Atenolol Induced HDL-C Change in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study

<div><p>We sought to identify novel pharmacogenomic markers for HDL-C response to atenolol in participants with mild to moderate hypertension. We genotyped 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study on the Illumina HumanCVD Beadchip. During PEAR, participants were randomized to receive atenolol or hydrochlorothiazide. Blood pressure and cholesterol levels were evaluated at baseline and after treatment. This study focused on participants treated with atenolol monotherapy. Association with atenolol induced HDL-C change was evaluated in 232 whites and 152 African Americans using linear regression. No SNPs achieved a Bonferroni corrected <i>P</i>-value. However, we identified 13 regions with consistent association across whites and African Americans. The most interesting of these regions were seven with prior associations with HDL-C, other metabolic traits, or functional implications in the lipid pathway: <i>GALNT2</i>, <i>FTO</i>, <i>ABCB1, LRP5</i>, <i>STARD3NL</i>, <i>ESR1</i>, and <i>LIPC</i>. Examples are rs2144300 in <i>GALNT2</i> in whites (<i>P</i>=2.29x10^-4, β=-1.85 mg/dL) and rs12595985 in <i>FTO</i> in African Americans (<i>P</i>=2.90x10^-4, β=4.52 mg/dL), both with consistent regional association (<i>P</i><0.05) in the other race group. Additionally, baseline <i>GALNT2</i> expression differed by rs2144300 genotype in whites (<i>P</i>=0.0279). In conclusion, we identified multiple gene regions associated with atenolol induced HDL-C change that were consistent across race groups, several with functional implications or prior associations with HDL-C.</p> </div

Plot of relative gene expression of <i>GALNT2</i> by rs2144300 genotype.

<p>Gene expression analysis performed in 34 PEAR whites, normalized to β-2-microglobulin. Error bars represent standard error.</p

<i>GALNT2</i> Regional Plots and adjusted HDL-C response by genotype.

<p>(A) Regional Plot in PEAR whites. (B) HDL-C response in PEAR whites by rs2144300 genotype. (C) Regional Plot in PEAR African Americans. (D) HDL-C response in PEAR African Americans by rs2144297 genotype. Error bars represent standard error.</p

GWAS + Replication, Validation and Overall <i>P</i>-values for susceptibility loci identified from the Overall meta-analysis (P<2.5×10⁻⁵).

<p>SNPs are ordered by chromosome and position (NCBI Build 36.1, hg18) with the major/minor alleles (positive strand) and corresponding gene (underlined) or nearest annotated genes (+/−500 kb). For each phase of the study, GWAS + Replication, Validation and Overall (GWAS+Replication+T2DM+IRAS+IRASFS) analyses, the minor allele frequency (MAF) in controls, additive <i>P</i>-value and odds ratio (OR) with associated 95% confidence interval (CI) with respect to the minor allele is listed.</p

Clinical Characteristics of Study Samples.

<p>Values are presented as trait mean and standard deviation.</p

Genome-Wide Association Study Results.

<p>Results are adjusted for admixture using PC1 as a covariate in the analysis. <i>P</i>-values are shown under the additive model. The blue line at -log₁₀(<i>P</i>-value) = 3 represents an additive <i>P</i>-value = 0.001 and the red line at -log₁₀(<i>P</i>-value) = 5 represents a <i>P</i>-value = 1.0×10⁻⁵.</p

Study Design.

<p>Study Design.</p

Genome-wide study of resistant hypertension identified from electronic health records

<div><p>Resistant hypertension is defined as high blood pressure that remains above treatment goals in spite of the concurrent use of three antihypertensive agents from different classes. Despite the important health consequences of resistant hypertension, few studies of resistant hypertension have been conducted. To perform a genome-wide association study for resistant hypertension, we defined and identified cases of resistant hypertension and hypertensives with treated, controlled hypertension among >47,500 adults residing in the US linked to electronic health records (EHRs) and genotyped as part of the electronic MEdical Records & GEnomics (eMERGE) Network. Electronic selection logic using billing codes, laboratory values, text queries, and medication records was used to identify resistant hypertension cases and controls at each site, and a total of 3,006 cases of resistant hypertension and 876 controlled hypertensives were identified among eMERGE Phase I and II sites. After imputation and quality control, a total of 2,530,150 SNPs were tested for an association among 2,830 multi-ethnic cases of resistant hypertension and 876 controlled hypertensives. No test of association was genome-wide significant in the full dataset or in the dataset limited to European American cases (n = 1,719) and controls (n = 708). The most significant finding was <i>CLNK</i> rs13144136 at p = 1.00x10^-6 (odds ratio = 0.68; 95% CI = 0.58–0.80) in the full dataset with similar results in the European American only dataset. We also examined whether SNPs known to influence blood pressure or hypertension also influenced resistant hypertension. None was significant after correction for multiple testing. These data highlight both the difficulties and the potential utility of EHR-linked genomic data to study clinically-relevant traits such as resistant hypertension.</p></div

Resistant hypertension genome-wide association study in the eMERGE Network.

<p>The eMERGE Network conducted a genome-wide association study for resistant hypertension among adults drawn from the two funding phases of the network. The eMERGE Network I study sites that contributed data are denoted in blue and include Group Health/University of Washington in Seattle, WA; Marshfield Clinic in Marshfield, WI; Mayo Clinic in Rochester, MN; Northwestern University in Chicago, IL; and Vanderbilt University in Nashville, TN. The eMERGE Network II study sites that contributed data are denoted in red and include Geisinger Health System in Danville, PA and Mount Sinai School of Medicine in Manhattan, NY. Denoted in gray are eMERGE Phase II pediatric study sites not included in the present study (Boston Children’s Hospital in Boston, MA; Children’s Hospital of Philadelphia in Philadelphia, PA; and Cincinnati Children’s Hospital in Cincinnati, OH).</p

Characteristics of resistant hypertension cases and controls.

<p>Race/ethnicity is self-reported or administratively-assigned. Here, ethnicity refers to “Hispanic” and race refers to European American, African American, or other.</p