The effect of nine common polymorphisms in coagulation factor genes (F2, F5, F7, F12 and F13 ) on the effectiveness of statins: the GenHAT study.
BACKGROUND
Pharmacogenetic research has shown that genetic variation may influence statin responsiveness. Statins exert a variety of beneficial effects beyond lipid lowering, including antithrombotic effects, which contribute to the risk reduction of cardiovascular disease. Statins have been shown to influence the expression of coagulation factors II, V, VII, XII and XIII.


OBJECTIVE
Data from a large randomized clinical trial of pravastatin, designed to show efficacy relative to usual care, were used to investigate whether a pharmacogenetic effect of polymorphisms in genes coding for coagulation factors II, V, VII, XII and XIII is associated with reduced fatal coronary heart disease (CHD) and nonfatal myocardial infarction, combined CHD and all-cause mortality.


METHODS
The Genetics of Hypertension Associated Treatment is an ancillary study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. The genotyped population in the lipid-lowering trial of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial included 9624 participants randomly assigned to pravastatin or to usual care. The efficacy of pravastatin in reducing risk of all-cause mortality, CHD and nonfatal myocardial infarction and combined CHD, was compared among genotype strata by examining an interaction term in a proportional hazards model.


RESULTS
None of the polymorphisms were associated with the clinical outcomes. For the F7 (-323) ins/del polymorphism there was no interaction with pravastatin for either outcome. For both the F5 Arg506Gln G>A (rs6025) polymorphism and F7 Arg353Gln G>A (rs6046) polymorphism there were no interactions with pravastatin in relation to all-cause mortality, but there were significant interactions with combined CHD [interaction hazard ratio = 1.33, 95% confidence interval (1.01-1.76) and interaction hazard ratio = 1.92, 95% confidence interval (1.00-3.65), respectively]. There were no interactions between the polymorphisms in the other coagulation genes and pravastatin in relation to any outcome.


CONCLUSIONS
Polymorphisms in anticoagulation genes (F5 and F7) seem to modify the efficacy of pravastatin in reducing risk of cardiovascular events.
Maitland-van der Zee
Anke-Hilse
AH
Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht University, Utrecht, The Netherlands. a.h.maitland@uu.nl
Peters
Bas J M
BJ
Lynch
Amy I
AI
Boerwinkle
Eric
E
Arnett
Donna K
DK
Cheng
Suzanne
S
Davis
Barry R
BR
Leiendecker-Foster
Catherine
C
Ford
Charles E
CE
Eckfeldt
John H
JH
D000368:Aged; D001779:Blood Coagulation Factors / Q000235:genetics*; D003327:Coronary Disease / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D017035:Pravastatin / Q000627:therapeutic use*; D016896:Treatment Outcome
D001779:Blood Coagulation Factors; D000960:Hypolipidemic Agents; D017035:Pravastatin