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Transcript
JACC: HEART FAILURE
VOL. 2, NO. 6, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 2213-1779/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jchf.2014.04.016
MINI-FOCUS ISSUE: PHARMACOGENETICS AND PERSONALIZED MEDICINE
CLINICAL RESEARCH
G-Protein Beta-3 Subunit Genotype
Predicts Enhanced Benefit of Fixed-Dose
Isosorbide Dinitrate and Hydralazine
Results of A-HeFT
Dennis M. McNamara, MD, MS,* Anne L. Taylor, MD,y S. William Tam, PHD,z Manuel Worcel, MD,x
Clyde W. Yancy, MD, MSC,k Karen Hanley-Yanez, BS,* Jay N. Cohn, MD,{ Arthur M. Feldman, MD, PHD#
ABSTRACT
OBJECTIVES The purpose of this study was to evaluate the influence of the guanine nucleotide-binding proteins
(G-proteins), beta-3 subunit (GNB3) genotype on the effectiveness of a fixed-dose combination of isosorbide dinitrate
and hydralazine (FDC I/H) in A-HeFT (African American Heart Failure Trial).
BACKGROUND GNB3 plays a role in alpha2-adrenergic signaling. A polymorphism (C825T) exists, and the T allele is
linked to enhanced alpha-adrenergic tone and is more prevalent in African Americans.
METHODS A total of 350 subjects enrolled in the genetic substudy (GRAHF [Genetic Risk Assessment of Heart Failure in
African Americans]) were genotyped for the C825T polymorphism. The impact of FDC I/H on a composite score (CS) that
incorporated death, hospital stay for heart failure, and change in quality of life (QoL) and on event-free survival were
assessed in GNB3 genotype subsets.
RESULTS The GRAHF cohort was 60% male, 25% ischemic, 97% New York Heart Association functional class III, age 57 13 years, with a mean qualifying left ventricular ejection fraction of 0.24 0.06. For GNB3 genotype, 184 subjects were TT
(53%), 137 (39%) CT, and 29 (8%) were CC. In GNB3 TT subjects, FDC I/H improved the CS (FDC I/H ¼ 0.50 1.6;
placebo ¼ 0.11 1.8, p ¼ 0.02), QoL (FDC I/H ¼ 0.69 1.4; placebo ¼ 0.24 1.5, p ¼ 0.04), and event-free survival
(hazard ratio: 0.51, p ¼ 0.047), but not in subjects with the C allele (for CS, FDC I/H ¼ 0.05 1.7; placebo ¼ 0.09 1.7,
p ¼ 0.87; for QoL, FDC I/H ¼ 0.28 1.5; placebo ¼ 0.14 1.5, p ¼ 0.56; and for event-free survival, p ¼ 0.35).
CONCLUSIONS The GNB3 TT genotype was associated with greater therapeutic effect of FDC I/H in A-HeFT. The role
of the GNB3 genotype for targeting therapy with FDC I/H deserves further study. (J Am Coll Cardiol HF 2014;2:551–7)
© 2014 by the American College of Cardiology Foundation.
A
s
first
(Vet-
with heart failure (1). After the development of
erans Affairs Vasodilator-Heart Failure Trial)
demonstrated
angiotensin-converting enzyme (ACE) inhibitors and
treatment
and
the demonstration in V-HeFT II of greater survival
hydralazine (I/H) improves survival in subjects
benefit with enalapril compared with I/H (2), I/H was
with
in
isosorbide
V-HeFT
dinitrate
From the *Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania;
yColumbia University College of Physicians and Surgeons, New York, New York; zIndependent consultant, Dover, Massachusetts;
xConsultant, Paris, France; kDivision of Cardiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois;
{University of Minnesota, Minneapolis, Minnesota; and the #Temple University School of Medicine, Philadelphia, Pennsylvania.
This study was funded in part by a research grant from NitroMed, Inc., of Lexington, Massachusetts, which funded the A-HeFT
investigation. It was also supported in part by grants from the National Heart, Lung, and Blood Institute (contracts K24 HL69912
and RO1 HL75038). Drs. Tam and Worcel are former employees of NitroMed. All other authors have reported that they have no
relationships relevant to the contents of this paper to disclose.
