A1166C angiotensin II type 1 receptor gene polymorphism may predict hemodynamic response to losartan in patients with cirrhosis and portal hypertension.
OBJECTIVE
Losartan, a dose of 25 mg/day, has been found to be effective in 50% of patients with portal hypertension without adverse effects. We evaluated the relationship between genetic polymorphisms of the renin-angiotensin system (A1166C angiotensin II type 1 receptor (AT1R), angiotensinogen T174M and M235T, and angiotensin-converting enzyme I/D) and the effects of losartan on portal and systemic hemodynamic in patients with cirrhosis and portal hypertension.


METHODS
We performed a longitudinal study that included 23 consecutive patients with cirrhosis and esophageal varices who received 25 mg/day of losartan during 12 wk. Hepatic venous pressure gradient (HVPG) and systemic hemodynamic were measured at baseline and after treatment. Genomic DNA was extracted from peripheral blood leukocytes; genetic polymorphisms of the renin-angiotensin system were investigated by polymerase chain reaction and restriction fragment length polymorphisms.


RESULTS
The homozygous patients for AT1R A allele showed higher pulmonary-wedged and free hepatic venous pressure on baseline. After treatment, they showed a higher decrease of HVPG (32.5%+/- 19.2) in comparison with patients with AC/CC genotype (2.4%+/-18.9), p < 0.01. Ten of 15 patients with AA genotype were responders, while only one of eight with AC/CC genotype (p < 0.002); genotype AA showed a positive predictive value of 66.6% and negative predictive value of 87.5%.


CONCLUSIONS
These results suggest that there is a relationship between the AT1R A1166C polymorphisms and the therapeutic response to losartan. The genetic testing may be used as a predictive factor of this response.
Sookoian
Silvia
S
Cardiología Molecular, Instituto de Investigaciones Médicas A Lanari, Universidad de Buenos Aires, Buenos Aires, Argentina.
Castaño
Gustavo
G
García
Silvia I
SI
Viudez
Pedro
P
González
Claudio
C
Pirola
Carlos J
CJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D004932:Esophageal and Gastric Varices / Q000503:physiopathology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006975:Hypertension, Portal / Q000503:physiopathology*; D008102:Liver Circulation / Q000187:drug effects; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000503:physiopathology*; D008137:Longitudinal Studies; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan