Renin-angiotensin system and alpha-adducin gene polymorphisms and their relation to responses to antihypertensive drugs: results from the GENRES study.
BACKGROUND
Polymorphisms in genes coding for components of the renin-angiotensin system (RAS) and alpha-adducin (ADD1) have been reported to be associated with blood pressure (BP) responses to antihypertensive agents. The results, however, have not been consistent and most of the earlier studies have been small and lacked placebo-control. Therefore, the association of common polymorphisms in these genes with BP responses to four different antihypertensive drugs was analyzed in a controlled study.


METHODS
The study included 208 hypertensive Finnish men from the GENRES study. All of them used amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide (HCT) 25 mg, and losartan 50 mg daily, each for 4 weeks as a monotherapy in a double-blind, randomized, study. The treatment periods were separated by 4-week placebo periods. Both 24-h ambulatory (ABP) and office BP (OBP) measurements were carried out. The polymorphisms analyzed were ADD1 Gly460Trp, angiotensinogen (AGT) Met235Thr, angiotensin converting enzyme (ACE) insertion/deletion (I/D), and angiotensin II type 1 receptor (AGTR1) 1166A/C.


RESULTS
The presence of 460Trp allele of ADD1, previously suggested to be a marker of thiazide responsiveness, did not predict a better response to HCT. There was no significant association of AGT Met235Thr, ACE I/D, and AGTR1 1166A/C polymorphisms with BP responses to the study drugs. ADD1 460Trp and AGT 235Thr alleles were associated with higher systolic white coat effect (WCE) during the placebo periods (P values 0.03 and 0.01, respectively).


CONCLUSIONS
Common polymorphisms of ADD1, AGT, ACE, and AGTR1 do not markedly predict BP responses to amlodipine, bisoprolol, HCT, and losartan, at least in white hypertensive men.
Suonsyrjä
Timo
T
Department of Medicine, University of Helsinki, Helsinki, Finland.
Hannila-Handelberg
Tuula
T
Fodstad
Heidi
H
Donner
Kati
K
Kontula
Kimmo
K
Hiltunen
Timo P
TP
D000328:Adult; D017311:Amlodipine / Q000627:therapeutic use; D000808:Angiotensinogen / Q000235:genetics; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D017298:Bisoprolol / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002148:Calmodulin-Binding Proteins / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use; D019808:Losartan / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D011110:Polymorphism, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics*; D000099291:Adducins
D017311:Amlodipine; D000808:Angiotensinogen; D000959:Antihypertensive Agents; D017298:Bisoprolol; D002148:Calmodulin-Binding Proteins; D006852:Hydrochlorothiazide; D019808:Losartan; D007703:Peptidyl-Dipeptidase A; D044140:Receptor, Angiotensin, Type 1; D000099291:Adducins