Manuscript received November 11, 2013; revised manuscript received April 10, 2014, accepted April 18, 2014.
552
McNamara et al.
JACC: HEART FAILURE VOL. 2, NO. 6, 2014
DECEMBER 2014:551–7
GNB3 Polymorphism and ISDN-HYD in Heart Failure
ABBREVIATIONS
relegated to less common use in heart failure.
institutions. Inclusion criteria for A-HeFT included
AND ACRONYMS
Interestingly, the survival benefit for I/H
self-designation as African Americans, heart failure
differed markedly in the V-HeFT studies be-
resulting from systolic dysfunction, and standard
tween black and white cohorts. Post hoc anal-
background therapy for heart failure with neuro-
ysis demonstrated a dramatic benefit of I/H
hormonal blockade including ACE inhibitors or an-
ACE = angiotensin-converting
enzyme
CS = composite score
for black subjects in V-HeFT I, with a lesser
giotensin receptor antagonists and beta blockers (4).
combination of isosorbide
impact evident in the larger white cohort
Subjects were randomized to FDC I/H or placebo in
FDC I/H = fixed-dose
dinitrates and hydralazine
(3). A similar analysis by race for V-HeFT II
addition to standard therapy. Subjects were enrolled
GNB3 = guanine nucleotide-
found that the superiority of ACE inhibitors
in the GRAHF genetic substudy at the A-HeFT
binding proteins (G-proteins),
was driven by the white subset, whereas in
6-month visits after providing informed consent. For
black subjects, the survival with enalapril
comparisons of allele frequencies by race, the cohort
and I/H appeared more equivalent. The
from GRACE (Genetic Risk Assessment of Cardiac
observed enhanced impact of I/H in black
Events), a single-center investigation based at the
subjects with heart failure in these landmark
heart failure clinic at the University of Pittsburgh,
studies led to A-HeFT (African American
Pennsylvania (11,12), was used (n ¼ 469).
beta-3 subunit
I/H = isosorbide dinitrate and
hydralazine
LVEF = left ventricular ejection
fraction
LVEDD = left ventricular
end-diastolic diameter
Heart Failure Trial) (4), in which a fixed-
QoL = quality of life
dose combination (FDC) of I/H added to back-
SNP = single nucleotide
ground therapy was demonstrated to improve
polymorphism
survival in a cohort of self-designated African
Americans with a reduced ejection fraction (5).
Hypertension is far more prevalent among blacks,
and investigations of the genomic basis for this disorder have demonstrated significant differences between black and white cohorts in the prevalence
of genetic variants that affect vascular tone. One
example extensively studied is the G-protein beta-3
subunit (GNB3). A common GNB3 polymorphism in
the coding region of exon-10, C825T, is associated
with enhanced alpha2-adrenergic receptor intracellular signaling (6). The GNB3 T allele is linked to the
risk of hypertension (7,8) and low plasma renin (9),
and it has a much higher prevalence in black cohorts
than among whites (10). Whether the T allele linked to
low plasma renin is also associated with a diminished
impact of ACE inhibitors remains unknown.
GNB3 GENOTYPING. DNA was isolated from periph-
eral blood by leukocyte centrifugation and cell lysis
using the PureGene DNA purification kit (Gentra Systems, Minneapolis, Minnesota). The guanine nucleotide binding protein (G-protein) beta polypeptide-3
(GNB3) position 825 C/T polymorphism was assessed
using a TaqMan SNP Genotyping Assay (Applied Biosystems, Inc., Foster City, California) with tagged
primers (reporter 1 tagged dye ¼ VIC; reporter 2 tagged
dye ¼ FAM). Context sequence for the GNB3 825 C/T
polymorphism was as follows: AGAGCATCATCTGC
GGCATCACGTC[C/T] GTGGCCTTCTCCCTCAGTGGCCG
CC. Products were read using the Applied Biosystems
7000 (ABI).
