Atenolol is used alone or in combination with other medications to treat hypertension. It is also used to prevent angina pectoris (pain in the chest) and for the treatment of heart attacks. Atenolol belongs to a class of medications called β-blockers. It works by relaxing blood vessels and decreasing heart rate to improve blood flow and lower blood pressure.

In recent years it has been seen that the high variability in the response to the different β-blockers in the market (propanolol, metoprolol, carvedilol, timolol, bisoprolol, atenolol) can have a significant genetic percentage. In this technical report we study the genetic polymorphisms (or genetic variants present in the population) described in the literature that are related to a differential response (positive or negative) to atenolol.

In 2015 Gong Y. et al defined several polymorphic variants close to the PTPRD gene in different populations whose presence was associated with a better response to atenolol. The only deficiency of this clinical study is that it consisted of 233 white patients and 150 black patients (in addition to 207 Finnish whites), the number of patients should be greater so that these studies could be given more confidence.

Near the PTPRD gene, the SNP or rs12346562, consisting in a change of a C nucleotide by an A nucleotide at position g.11018077 C>A, was associated in white patients with a difference in the response to atenolol. Those patients who presented the CC genotype had the best response and those who presented CA genotype had a better response than the individuals with AA genotype. It was also found that this same association in the response was in Finnish patients in response to another β-blocker, bisoprolol.

In this same study, it was shown that another SNP close to the PTPRD gene was associated with the response to atenolol in black patients (150 patients). This SNP is rs10739150, which consists of a substitution of a G nucleotide by a T nucleotide at position g.8176226 G>T. In this case, those black patients who were carriers of a T allele (GT genotype) responded better to treatment with atenolol and those patients who presented TT genotype responded even better.

The PTPRD gene encodes the type D tyrosine phosphate receptor that has been associated with tumor suppressor activity and that regulates the transcription factor STAT3. Recently it has been seen that the PTPRD gene is related to diabetes, hypertension and acute coronary disease, hence the explanation of why variants in this gene may result in a better or worse response to β-blocking drugs.

In addition to this study, the PharmGKB international pharmacogenetics website contains more relevant clinical studies with genetic variants that affect the response to atenolol (https://www.pharmgkb.org/chemical/PA448499/variantAnnotation). We describe those that are more significant because of the number of patients and the clinical relevance demonstrated.

In 2008 Cresci S. et al. described a clinical trial with 735 patients in which they observed an association between rs4253778 in the PPARA gene and the response to atenolol (and to other β-blockers). Those patients with the GG genotype responded better to atenolol (and to other β-blockers) than those with GC or CC genotypes. GG patients had a lower risk of rehospitalization due to cardiac events after treatment with β-blockers.

In the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) trial, 768 patients with hypertension were evaluated and different genetic polymorphisms that affected the response to atenolol were identified. The SNPs or genetic variants were within the GRK4 gene (Protein G Receptor Kinase 4), which seems to be involved in the regulation of the β1-adrenergic receptor, target of the β-blocking drugs. The rs2960306 (c.194G>T) also called p.Arg65L (R65L) by the change it produces in the amino acids of the GRK4 protein, was involved in the response to atenolol so that the presence of a variant allele (allele T) reduced the efficiency of treatment with atenolol. The same was true for rs1024323 (c.425 C>T) or p.Ala142V (A142V). For rs1801058 (c.1457 T>C) also named p.Val486Ala (V486A) for its amino acid change also within the GRK4 gene, the relationship with the low response to atenolol was the presence of the original allele, which in any case is a T allele. Thus, it can be said that those individuals with at least one copy of any of the three amino acid variants 65L/142V/486V responded worse to atenolol and the more copies they presented, the worse they responded.

Another study carried out by Lobmeyer MT et al. in 2011, in which they used data from 418 patients from the aforementioned PEAR clinical trial, they found a polymorphism in the GR5K gene associated with a better response to atenolol. The SNP with code rs2230345 consists of a substitution of an A nucleotide by a T nucleotide at position c.122 A>T. Hypertensive patients or patients with coronary artery disease who presented at least one copy of the T allele (AT and TT genotypes) had a better response to atenolol and a lower risk of adverse cardiovascular events than patients with AA genotype. It is known that the GR5K gene codes for a protein that regulates β-adrenergic receptors, which are the targets of β-blocking drugs, this may explain why variations in GR5K can have effects on the pharmacogenetics of this type of drugs.

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