Influence of Receptor Polymorphisms on the Response to α-Adrenergic Receptor Blockers in Pheochromocytoma Patients

Annika M A Berends; Mathieu S Bolhuis; Ilja M Nolte; Edward Buitenwerf; Thera P Links; Henri J L M Timmers; Richard A Feelders; Elisabeth M W Eekhoff; Eleonora P M Corssmit; Peter H Bisschop; Harm R Haak; Ron H N van Schaik; Samira El Bouazzaoui; Bob Wilffert; Michiel N Kerstens

doi:10.3390/biomedicines10040896

Influence of Receptor Polymorphisms on the Response to α-Adrenergic Receptor Blockers in Pheochromocytoma Patients

Biomedicines. 2022 Apr 13;10(4):896. doi: 10.3390/biomedicines10040896.

Authors

Annika M A Berends¹, Mathieu S Bolhuis², Ilja M Nolte³, Edward Buitenwerf¹, Thera P Links¹, Henri J L M Timmers⁴, Richard A Feelders⁵, Elisabeth M W Eekhoff⁶, Eleonora P M Corssmit⁷, Peter H Bisschop⁸, Harm R Haak^{9

10

11}, Ron H N van Schaik¹², Samira El Bouazzaoui¹², Bob Wilffert^{2

13}, Michiel N Kerstens¹

Affiliations

¹ Department of Endocrinology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
² Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.
³ Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands.
⁴ Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
⁵ Department of Endocrinology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.
⁶ Department of Internal Medicine Section Endocrinology, Amsterdam University Medical Centers Location VUmc, 1117 HV Amsterdam, The Netherlands.
⁷ Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
⁸ Department of Internal Medicine Section Endocrinology, Amsterdam University Medical Centers Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
⁹ Department of Internal Medicine, Máxima Medical Center, 5504 DB Eindhoven/Veldhoven, The Netherlands.
¹⁰ CAPHRI School for Public Health and Primary Care, Ageing and Long-Term Care, Maastricht University, 6229 HX Maastricht, The Netherlands.
¹¹ Department of Internal Medicine, Division of General Internal Medicine, Maastricht University Medical Centre+, 6229 HX Maastricht, The Netherlands.
¹² Department of Clinical Chemistry, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands.
¹³ Department of Pharmacotherapy, Epidemiology & Economics, Groningen Research Institute of Pharmacy, University of Groningen, 9713 GZ Groningen, The Netherlands.

Abstract

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.

Keywords: adrenergic receptor; alpha-adrenergic receptor blocker; paraganglioma; personalized medicine; pharmacogenetics; pheochromocytoma; single nucleotide polymorphism.