Influence of Receptor Polymorphisms on the Response to alpha-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 alpha-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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	896
Number of pages	15
Journal	Biomedicines
Volume	10
Issue number	4
DOIs	https://doi.org/10.3390/biomedicines10040896
Publication status	Published - 13-Apr-2022

Keywords

pheochromocytoma
paraganglioma
single nucleotide polymorphism
adrenergic receptor
alpha-adrenergic receptor blocker
pharmacogenetics
personalized medicine
GENOME-WIDE ASSOCIATION
GENETIC-VARIATION
BLOOD-PRESSURE
ALPHA(1B)-ADRENERGIC RECEPTOR
ALPHA(2B)-ADRENERGIC RECEPTOR
ALPHA-1-ADRENERGIC RECEPTOR
FASTING GLUCOSE
ADRA2A
VARIANTS
HYPERTENSION

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Berends, A. M. A., Bolhuis, M. S., Nolte, I. M., Buitenwerf, E., Links, T. P., Timmers, H. J. L. M., Feelders, R. A., Eekhoff, E. M. W., Corssmit, E. P. M., Bisschop, P. H., Haak, H. R., van Schaik, R. H. N., El Bouazzaoui, S., Wilffert, B., & Kerstens, M. N. (2022). Influence of Receptor Polymorphisms on the Response to alpha-Adrenergic Receptor Blockers in Pheochromocytoma Patients. Biomedicines, 10(4), Article 896. https://doi.org/10.3390/biomedicines10040896

@article{1d567665dc6848b6b8b8a3b3310b28df,

title = "Influence of Receptor Polymorphisms on the Response to alpha-Adrenergic Receptor Blockers in Pheochromocytoma Patients",

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 = "pheochromocytoma, paraganglioma, single nucleotide polymorphism, adrenergic receptor, alpha-adrenergic receptor blocker, pharmacogenetics, personalized medicine, GENOME-WIDE ASSOCIATION, GENETIC-VARIATION, BLOOD-PRESSURE, ALPHA(1B)-ADRENERGIC RECEPTOR, ALPHA(2B)-ADRENERGIC RECEPTOR, ALPHA-1-ADRENERGIC RECEPTOR, FASTING GLUCOSE, ADRA2A, VARIANTS, HYPERTENSION",

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

year = "2022",

month = apr,

day = "13",

doi = "10.3390/biomedicines10040896",

language = "English",

volume = "10",

journal = "Biomedicines",

issn = "2227-9059",

publisher = "MDPI AG",

number = "4",

}

Berends, AMA , Bolhuis, MS , Nolte, IM, Buitenwerf, E, Links, TP, Timmers, HJLM, Feelders, RA, Eekhoff, EMW, Corssmit, EPM, Bisschop, PH, Haak, HR, van Schaik, RHN, El Bouazzaoui, S, Wilffert, B & Kerstens, MN 2022, 'Influence of Receptor Polymorphisms on the Response to alpha-Adrenergic Receptor Blockers in Pheochromocytoma Patients', Biomedicines, vol. 10, no. 4, 896. https://doi.org/10.3390/biomedicines10040896

TY - JOUR

T1 - Influence of Receptor Polymorphisms on the Response to alpha-Adrenergic Receptor Blockers in Pheochromocytoma Patients

AU - Berends, Annika M A

AU - Bolhuis, Mathieu S

AU - Nolte, Ilja M

AU - Buitenwerf, Edward

AU - Links, Thera P

AU - Timmers, Henri J L M

AU - Feelders, Richard A

AU - Eekhoff, Elisabeth M W

AU - Corssmit, Eleonora P M

AU - Bisschop, Peter H

AU - Haak, Harm R

AU - van Schaik, Ron H N

AU - El Bouazzaoui, Samira

AU - Wilffert, Bob

AU - Kerstens, Michiel N

PY - 2022/4/13

Y1 - 2022/4/13

N2 - 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.

AB - 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.

KW - pheochromocytoma

KW - paraganglioma

KW - single nucleotide polymorphism

KW - adrenergic receptor

KW - alpha-adrenergic receptor blocker

KW - pharmacogenetics

KW - personalized medicine

KW - GENOME-WIDE ASSOCIATION

KW - GENETIC-VARIATION

KW - BLOOD-PRESSURE

KW - ALPHA(1B)-ADRENERGIC RECEPTOR

KW - ALPHA(2B)-ADRENERGIC RECEPTOR

KW - ALPHA-1-ADRENERGIC RECEPTOR

KW - FASTING GLUCOSE

KW - ADRA2A

KW - VARIANTS

KW - HYPERTENSION

U2 - 10.3390/biomedicines10040896

DO - 10.3390/biomedicines10040896

M3 - Article

C2 - 35453646

SN - 2227-9059

VL - 10

JO - Biomedicines

JF - Biomedicines

IS - 4

M1 - 896

ER -