FOLLOW-UP AND CLINICAL OUTCOMES. Subjects in
A-HeFT were followed for 18 months with assessment
of deaths, hospital stays for heart failure, and quality
of life (QoL) as endpoints (4). QoL assessment was
performed by the Minnesota Living with Heart Failure Questionnaire at baseline and at the 6-month
SEE PAGE 558
We hypothesized that genomic differences in
GNB3-mediated alpha 2-adrenergic receptor activation
may underlie the racial differences in the therapeutic
efficacy of FDC I/H, and that the GNB3 T allele more
prevalent among African Americans would be associated with a greater impact of I/H. We investigated
the interaction of drug therapy and GNB3 genotype in
the genetic substudy of A-HeFT, GRAHF (Genetic Risk
of Heart Failure in African Americans).
visit. All subjects enrolled in A-HeFT had a clinical
assessment of left ventricular ejection fraction (LVEF)
before enrollment (qualifying LVEF). In addition, in a
subset of subjects in a remodeling substudy, LVEF
and left ventricular end-diastolic diameter (LVEDD)
were quantified by echocardiography at a central core
laboratory at baseline (n ¼ 267) and at the 6-month
follow-up visit (n ¼ 259). The primary endpoint for
A-HeFT was a composite weighted score with 3
components: mortality, hospital stay for heart failure,
and change in QoL at 6 months (4,5). The change in
METHODS
STUDY POPULATION. A total of 350 subjects in
QoL score was reported as a component of the composite score (CS) ranging from most worsening to
most improvement scores of 2 to 2 (4,5).
A-HeFT were enrolled in GRAHF, a substudy of ge-
STATISTICAL
netic risk assessment of heart failure in African
compared by genotype class by Kaplan-Meier log rank
ANALYSIS. Event-free
Americans. This investigation was approved by the
analysis. Continuous variables such as CS were
institutional review boards at the participating
compared by genotype class by analysis of variance
survival was
McNamara et al.
JACC: HEART FAILURE VOL. 2, NO. 6, 2014
DECEMBER 2014:551–7
(ANOVA). Statistical analysis was performed using
SPSS version 20.0 (SPSS Inc., Chicago, Illinois).
T A B L E 1 Baseline Clinical Characteristics of Patients in the GRAHF by GNB3 Genotype
Results are presented as mean SD. Categorical
variables were compared using a nonparametric
chi-square Fisher-exact test.
RESULTS
553
GNB3 Polymorphism and ISDN-HYD in Heart Failure
All
(N ¼ 350)
TT
(N ¼ 184)
TCþCC
(N ¼ 166)
p Value
57 13
57 12
58 13
0.699
40
40
40
0.930
97/3
97/3
97/3
0.894
25
24
26
0.755
Age (yrs)
Female (%)
NYHA functional class (%/III/IV)
Ischemic (%)
0.24 0.06
0.24 0.06
0.23 0.07
0.155
jects from GRAHF were genotyped for the GNB3
LVDD (cm) qualifying
6.4 0.9
6.4 0.8
6.4 1.1
0.680
BP systolic (mm Hg)
127 17
128 16
126 17
0.290
C825T polymorphism. Of the GRAHF cohort, 184
BP diastolic (mm Hg)
77 10
77 10
76 11
0.520
subjects (53%) were homozygous for the T allele, and
Heart rate (beats/min)
73 11
73 12
74 11
0.445
166 (47%) had a least 1 copy of the C allele: 137 (39%)
ACE inhibitor (%)
76
76
76
0.743
were heterozygous and 29 (8%) were homozygous for
Aldosterone receptor antagonist (%)
36
35
37
0.782
the C allele. Comparison with the GRACE study
Beta blocker (%)
84
85
83
0.569
GNB3 GENOTYPE FREQUENCIES. A total of 350 sub-
demonstrated that the prevalence of the GNB3 T
allele in GRAHF was similar to that seen in the black
cohort from GRACE, but it was significantly greater
than in the white cohort (% TT/CT/CC GRAHF ¼ 53/
LVEF qualifying
Values are mean SD or %.
ACE ¼ angiotensin-converting enzyme; BP ¼ blood pressure; GRAHF ¼ Genetic Risk Assessment of Heart
Failure in African Americans; LVDD ¼ left ventricular diastolic diameter; LVEF ¼ left ventricular ejection fraction;
NYHA ¼ New York Heart Association.
