Turnes Juan, Hernández-Guerra Manuel, Abraldes Juan G, Bellot Pau, Oliva Rafael, García-Pagán Juan Carlos, Bosch Jaime
Hepatic Hemodynamic Laboratory, Institut de Malalties Digestives i Metaboliques, Hospital Clínic, IDIBAPS, Barcelona, Spain.
Hepatology. 2006 Jan;43(1):34-41. doi: 10.1002/hep.21000.
The beta-2-adrenergic receptor (beta(2-)-AR) has several single-nucleotide polymorphisms. These influence the functional response to adrenergic stimulation; genotypes homozygous for Gly16-Glu27 or Gly16-Gln27 alleles (Gly16-Glu/Gln27 haplotypes) are associated with enhanced response, whereas genotypes homozygous for Arg16-Gln27 alleles (Arg16-Gln27) show a decreased response. We hypothesized that gene polymorphisms at the beta2-AR may influence the hemodynamic response to propranolol in patients with cirrhosis. The beta2-AR gene polymorphisms were determined by direct sequencing of the polymerase chain reaction (PCR) products in 48 patients with cirrhosis. All patients also had hepatic and systemic hemodynamic studies before and after propranolol administration. Prevalence of Gly16-Glu/Gln27 haplotypes was 29.1%, Arg16-Gln27 haplotype was 16.7%, and 54.2% were compound heterozygotes. Patients with cirrhosis with Gly16-Glu/Gln27 haplotypes had a greater decrease in heart rate, cardiac index, and hepatic blood flow after propranolol administration than those with Arg16-Gln27 haplotype. However, the HVPG response to propranolol was similar in both groups, whereas estimated hepatic sinusoidal resistance increased significantly in Gly16-Glu/Gln27 haplotypes but not in Arg16-Gln27 (+27.1 +/- 17.8% vs -17.9 +/- 13.9%, P = .042), suggesting that unopposed vasoconstrictive activity at the intrahepatic circulation hinders the fall in HVPG despite enhanced hemodynamic response to propranolol in Gly16-Glu/Gln27 haplotypes. In conclusion, beta2-AR gene polymorphisms influence the response to beta-blockade. However, HVPG reduction cannot be predicted from polymorphism analysis. Patients with the Gly16-Glu/Gln27 haplotypes may benefit from the association of hepatic vasodilators to propranolol therapy.
β2 - 肾上腺素能受体（β(2 - ) - AR）存在多种单核苷酸多态性。这些多态性会影响对肾上腺素能刺激的功能反应；纯合子Gly16 - Glu27或Gly16 - Gln27等位基因（Gly16 - Glu/Gln27单倍型）的基因型与增强的反应相关，而纯合子Arg16 - Gln27等位基因（Arg16 - Gln27）的基因型则表现出反应降低。我们推测β2 - AR基因多态性可能会影响肝硬化患者对普萘洛尔的血流动力学反应。通过对48例肝硬化患者聚合酶链反应（PCR）产物进行直接测序来确定β2 - AR基因多态性。所有患者在服用普萘洛尔前后均进行了肝脏和全身血流动力学研究。Gly16 - Glu/Gln27单倍型的患病率为29.1%，Arg16 - Gln27单倍型为16.7%，54.2%为复合杂合子。与Arg16 - Gln27单倍型的肝硬化患者相比，具有Gly16 - Glu/Gln27单倍型的患者在服用普萘洛尔后心率、心脏指数和肝血流量下降幅度更大。然而，两组对普萘洛尔的肝静脉压力梯度（HVPG）反应相似，而Gly16 - Glu/Gln27单倍型的估计肝窦阻力显著增加，Arg16 - Gln27单倍型则未增加（分别为+27.1±17.8%对 - 17.9±13.9%，P = 0.042），这表明尽管Gly16 - Glu/Gln27单倍型对普萘洛尔的血流动力学反应增强，但肝内循环中未受拮抗的血管收缩活性阻碍了HVPG的下降。总之，β2 - AR基因多态性会影响对β受体阻滞剂的反应。然而，无法通过多态性分析预测HVPG降低情况。具有Gly16 - Glu/Gln27单倍型的患者可能会从肝血管扩张剂与普萘洛尔治疗联合应用中获益。
