The Association Between The Effect Of Propranolol To Prevent Esophageal Varices Bleeding And The β2-adrenergic Receptor Gene Single Nucleotide Polymorphisms

Background and Aim Esophagogastric variceal bleeding (EVB) is one of the severecomplications of decompensated liver cirrhosis and is associated with an increasedrisk of bleeding. With the progress of illness and the severity of liver dysfunction, therisk of variceal bleeding will significant increases, which is associated with anincreased risk of death. Clinically, there exists a variety of methods to prevent varicealbleeding. As to drug administration, the β2adrenergic receptor blocker(NSBB)propranolol announces an accurate effect, which is the most commonly used drugs forpreventing esophageal variceal bleeding. Previous studies found that propranolol havea reliable effect to prevent first variceal bleeding, which was shown to be as effectiveas endoscopic variceal ligation (EVL) and endoscopic injection sclerosis (EIS).However, other studies indicated that, the effect of propranolol to prevent varicealbleeding shown an obvious discrepancy individually. A certain part of patients whotake the maximal tolerated dose of propranolol still suffer from bleeding frequently,and there also doesn’t display a significant decrease in the level of hepatic venouspressure gradient (HVPG). Some studies show that the β2AR displays a lot of singlenucleotide polymorphisms(SNPs) in different gene site, especially the two mutationsin β2AR gene+46site and+79site, which play the most important role in thedetermination of drug effectiveness. However, this previous study only evaluates anacute HVPG response difference after short-term propranolol therapy according toβ2-adrenergic receptor gene SNPs, which never take account of a long-term outcome, that is, the difference of bleeding rate among these different genotype. Therefore, theaim of our study is to evaluate the association between β2-AR in+46and+79siteSNPs and the effect of long-term propranolol to prevent variceal bleeding.Methods A group of64cirrhotic patients who were in-hospital from2010to2012were involved in the study. The β2-AR gene SNPs, Arg16Gly and Gln27Glu, wereanalyzed by allele-specific Polymerase Chain Reaction (PCR). All the subjectsaccepted a therapy of oral propranolol and a follow-up as long as fifteen-months torecord the esopide of variceal bleeding or not. The basal conditions and endoscopicfindings were also recorded to evaluate drug effect.Results The basal conditions in each group don’t show a significant change afterpropranolol administration. During the period of follow-up,22(34.38%) patientssuffer from variceal bleeding. In the46site of β2-adrenergic gene, the rate of bleedingdisplay an obvious difference(Arg16Arg71.43%, Arg16Gly36.84%, Gly16Gly15.79%(P=0.025), respectively), however, which is not between groups in79site.The average bleeding-times among three groups in46site is also without change,nevertheless, the level in Arg16Arg(1.60±0.55) group is more than that in Arg16Glygroup(1.21±0.43) and Gly16Gly group(1.33±0.58) obviously. The analysis of linkedgene indicates that patients who share an Arg16Arg-Gln27Glu genotype exert ahighest rate of bleeding than who share an Arg16Gly-Gln27Glu orGly16Gly-Gln27Glu genotype(71.43%、35.29%and21.43%, respectively), however,the average bleeding-times among these groups don’t have a significant difference.The medium time of first-bleeding after propranolol therapy displays a sharp put-offin both Gly16Gly group and Glu27Glu group. The level of Hb in Arg16Arg groupdecreases to a largest extent at the end of the follow-up when compared with the othertwo groups. In the16site of β2-AR, patients who share a type of Arg16Arggenotype never show a slight change of endoscopic findings after propranololadministration. After drug therapy, patients sharing Arg6Gly or Gly16Gly genotype both show a marked decrease in the number, size and red colors of varix. Comparingwith Arg16Gly, a more obvious decrease of size and red color is expressed inGly16Gly genotypic patients. The length of varices to fore-teeth decreases obviouslyin Gly16Gly group, but not in Arg16Gly group. The appearance of varices in bothgroups doesn’t vary significantly after drug therapy. However the large varices inGly16Gly group are found a more obvious decrease than Arg16Gly group. In the27site, the length, size and rosary-like of varices both decrease significantly. Thenumber and red sign in Gln27Glu group diminish, which don’t vary in Glu27Glugroup.Conclusion The long-term effect of propranolol to prevent variceal bleeding isassociated with β2-receptor gene46site SNP, patients who share a Gly allele show abetter outcome due to propranolol administration.