39/8; GRACE (black cohort) ¼ 54/27/19; GRACE (white
cohort) ¼ 14/41/45, p < 0.001) (Figure 1).
therapy, blood pressure, and NYHA class were all
PATIENT CHARACTERISTICS. The GRAHF popula-
similar in subjects homozygous with the T allele
tion was 60% male, 25% ischemic, and 97% New York
compared with subjects with 1 or 2 copies of the C
Heart Association (NYHA) class III, with a mean age of
allele.
57 13 years (Table 1). Most subjects were taking beta
COMPOSITE SCORE, GNB3 GENOTYPE, AND IMPACT
blockers (85%) and ACE inhibitors (75%) at time of
OF THERAPY. Although in A-HeFT, treatment with
study entry, and more than one third (36%) were
FDC I/H significantly improved both CS and QoL (5),
taking aldosterone receptor antagonists. Compari-
in the smaller GRAHF subset, treatment with FDC I/H
sons of baseline characteristics by GNB3 genotype
was associated with a trend toward improved CS and
class revealed no significant differences. Medical
QoL
that
failed
to
reach
significance
(CS:
placebo ¼ 0.10 1.8; FDC I/H ¼ 0.23 1.6, p ¼ 0.07;
and for QoL: placebo ¼ 0.19 1.5; FDC I/H ¼ 0.49 1.4, p ¼ 0.07). When analyzed by GNB3 genotype, FDC
I/H
improved
the
CS
among
TT
homozygotes
(placebo ¼ 0.11 1.8; FDC I/H ¼ 0.50 1.6, p ¼ 0.02)
(Figure 2), but it had no impact among subjects with
the C allele (placebo ¼ 0.09 1.7; FDC I/H¼ 0.05 1.7, p ¼ 0.87). Improvement for QoL score with FDC
I/H was also evident for GNB3 TT subjects (QoL
component for GNB3 TT subset: placebo ¼ 0.24 1.5;
FDC I/H ¼ 0.69 1.4, p ¼ 0.04) (Figure 3) but not
among those with the C allele (placebo ¼ 0.14 1.5;
FDC I/H ¼ 0.28 1.5, p ¼ 0.56).
EVENT-FREE SURVIVAL. Over the course of follow-
up, there were 61 (17.3%) hospital stays for heart
F I G U R E 1 GNB3 Genotype Frequencies in GRAHF (A-HeFT)
and the Black and White Subsets From GRACE
failure and 12 deaths (3.4%). When evaluating the
combined endpoint of death or hospital stays for
heart failure, the percentages of event-free survival at
Frequency of the GNB3 T haplotype is significantly greater in
GRAHF (p < 0.001) compared with the white subset from GRACE.
A-HeFT ¼ African American Heart Failure Trial; GNB3 ¼ guanine
nucleotide-binding proteins (G-proteins) beta-3 subunit;
GRACE ¼ Genetic Risk Assessment of Cardiac Events; GRAHF ¼
Genetic Risk Assessment of Heart Failure in African Americans.
6, 12, and 18 months were 91%, 81%, and 73%,
respectively. Overall in GRAHF, treatment with FDC
I/H did not improve event-free survival (FDC I/H
event-free survival at 6, 12 and 18 months ¼ 91%,
83%, 76%; placebo ¼ 90%, 78%, 69%, p ¼ 0.41)
(Figure 4A). However, when evaluated in the GNB3 TT
554
McNamara et al.
JACC: HEART FAILURE VOL. 2, NO. 6, 2014
DECEMBER 2014:551–7
GNB3 Polymorphism and ISDN-HYD in Heart Failure
poorer event-free survival was evident with the
GNB3 TT genotype for subjects receiving placebo
(p ¼ 0.048) (Figure 5A); this impact was not apparent
in subjects treated with FDC I/H (p ¼ 0.35) (Figure 5B).
