Variation at the angiotensin-converting enzyme and endothelial nitric oxide synthase genes is associated with the risk of esophageal varices among patients with alcoholic cirrhosis

Esophageal varices are a frequent complication among patients with liver cirrhosis. Nitric oxide and other vasoactive molecules regulate the vascular tone in both the liver microcirculation and the systemic and splanchnic circulation. Several genes that encode proteins involved in the maintenance of vascular tone, such as the endothelial-constitutive nitric oxide synthase (ecNOS), the angiotensinogen (AGT), the angiotensin-converting enzyme DACE), and the angiotensin II receptor type 1 (AT1R) are polymorphic, and these polymorphisms have been associated with several cardiovascular diseases. Our aim was to define a possible role for DNA polymorphisms at these genes in the risk of developing esophageal varices among patients with alcoholic cirrhosis. We analyzed 145 male patients with liver cirrhosis. Patients and 200 healthy controls were genotyped by polymerase chain reaction for the ACE-I/D, the AGT-M235T, the AT1R-A1166C, and the ecNOS-4/5 (intron 4) polymorphisms. Ninety-five patients had varices and 50 did not show this complication. Carriers of the ACE-I allele (ID + II genotypes) were at a significantly higher frequency among patients with varices (p = 0.013). Patients without varices had a higher frequency of the ecNOS-4 allele compared with patients with varices (p = 0.026). ACE-I carriers + ecNOS-55 were at a significantly higher frequency (p = 0.0012; odds ratio = IM 95% CI = 1.55-6.55) among patients with varices (51 of 95, 54%) compared with patients without (18 of 50, 36%). Allele and genotype frequencies for the AGT and AT1R polymorphisms did not differ between the two groups. The genotypes associated with an increased risk for varices have been linked to higher plasma levels of nitric oxide and reduced levels of ACE. These genotypes could have a vasodilatory effect in the systemic and splanchnic circulation, thus favoring the development of portocollaterals.