Genetic influence in antithrombotic actions of atorvastatin in hypercholesterolaemia.
BACKGROUND
Recent data indicate that statins could offer coronary artery disease (CAD) benefit even by mechanisms beyond lipid lowering. Genetic influence has been shown for some antithrombotic actions of statins via oxidized-low-density lipoprotein cholesterol (ox-LDL) receptors and nitric oxide synthase (NOS) activity modulation. The present study was designed to evaluate the influence of ox-LDL lectin-like receptor-1 (LOX-1) and NOS polymorphisms in the incidence of cardiovascular events in pure hypercholesterolaemic subjects during statin treatment.


METHODS
A prospective 4-year study involving 1039 event-free subjects (643 males, 396 females) treated with atorvastatin (10-40 mg day(-1)) to reach the appropriate Adult Treatment Panel-III LDL target of 3.36 mmol L(-1). Enrolled subjects were evaluated every 6 months or at a clinical event. LOX-1 3'UTR/T-C and NOS G894T polymorphisms were detected by allelic discrimination assays (polymerase chain reaction), lipid profile by enzymatic-colorimetric method, ox-LDL by enzyme linked immunosorbent assay, platelet activation by P-selectin (P-sel) expression (FACScan), NOS activity (by intracellular citrullin recovery) and homocysteine (high performance liquid chromatography), C-reactive protein (CRP) by sensitive nephelometric technique.


RESULTS
LOX-1 3'UTR/T showed the strongest association with events in the whole cohort with respect to each other variable including LDL reduction and NOS G894T (OR 4.90, 95% CI 3.19-6.98, P < 0.00001). Smoking influenced events in LDL-targeted subjects (P < 0.0001). Ox-LDL and P-sel were better indicators than LDL or other variables according to 3'UTR/C genotype regardless of the magnitude of LDL reduction (OR 4.21, 95% CI 2.29-6.70 P < 0.0001).


CONCLUSIONS
LOX-1 polymorphisms could influence statin effectiveness in CAD prevention by induction of sensitivity to antithrombotic mechanisms such as antiplatelet activity.
Puccetti
L
L
Department of Clinical Medicine and Immunology, Internal Medicine Division, Centre for Atherosclerosis Research, University of Siena, Siena, Italy. puccetti@unisi.it
Bruni
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Pasqui
A L
AL
Pastorelli
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M
Ciani
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F
Palazzuoli
A
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Acampa
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Auteri
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D000293:Adolescent; D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000097:blood / Q000627:therapeutic use; D000069059:Atorvastatin; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006538:Heptanoic Acids / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D019001:Nitric Oxide Synthase / Q000235:genetics; D011110:Polymorphism, Genetic; D011758:Pyrroles / Q000097:blood / Q000627:therapeutic use*; D051127:Scavenger Receptors, Class E / Q000235:genetics
D000924:Anticholesteremic Agents; D005343:Fibrinolytic Agents; D006538:Heptanoic Acids; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D011758:Pyrroles; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D000069059:Atorvastatin; D019001:Nitric Oxide Synthase