Common genetic variations of the renin-angiotensin-aldosterone system and response to acute angiotensin I-converting enzyme inhibition in essential hypertension.
OBJECTIVE
In order to get insight into possible genetic determinants of antihypertensive drug action, we analysed the relations between polymorphisms of the genes of the renin-angiotensin-aldosterone system and acute effects of ACE inhibition on blood pressure as well as circulating renin and aldosterone levels in hypertensive patients.


METHODS
A total of 315 hypertensive patients referred for problems in drug treatment were given a single 50 mg dose of captopril. Plasma renin and aldosterone were measured before and 60 min after the drug administration. Four DNA variants, including angiotensin type I receptor (AGTR1) 1166 A/C, angiotensin-converting enzyme (ACE) I/D, angiotensinogen (AGT) M235T and AGT -217 G/A, were genotyped in the patients and normotensive men (n = 175). A replication study on the relation between AGTR1 1166 A/C and plasma renin and aldosterone levels was carried out in the 244 hypertensive men of the pharmacogenetic GENRES Study.


RESULTS
Referred hypertensive patients with the AGTR1 CC genotype had higher aldosterone at baseline (P = 0.02) and after 60 min of captopril administration (P = 0.01) compared with the AA genotype. Replicate analysis in the GENRES patients showed a similar trend. When the two studies were combined (315 and 244 patients, respectively), plasma aldosterone level (P = 0.007) as well as aldosterone/renin ratio (P = 0.04) were significantly higher in the CC genotype (n = 13) than in the AA genotype (n = 370). Transfection studies in cultured HEK293 cells indicated that the 1166C allele was associated with higher mRNA levels than the 1166A allele.


CONCLUSIONS
The AGTR1 1166C allele when present in homozygous form may be associated with a form of essential hypertension characterized by high plasma aldosterone and low plasma renin levels, possibly due to increased AGTR1 mRNA levels and augmented angiotensin II action.
Hannila-Handelberg
Tuula
T
Department of Medicine, University of Helsinki, Helsinki, Finland.
Kontula
Kimmo K
KK
Paukku
Kirsi
K
Lehtonen
Jukka Y
JY
Virtamo
Jarmo
J
Tikkanen
Ilkka
I
Hiltunen
Timo P
TP
D000328:Adult; D000450:Aldosterone / Q000097:blood; D000483:Alleles; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000808:Angiotensinogen / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002216:Captopril / Q000494:pharmacology / Q000627:therapeutic use; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011945:Receptors, Angiotensin / Q000235:genetics / Q000627:therapeutic use; D012016:Reference Values; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D011945:Receptors, Angiotensin; D000808:Angiotensinogen; D000450:Aldosterone; D002216:Captopril; D012083:Renin