RESUMEN
BACKGROUND: Plasma renin is an important regulator of blood pressure (BP). Plasma renin activity (PRA) has been shown to correlate with variability in BP response to antihypertensive agents. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with baseline PRA using data from the PEAR study (Pharmacogenomic Evaluation of Antihypertensive Responses). METHODS: Multiple linear regression analysis was performed in 461 whites and 297 blacks using an additive model, adjusting for age, sex, and ancestry-specific principal components. Top SNPs were prioritized by testing the expected direction of association for BP response to atenolol and hydrochlorothiazide. Top regions from the BP response prioritization were tested for functional evidence through differences in gene expression by genotype using RNA sequencing data. Regions with functional evidence were assessed for replication with baseline PRA in an independent study (PEAR-2). RESULTS: Our top SNP rs3784921 was in the SNN-TXNDC11 gene region. The G allele of rs3784921 was associated with higher baseline PRA (ß=0.47; P=2.09×10-6) and smaller systolic BP reduction in response to hydrochlorothiazide (ß=2.97; 1-sided P=0.006). In addition, TXNDC11 expression differed by rs3784921 genotype (P=0.007), and rs1802409, a proxy SNP for rs3784921 (r2=0.98-1.00), replicated in PEAR-2 (ß=0.15; 1-sided P=0.038). Additional SNPs associated with baseline PRA that passed BP response prioritization were in/near the genes CHD9, XIRP2, and GHR. CONCLUSIONS: We identified multiple regions associated with baseline PRA that were prioritized through BP response signals to 2 mechanistically different antihypertensive drugs. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00246519.
Asunto(s)
Antihipertensivos/uso terapéutico , Atenolol/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Renina/sangre , Adolescente , Adulto , Anciano , Presión Sanguínea/genética , Estudio de Asociación del Genoma Completo , Humanos , Hipertensión/sangre , Hipertensión/genética , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Renina/genética , Resultado del Tratamiento , Estados Unidos , Adulto JovenRESUMEN
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 P-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: GALNT2, FTO, ABCB1, LRP5, STARD3NL, ESR1, and LIPC. Examples are rs2144300 in GALNT2 in whites (P=2.29x10(-4), ß=-1.85 mg/dL) and rs12595985 in FTO in African Americans (P=2.90x10(-4), ß=4.52 mg/dL), both with consistent regional association (P<0.05) in the other race group. Additionally, baseline GALNT2 expression differed by rs2144300 genotype in whites (P=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.