F I G U R E 2 Composite Score in GRAHF by Treatment With
FDC I/H Versus Placebo overall and in GNB3 Genotype
Subsets GNB3 C (CTþCC) and GNB3 TT
Treatment is associated with a significantly higher composite
score in GNB3 TT subjects (p ¼ 0.02). FDC I/H ¼ fixed-dose
combination of isosorbide dinitrate and hydralazine; other
abbreviations as in Figure 1.
subset (n ¼ 184), a significant impact of treatment was
evident (FDC I/H event-free survival at 6, 12, and
18 months ¼ 92%, 86%, 79%; placebo ¼ 89%, 74%,
61%, p ¼ 0.047) (Figure 4B) that was not apparent for
subjects with the C allele (FDC I/H event-free survival
at 6, 12 and 18 months ¼ 90%, 80%, 73%; placebo ¼
92%, 82%, 78%, p ¼ 0.35) (Figure 4C). When evaluating the impact of genotype by treatment subset,
F I G U R E 3 Improvement in QoL in GRAHF at 6 Months by
F I G U R E 4 Event-Free Survival by Treatment
Treatment With FDC I/H Versus Placebo Overall and in
With FDC I/H Versus Placebo
GNB3 Genotype Subsets GNB3 C (CTþCC) and GNB3 TT
(A) Overall GRAHF cohort (n ¼ 350, p ¼ 0.41). (B) GNB3
Treatment is associated with a significantly greater improvement
TT subjects (n ¼ 184, p ¼ 0.047); (C) GNB3 CTþCC subjects
in quality of life (QoL) score in GNB3 TT subjects (p ¼ 0.04). FDC
(N ¼ 166, p ¼ 0.35) Impact of therapy is evident only in the GNB3
I/H ¼ fixed-dose combination of isosorbide dinitrate and
TT subset. FDC I/H ¼ fixed-dose combination of isosorbide
hydralazine; other abbreviations as in Figure 1.
dinitrate and hydralazine; other abbreviations as in Figure 1.
McNamara et al.
JACC: HEART FAILURE VOL. 2, NO. 6, 2014
DECEMBER 2014:551–7
GNB3 Polymorphism and ISDN-HYD in Heart Failure
genotype and the impact of treatment with FDC I/H
on remodeling was apparent (Table 2).
DISCUSSION
In GRAHF, subjects with the GNB3 TT genotype
received therapeutic benefit from FDC I/H, as
demonstrated by an improved event-free survival
and QoL and a higher CS. In contrast, no therapeutic
impact was evident in subjects with 1 or 2 copies of
the C allele. The prevalence of the T allele differs
markedly by race; more than 50% of black cohorts
have the homozygous GNB3 TT genotype associated
with enhanced benefit of FDC I/H, compared with less
than 15% of whites. These findings suggest that racial
differences in the prevalence of the GNB3 T allele may
underlie the apparent racial differences in the impact
of therapy.
The GNB3 C825T polymorphism is a functionally
silent single nucleotide polymorphism (SNP) in exon
10 that does not change the amino acid sequence (14).
Common SNPs are also evident in the GNB3 promoter
region (G-350A), intron 9 (A3882C and G5249A), the 3 0
untranslated region (C1429T), in addition to an
insertion/deletion polymorphism of 4 base pairs
(6496 CACA) in intron 10. These polymorphisms are in
near complete linkage disequilibrium with the 350A,
3882C, 5249A, 1429T and 6496 CACA insertion alleles
co-inherited with the 825T allele as the “T haplotype”
F I G U R E 5 Event-Free Survival by GNB3 Genotype
GNB3 (guanine nucleotide-binding proteins [G proteins], beta
(15). This haplotype is strongly associated with a
splicing variant of GNB3, GNB3s, which is evident only
3 subunit) TT subset versus subjects with GNB3 C (CTþCC). (A)
in cell lines with the 825T allele (7). When compared
Subjects receiving placebo (n ¼ 186, p ¼ 0.047). (B) Subjects
with the wild-type protein, GNB3s is missing 41 amino
receiving a fixed-dose combination of isosorbide dinitrate and
acids, a complete repeated loop domain, but it re-
hydralazine (FDC I/H) (n ¼ 164, p ¼ 0.38).
