CYP2C9 genotype modifies activity of the renin-angiotensin-aldosterone system in hypertensive men.
BACKGROUND
Two variants of the CYP2C9 gene, CYP2C9*2 and CYP2C9*3, have been indicated to have impaired enzyme function, and thus suspected to reduce the formation of the active metabolite of losartan. Cytochrome P450 (CYP) enzymes are also involved in eicosanoid biosynthesis and regulation of blood pressure (BP) and sodium homeostasis.


METHODS
We studied the impact of these variants on BP response to losartan and three other antihypertensive drugs and on baseline indicators of the activity of the renin-angiotensin-aldosterone system. The participants were 217 moderately hypertensive Finnish men that participated in the double-blind, cross-over, placebo-controlled GENRES Study.


RESULTS
BP responses to losartan did not differ between CYP2C9*2 or CYP2C9*3 allele carriers and CYP2C9*1*1 patients. A suggestive finding of less pronounced ambulatory BP response to losartan in CYP2C9*1*3 patients with low-normal kidney function was made. At baseline of the GENRES Study, CYP2C9*1*3 patients had significantly lower plasma renin activity and aldosterone levels than CYP2C9*1*1 patients (both P values 0.004). In a replication study in patients with treatment-resistant hypertension, men with CYP2C9*3 allele also had lower plasma renin activity (P = 0.03) and aldosterone levels (P = 0.18). In addition, these men had attenuated renin and aldosterone responses in captopril challenge test (P = 0.29 and 0.006, respectively).


CONCLUSIONS
The CYP2C9*3 allele was associated with lower activity of the renin-angiotensin-aldosterone system in hypertensive men, which may reflect a more efficient sodium reabsorption capacity. CYP2C9*2 and CYP2C9*3 alleles do not influence the antihypertensive effect of losartan in men with essential hypertension and normal kidney function.
Donner
Kati M
KM
Department of Medicine, University of Helsinki, FIN-00029 Helsinki, Finland.
Hiltunen
Timo P
TP
Suonsyrjä
Timo
T
Hannila-Handelberg
Tuula
T
Tikkanen
Ilkka
I
Antikainen
Miia
M
Hirvonen
Ari
A
Kontula
Kimmo
K
D000328:Adult; D000450:Aldosterone / Q000097:blood; D017311:Amlodipine / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D017298:Bisoprolol / Q000627:therapeutic use; D018592:Cross-Over Studies; D065729:Cytochrome P-450 CYP2C9; D004311:Double-Blind Method; D004351:Drug Resistance / Q000235:genetics; D004573:Electrolytes / Q000097:blood; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000235:genetics*; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010919:Placebos; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics
D000959:Antihypertensive Agents; D004573:Electrolytes; D010919:Placebos; D017311:Amlodipine; D000450:Aldosterone; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D012083:Renin; D019808:Losartan; D017298:Bisoprolol