Aldosterone synthase (CYP11B2)-344T/C polymorphism and renoprotective response to losartan treatment in diabetic nephropathy.
OBJECTIVE
It has been suggested that an aldosterone synthase gene polymorphism (CYP11B2 -344T/C) is predictive of the blood pressure lowering effect of angiotensin II receptor blockers in essential hypertension. We investigated whether this polymorphism is predictive of reductions in blood pressure and albuminuria and preservation of glomerular filtration rate (GFR) during short-term and long-term treatment with losartan in 57 hypertensive type-1 diabetic patients with diabetic nephropathy.


METHODS
After a 4-week washout period, patients received losartan (100 mg o.d.) and were followed for a mean follow-up of 36 months. At baseline, after 2 and 4 months, and every 6 months thereafter, GFR (51Cr-EDTA-clearance), albuminuria and 24-h blood pressure were determined. The CYP11B2 -344T/C polymorphism was determined by standard polymerase chain reaction (PCR).


RESULTS
The TT, CT and CC genotypes were found in 28 %, 58 % and 14 % of patients, respectively. At baseline albuminuria and blood pressure did not differ between genotype groups. Plasma aldosterone levels (geometric mean (95 % CI)) were similar at baseline: 87 (60-125), 77 (53-112), and 89 (49-161) pg mL(-1) and during follow-up (not significant). After initiation of losartan treatment, comparable mean (SE) reductions in blood pressure and albuminuria were seen in patients with TT, CT and CC genotypes (p >0.6 between groups). After long-term follow-up, there was a tendency towards a difference in systolic blood pressure reduction (p = 0.07, one-way ANOVA), suggesting a poorer response in patients with the CC genotype. No significant difference in rate of decline in GFR (median (range)) was seen between groups (TT, CT, CC): 4.2 (-1.0 to 16.0), 3.2 (-1.6 to 13.8) and 2.6 (-0.1 to 11.0) mL min(-1)year(-1), respectively (p = 0.5).


CONCLUSIONS
Compared to a previous smaller study of angiotensin II receptor blockade in essential hypertension, we could not confirm that CYP11B2 -344T/C genotypes contribute towards explaining the observed variability in response to treatment with angiotensin II receptor blockers, which could be due to lack of power.
Schjoedt
K J
KJ
Steno Diabetes Center, Gentofte, Denmark.
Lajer
M
M
Andersen
S
S
Tarnow
L
L
Rossing
P
P
Parving
H-H
HH
D000328:Adult; D000419:Albuminuria / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012084:Renin-Angiotensin System / Q000187:drug effects; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D019405:Cytochrome P-450 CYP11B2; D019808:Losartan