Berends Annika M A, Bolhuis Mathieu S, Nolte Ilja M, Buitenwerf Edward, Links Thera P, Timmers Henri J L M, Feelders Richard A, Eekhoff Elisabeth M W, Corssmit Eleonora P M, Bisschop Peter H, Haak Harm R, van Schaik Ron H N, El Bouazzaoui Samira, Wilffert Bob, Kerstens Michiel N
Department of Endocrinology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.
Biomedicines. 2022 Apr 13;10(4):896. doi: 10.3390/biomedicines10040896.
Background: Presurgical treatment with an α-adrenergic receptor blocker is recommended to antagonize the catecholamine-induced α-adrenergic receptor mediated vasoconstriction in patients with pheochromocytoma or sympathetic paraganglioma (PPGL). There is, however, a considerable interindividual variation in the dose-response relationship regarding the magnitude of blood pressure reduction or the occurrence of side effects. We hypothesized that genetically determined differences in α-adrenergic receptor activity contribute to this variability in dose-response relationship. Methods: Thirty-one single-nucleotide polymorphisms (SNPs) of the α1A, α1B, α1D adrenoreceptor (ADRA1A, ADRA1B, ADRA1D) and α2A, α2B adrenoreceptor (ADRA2A, ADRA2B) genes were genotyped in a group of 116 participants of the PRESCRIPT study. Haplotypes were constructed after determining linkage disequilibrium blocks. Results: The ADRA1B SNP rs10515807 and the ADRA2A SNPs rs553668/rs521674 were associated with higher dosages of α-adrenergic receptor blocker (p < 0.05) and with a higher occurrence of side effects (rs10515807) (p = 0.005). Similar associations were found for haplotype block 6, which is predominantly defined by rs10515807. Conclusions: This study suggests that genetic variability of α-adrenergic receptor genes might be associated with the clinically observed variation in beneficial and adverse therapeutic drug responses to α-adrenergic receptor blockers. Further studies in larger cohorts are needed to confirm our observations.
对于嗜铬细胞瘤或交感神经节旁神经瘤（PPGL）患者，推荐使用α-肾上腺素能受体阻滞剂进行术前治疗，以对抗儿茶酚胺诱导的α-肾上腺素能受体介导的血管收缩。然而，在血压降低幅度或副作用发生方面，剂量反应关系存在相当大的个体差异。我们假设α-肾上腺素能受体活性的基因决定差异导致了这种剂量反应关系的变异性。方法：在PRESCRIPT研究的116名参与者中，对α1A、α1B、α1D肾上腺素能受体（ADRA1A、ADRA1B、ADRA1D）和α2A、α2B肾上腺素能受体（ADRA2A、ADRA2B）基因的31个单核苷酸多态性（SNP）进行基因分型。在确定连锁不平衡块后构建单倍型。结果：ADRA1B SNP rs10515807和ADRA2A SNPs rs553668/rs521674与更高剂量的α-肾上腺素能受体阻滞剂相关（p<0.05），并与更高的副作用发生率（rs10515807）相关（p = 0.005）。对于主要由rs10515807定义的单倍型块6，也发现了类似的关联。结论：本研究表明，α-肾上腺素能受体基因的遗传变异性可能与临床上观察到的α-肾上腺素能受体阻滞剂有益和不良治疗药物反应的变异性相关。需要在更大的队列中进行进一步研究以证实我们的观察结果。