mains functionally active. Enhanced activation of G
LEFT
VENTRICULAR
REMODELING,
TREATMENT
AND GNB3 GENOTYPE. Overall in A-HeFT, treatment
T A B L E 2 Core Lab Assessment LVEF and LVDD at Baseline
and 6 Months by GNB3 Genotype Overall and by Treatment
(FDC I/H or Placebo)
with FDC I/H was associated with significant reverse
All
TT
TCþCC
p Value
LVEF baseline all (%)
35 8
36 8
34 9
0.052
LVEF baseline placebo
35 9
36 8
34 9
0.165
LVEF baseline FDC I/H
36 8
34 9
0.180
not significantly different by treatment group (LVEF
35 8
LVDD baseline all (cm)
6.4 1.2
6.3 1.3
6.5 1.2
0.134
at 6 months: placebo ¼ 0.36 0.10; FDC I/H ¼ 0.38 LVDD baseline placebo
6.4 1.2
6.4 1.2
6.5 1.2
0.523
0.09, p ¼ 0.16; change from baseline at 6 months:
LVDD baseline FDC I/H
6.4 1.3
6.2 1.3
6.6 1.2
0.141
placebo ¼ 0.02 0.09; FDC I/H ¼ 0.03 0.08,
LVEF 6 months all (%)
37 9
37 10
37 9
0.644
p ¼ 0.18). No clear interaction of GNB3 genotype
LVEF 6 months placebo
36 10
37 11
35 9
0.160
LVEF 6 months FDC I/H
38 9
37 9
39 10
0.337
LVDD 6 months all (cm)
6.2 1.3
6.0 1.4
6.3 1.3
0.105
LVDD 6 months placebo
6.2 1.3
6.0 1.3
6.4 1.2
0.072
LVDD 6 months FDC I/H
6.2 1.4
6.1 1.4
6.2 1.4
0.608
remodeling, as assessed by the change in LVEF by
echocardiography at 6 months (13). In the GRAHF
substudy, improvements in LVEF at 6 months were
with remodeling was evident. For subjects with the
GNB3 TT genotype the mean LVEF was slightly
higher at baseline (LVEF GNB3 TT: 0.36 0.08
versus C allele: 0.34 0.09, p ¼ 0.052); however,
this difference at baseline was not evident at
Values are mean SD.
6 months (GNB3 TT: LVEF ¼ 0.37 0.10; C allele: ¼
FDC I/H ¼ fixed-dose combination of isosorbide dinitrate and hydralazine;
LVDD ¼ left ventricular diastolic diameter; LVEF ¼ left ventricular ejection fraction.
0.37 0.09, p ¼ 0.64). No clear interaction of GNB3
555
556
McNamara et al.
JACC: HEART FAILURE VOL. 2, NO. 6, 2014
DECEMBER 2014:551–7
GNB3 Polymorphism and ISDN-HYD in Heart Failure
proteins is evident in immortalized cell lines from
Subjects with the GNB3 TT genotype had a signifi-
hypertensive compared with normotensive subjects
cantly higher risk of cerebral vascular events (HR:
(16), and in these same cell lines it is tightly linked to
2.22, 95% CI: 1.31 to 3.79) which remained significant
the presence of the 825T allele and GNB3s (7).
when adjusting for blood pressure and other cardio-
The role of the GNB3 polymorphism in the risk of
vascular risk factors (32).
hypertension has been studied extensively (17–19),
In a small Brazilian cohort with systolic heart fail-
and pharmacogenetic investigations have suggested
ure, the GNB3 825T and the Arg389 b1 alleles were
increased alpha2-adrenergic activation with the T
associated with increased cardioverter-defibrillator
allele as a potential mechanism. In subjects with hy-
therapies (33). In these previous studies, the GNB3
pertension, the GNB3 T allele has been associated with
TT genotype subset represented only 10% to 20% of
an increased response to clonidine, a centrally acting
the entire cohort, whereas in the GRAHF study in
alpha2-adrenergic receptor antagonist (20). In inves-
African Americans, this high-risk genotype was pre-
tigation of coronary vasomotor response, subjects
sent in more than 50% of subjects. Consistent with
with the T allele also demonstrate enhanced vaso-
these previous reports, GRAHF subjects with the GNB3
constriction (8,21), and this enhanced impact can be
TT genotype who received standard heart failure
eliminated by selective blockade of the alpha 2 , but not
therapy plus placebo demonstrated the lowest CS and
the alpha1 , adrenergic receptor (22). Although in-
poorest event-free survival. Importantly, treatment
vestigations of the role of GNB3 in cardiovascular dis-
with FDC I/H appeared to eliminate this genetic risk.
