Interactions between the single nucleotide polymorphisms in the homocysteine pathway (MTHFR 677C>T, MTHFR 1298 A>C, and CBSins) and the efficacy of HMG-CoA reductase inhibitors in preventing cardiovascular disease in high-risk patients of hypertension: the GenHAT study.
BACKGROUND
High homocysteine blood concentrations predispose to coronary artery disease and statins influence homocysteine levels.


OBJECTIVE
To study whether genes that regulate homocysteine metabolism interact with statins to modify the risk of coronary heart disease (CHD) and other cardiovascular outcomes.


METHODS
The Genetics of Hypertension Associated Treatment is an ancillary study of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). 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 and CHD was compared among genotype strata (MTHFR 677 CC, CT, and TT, MTHFR 1298 AA, AC, and CC, CBSins DD and I) by examining an interaction term in a proportional hazards model.


RESULTS
No evidence existed of a pharmacogenetic effect on statins with the MTHFR 1298 A>C genotype for CHD risk. However, in persons with the CC variant for the MTHFR 677 C>T genotype, a significantly protective effect against CHD [0.71 (95% CI 0.58-0.87)] was shown, although in the CT [1.25 (95% CI 0.97-1.61)] and TT groups [0.80 (95% CI 0.50-1.28)] there were no such effects (interaction hazard ratio P=0.004). The CBSins, I+ variant was associated with a significantly reduced risk for CHD among those on statin treatment [0.58 (95% CI 0.44-0.78)] whereas the DD genotype showed no effect of statin therapy [1.01 (95% CI 0.84-1.20; P=0.002 for interaction]. For the endpoint all-cause mortality, no significant differences in efficacy were noted.


CONCLUSIONS
Polymorphisms in genes in the homocysteine pathway (MTHFR 677 C>T and CBSins) appear 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 Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands. a.h.maitland@uu.nl
Lynch
Amy
A
Boerwinkle
Eric
E
Arnett
Donna K
DK
Davis
Barry R
BR
Leiendecker-Foster
Catherine
C
Ford
Charles E
CE
Eckfeldt
John H
JH
D000368:Aged; D005260:Female; D020022:Genetic Predisposition to Disease; D006710:Homocysteine / Q000235:genetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000517:prevention & control*; D053208:Kaplan-Meier Estimate; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016896:Treatment Outcome
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)