Adrenergic-pathway gene variants influence beta-blocker-related outcomes after acute coronary syndrome in a race-specific manner.
OBJECTIVE
Overcoming racial differences in acute coronary syndrome (ACS) outcomes is a strategic goal for U.S. health care. Genetic polymorphisms in the adrenergic pathway seem to explain some outcome differences by race in other cardiovascular diseases treated with β-adrenergic receptor blockade (BB). Whether these genetic variants are associated with survival among ACS patients treated with BB, and if this differs by race, is unknown.


BACKGROUND
β-adrenergic receptor blockade after ACS is a measure of quality care, but the effectiveness across racial groups is less clear.


METHODS
A prospective cohort of 2,673 ACS patients (2,072 Caucasian; 601 African-American) discharged on BB from 22 U.S. hospitals were followed for 2 years. Subjects were genotyped for polymorphisms in ADRB1, ADRB2, ADRA2C, and GRK5. We used proportional hazards regression to model the effect of genotype on mortality, stratified by race and adjusted for baseline factors.


RESULTS
The overall 2-year mortality rate was 7.5% for Caucasians and 16.7% for African Americans. The prognosis associated with different genotypes in these BB-treated patients differed by race. In Caucasians, ADRA2C 322-325 deletion carriers had significantly lower mortality as compared with homozygous individuals lacking the deletion (hazard ratio: 0.46; confidence interval [CI]: 0.21 to 0.99; p = 0.047; race × genotype interaction p = 0.053). In African Americans, the ADRB2 16R allele was associated with significantly increased mortality (hazard ratio for RG vs. GG: 2.10; CI: 1.14 to 3.86; RR vs. GG: 2.65; CI: 1.38 to 5.08; p = 0.013; race × genotype interaction p = 0.096).


CONCLUSIONS
Adrenergic pathway polymorphisms are associated with mortality in ACS patients receiving BB in a race-specific manner. Understanding the mechanism by which different genes impact post-ACS mortality differently in Caucasians and African Americans might illuminate opportunities to improve BB therapy in these groups.
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Sharon
S
Cresci
Gerald W
GW
Dorn
Philip G
PG
Jones
Amber L
AL
Beitelshees
Allie Y
AY
Li
Petra A
PA
Lenzini
Michael A
MA
Province
John A
JA
Spertus
David E
DE
Lanfear
D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000208:ethnology* / Q000235:genetics / Q000401:mortality; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000789:Angina, Unstable / Q000188:drug therapy / Q000208:ethnology; D015331:Cohort Studies; D015986:Confounding Factors, Epidemiologic; D005260:Female; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics*; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D009203:Myocardial Infarction / Q000188:drug therapy / Q000208:ethnology; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012107:Research Design; D015398:Signal Transduction / Q000235:genetics; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics*
C547774:ADRA2C protein, human; C547787:ADRB1 protein, human; C553443:ADRB2 protein, human; D000319:Adrenergic beta-Antagonists; D018341:Receptors, Adrenergic, alpha-2; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human