
HM
Department of Epidemiology and Public Health, EURODIAB, Royal Free and University College London Medical School, 1-19 Torrington Place, UK. helen@public-health.ucl.ac.uk
Zito
Francesco
F
Norman Chan
N
N
Rubens
Michael B
MB
Fuller
John H
JH
Humphries
Steve E
SE
D000328:Adult; D015415:Biomarkers / Q000032:analysis; D002114:Calcinosis / Q000209:etiology*; D003324:Coronary Artery Disease / Q000209:etiology; D003327:Coronary Disease / Q000209:etiology*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000503:physiopathology; D015956:Factor XIIa / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D011110:Polymorphism, Genetic; D011897:Random Allocation; D012306:Risk
D015415:Biomarkers; D009569:Nitric Oxide; D015956:Factor XIIa