G-protein-coupled receptor kinase 4 polymorphisms and blood pressure response to metoprolol among African Americans: sex-specificity and interactions.
BACKGROUND
African Americans have a disproportionate burden of hypertension and comorbid disease. Pharmacogenetic markers of blood pressure response have yet to be defined clearly. This study explores the association between G-protein-coupled receptor kinase type 4 (GRK4) variants and blood pressure response to metoprolol among African Americans with early hypertensive nephrosclerosis.


METHODS
Participants from the African American Study of Kidney Disease and Hypertension (AASK) trial were genotyped at three GRK4 polymorphisms: R65L, A142V, and A486V. A Cox proportional hazards model, stratified by gender, was used to determine the relationship between GRK4 variants and time to reach a mean arterial pressure (MAP) of 107 mm Hg, adjusted for other predictors of blood pressure response. Potential interactions between the three polymorphisms were explored by analyzing the effects of gene haplotypes and by stratifying the analysis by neighboring sites.


RESULTS
The hazard ratio with 95% confidence interval by A142V among men randomized to a usual MAP (102-107 mm Hg) was 1.54 (1.11-2.44; P = 0.0009). The hazard ratio by A142V with R65/L65 or L65/L65 was 2.14 (1.35-3.39; P = 0.001). Haplotype analyses were consistent but inconclusive. There was no association between A142V and blood pressure response among women.


CONCLUSIONS
Results suggest a sex-specific relationship between GRK4 A142V and blood pressure response among African-American men with early hypertensive nephrosclerosis. Men with a GRK4 A142 were less responsive to metoprolol if they had a GRK4 L65 variant. The effect of GRK4 variants and blood pressure response to metoprolol should be studied in larger clinical trials.
Bhatnagar
Vibha
V
Deparment of Family and Preventive Medicine, University of California San Diego, La Jolla, California, USA. vbhatnag@ucsd.edu
O'Connor
Daniel T
DT
Brophy
Victoria H
VH
Schork
Nicholas J
NJ
Richard
Erin
E
Salem
Rany M
RM
Nievergelt
Caroline M
CM
Bakris
George L
GL
Middleton
John P
JP
Norris
Keith C
KC
Wright
Jackson
J
Hiremath
Leena
L
Contreras
Gabriel
G
Appel
Lawrence J
LJ
Lipkowitz
Michael S
MS
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D001741:Black or African American; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects* / Q000235:genetics*; D004247:DNA / Q000235:genetics; D005260:Female; D054771:G-Protein-Coupled Receptor Kinase 4 / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008790:Metoprolol / Q000627:therapeutic use*; D008875:Middle Aged; D009400:Nephrosclerosis / Q000150:complications / Q000188:drug therapy* / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012727:Sex Characteristics; D015398:Signal Transduction / Q000502:physiology
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D004247:DNA; D054771:G-Protein-Coupled Receptor Kinase 4; C517855:GRK4 protein, human; D008790:Metoprolol