Genomic Association Analysis Reveals Variants Associated With Blood Pressure Response to Beta‐Blockers in European Americans

Abstract

European Americans (EA) have a better antihypertensive response to β‐blockers when compared with African Americans, albeit with some variability. We undertook a genomewide association study to elucidate the underlying genetic determinants in EA contributing to this variability in blood pressure (BP) response. A discovery genomewide association study of change in BP post–metoprolol treatment was performed in EA participants (n = 201) from the Pharmacogenomic Evaluation of Antihypertensive Responses‐2 (PEAR‐2) study and tested for replication in the atenolol‐treated EA from the PEAR study (n = 233). Rs294610 in the FGD5, which encodes for FYVE, RhoGEF and PH Domain Containing 5, (expression quantitative trait loci for FGD5 in the small intestine) was significantly associated with increased diastolic BP response to β‐blockers in the PEAR‐2 study (P = 3.41 × 10−6, β = −2.70) and replicated (P = 0.01, β = −1.17) in the PEAR study. Post–meta‐analysis of these studies, an additional single nucleotide polymorphism rs45545233 in the SLC4A1, encoding for Solute Carrier Family 4 Member 1, (expression quantitative trait loci for dual specificity phosphatase 3 in the artery tibial) was identified that was significantly associated with a poor response to β‐blockers (P = 3.43 × 10−6, β = 4.57) and was replicated in the atenolol add‐on cohort (P = 0.007, β = 4.97). We identified variants in FGD5 and SLC4A1, which have been previously cited as candidate genes for hypertension, to be associated with a β‐blocker BP response in EA. Further elucidation is warranted of the underlying mechanisms of these variants and genes by which they influence the BP response to β‐blockers.

<p>Pharmacogenomics And Hypertension: Current Insights</p>

“…Given that black subjects have different antihypertensive responses to β-blockers compared to Caucasians, recent GWAS have focused on this last population 41,64,65. Hiltunen et al identified the SNPs rs2514036, rs948445, and rs2514037 in the ACY3 gene (coding for aminoacylase III) associated with blood pressure responses to the β‑blocker bisoprolol in Caucasians 41.…”

Association of West African ancestry and blood pressure control among African Americans taking antihypertensive medication in the Jackson Heart Study

“…Although blood pressure has a high degree of heritability, genetic variants identified to date explain only a small percentage (~<3%) of the interindividual variation in blood pressure . Candidate gene and genome‐wide studies have identified pharmacogenetic variants associated with the BP‐lowering response to antihypertensive medications (particularly thiazide diuretics [ NEDD4L] and beta blockers [ ADRB1] ) although the effect sizes of individual variants are quite small . However, the effectiveness of antihypertensive medication does vary by ancestral group (eg, African, Asian, and European ancestry), which may be related, in part, to genetic factors that vary in frequency according to historical geographic separations (ie, Europeans, Asians, and Africans living partially isolated in unique environments for tens of thousands of years) .…”

Pharmacogenomics of Hypertension Treatment

“…GRK4 65L and 142V are associated with reduced BP responses to atenolol in both Caucasians and African Americans [ 66 ]. In a genome-wide association study of metoprolol treated individuals from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and atenolol treated subjects from the PEAR study, rs294610 (an intronic SNP resulting in C/A transversion) in the FGD5 gene (encoding FYVE, RhoGEF, and the PH domain containing protein 5) was found to significantly improve BP response following metoprolol and atenolol treatment (the latter analysis was carried out in an independent cohort of European Americans) [ 68 ]. Carriers of the A allele had considerably better BP responses than non-carriers.…”

“…However, further studies are necessary to understand the functional role of SNPs within the FGD5 gene in improved BP responses to β-blockers. In turn, in an analysis of the results obtained from two studies (PEAR-2 and PEAR) with an independent atenolol add-on therapy, Singh et al [ 68 ] identified rs45545233 polymorphism in the SLC4A1 gene, which was significantly associated with a reduced BP response to β-blockers. The PEAR-2 metoprolol-treated cohort analysis also found the SLC4A1 gene encoding for glycoprotein in the plasma membrane (the band 3 anion transporter belonging to the anion exchanger family) to be related to drug response.…”

“…The PEAR-2 metoprolol-treated cohort analysis also found the SLC4A1 gene encoding for glycoprotein in the plasma membrane (the band 3 anion transporter belonging to the anion exchanger family) to be related to drug response. SLC4A1 is mainly expressed in the erythrocyte membrane and the collecting ducts of the kidney, where it is involved in the electro–neutral exchange of HCO 3 − for Cl − and the transport of glucose and water [ 68 ]. According to Kokubo et al [ 72 ], polymorphisms in SLC4A1 are significantly associated with hypertension and BP variation in the Japanese population.…”