ease have focused on vascular reactivity, duplication
STUDY LIMITATIONS. The current study is limited by
of the GNB3 locus has been implicated as a cause of
study number, which diminishes the power to
obesity both in murine models and in human syn-
address pharmacogenetic interactions. In particular,
dromes of chromosomal translocation (23). In contrast,
the small number of subjects homozygous for the C
genome-wide association studies (GWAS) evaluating
allele limits the ability to evaluate the impact of gene
the genomic basis of obesity (24) and hypertension (25)
dose on the outcomes observed. In addition, although
have not identified GNB3 as a disease-associated locus.
the T allele has been previously linked to low plasma
Pharmacogenetic investigations suggest that the
renin, renin and neurohormones were not measured
GNB3 C825T polymorphism influences therapeutics
as part of the GRAHF analysis. Finally, whereas the
directed at the nitric oxide (NO) pathway. The en-
current analysis is focused on GNB3, the influence of
hanced vasoconstriction in subjects with the GNB3 T
genomics on the effectiveness of heart failure therapy
allele can be eliminated by pretreatment with the NO
is almost certainly polygenic. Previous analysis in
synthase (NOS) inhibitor L-NMMA (26). Carriers of the
GRAHF suggests that genetic heterogeneity of NOS3
T allele also have an enhanced vasodilator response to
(34) influences the benefit of FDC I/H, and variation of
nitroglycerin (27), as well as an enhanced therapeutic
the aldosterone synthase promoter affects event-free
response to the phosphodiesterase type 5 inhibitor
survival (35); however, the limited study number in
(PDE5) sildenafil in subjects with erectile dysfunction
GRAHF prevents analysis of gene-gene interactions.
(28) and in those with pulmonary arterial hypertension
An individual’s response to pharmacological inter-
(29). Insulin-induced venodilation, a response medi-
vention almost certainly involves multiple genomic
ated by the NO pathway, is diminished in healthy car-
loci, and as a result many previous attempts to
riers of the GNB3 T allele (30). Together with GRAHF,
replicate other pharmacogenetic reports of single SNP
these studies suggest that the GNB3 TT genotype may
interactions have not succeeded.
identify subjects who would obtain maximal benefit
from therapeutic strategies that enhance NO.
CONCLUSIONS
Recent reports from 2 separate longitudinal population studies suggest a higher risk of cardiovascular
A-HeFT demonstrated that treatment with FDC I/H
or cerebrovascular events in subjects with the GNB3
improved survival for a cohort of self-designated Af-
TT genotype. In the Fungata study of a rural Japanese
rican Americans with heart failure, and it remains a
cohort of 1,524 subjects, those with the GNB3 TT
pivotal study that for the first time resulted in the
genotype had a higher incidence of cardiovascular
approval by the Food and Drug Administration of a
disease (hazard ratio [HR]: 1.82, 95% confidence in-
heart failure therapy in a specific racial or ethnic
terval [CI]: 1.14 to 2.89) and stroke (HR: 1.76, 95% CI:
group (36,37). The ability of race to predict the ther-
1.01 to 3.07) despite no differences in blood pressure
apeutic impact of I/H likely reflects its role as a
or hypertension (31). In the Italian LEOGRA study,
marker of functional genomic differences. Pharma-
Last Evidence of Genetic Risk in the Aged, a cohort of
cogenomic analysis should be more effective than
subjects from 2 small towns was followed for 10 years.
race in predicting efficacy and targeting heart failure
McNamara et al.
JACC: HEART FAILURE VOL. 2, NO. 6, 2014
DECEMBER 2014:551–7
GNB3 Polymorphism and ISDN-HYD in Heart Failure
therapeutics. Although the current investigation
suggests that the GNB3 genotype predicts the thera-
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
peutic impact of FDC I/H for an individual, these
Dennis M. McNamara, Center for Heart Failure Research,
findings should be considered hypothesis generating
Heart, Lung, Blood and Vascular Medicine Institute,
and will require prospective validation. Further
University of Pittsburgh Medical Center, 566 Scaife Hall,
investigation is warranted to explore its potential
200 Lothrop Street, Pittsburgh, Pennsylvania 15213.
utility for targeting heart failure therapeutics.
E-mail: [email protected].
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KEY WORDS heart failure, outcomes,
pharmacogenetics, race
557