Genetic variants associated with bisoprolol plasma levels in the Pharmacogenetics of Acute Coronary Syndrome Study - PhACS

V. Fontana¹, R. Turner¹, P. Yin², R. Fitzgerald¹, M. Bayliss¹, S. Whalley¹, A. Santoyo-Castelazo¹, B. Pütz³, B. Müller-Myhsok³, M. Pirmohamed¹. ¹Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom, ²Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom, ³Transitional Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany

Introduction: Acute coronary syndrome is a common cause of medical hospitalizations and mortality worldwide. Treatment with beta-blockers is associated with risk reduction in mortality. Bisoprolol (BSP) is a widely used beta blocker in ACS. This study aimed to identify genetic loci associated with bisoprolol circulating levels in non-ST elevation acute coronary syndrome (NSTE-ACS).

Methods: NSTE-ACS patients discharged on BSP (1.25-10 mg daily) from a UK-based prospective cardiovascular study were included (1). Informed consent was obtained in accordance with the Declaration of Helsinki. BSP was quantified in plasma samples obtained one month after discharge employing LC-MS/MS methodology and deuterated internal standards. The method was validated according to FDA bioanalytical Guidance (2). Patients were genotyped using the lllumina OmniExpress array and imputation was based on 2000 Genomes Phase I reference panel, covering around 7 million single nucleotide polymorphisms (SNPs). A total of 661 samples were included in the genome-wide association analysis for log-transformed BSP levels using linear regression under an additive dosage model after adjusting for clinical covariates and principal components.

Results: Three variants reached genome-wide statistical significance: rs78917900 (p=2.02x20-8) and rs74744856 (p=2.16x10^-8) and rs148867800 (p=3.88x10^-8) mapping to MYelin Transcription factor 1 gene (MYT1). In addition, we found strong evidence of association in the region 7q.21 (lead SNP in the region rs201328808, p= 6.67x10-7). This region comprises the G protein subunit alpha transducin 3 (GNAT3) and CD36 genes; variations in this region have been linked to metabolic syndrome (3). GNAT3 protein is largely expressed in the gut epithelium, and CD36 encodes a receptor for thrombospondins, which plays an important role in cell adhesion processes. No signals were detected in the two main genes responsible for the metabolism of bisoprolol, CYP2D6 and CYP3A4.

Conclusions: Our study highlights that variants mapping to MYT1 are associated with bisoprolol drug levels. The functional mechanism for this association is unclear, and will require further work. We did not find an association for variants in the CYP2D6 and CYP3A4 genes which code for the main enzymes involved in BSP metabolism, which is perhaps not surprising since 50% of the drug is renally eliminated.

References:

1. Roffi M et al (2016). European Heart Journal 37, 267-315. FDA.

2. Guidance for Industry. Bioanalytical Method Validation, https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm368107.pdf

3. Turner RM et al (2016). J Clin Lipidol 1:204-214.

4. Farook VS et al (2012). Obesity 20:2083-92.