Prox1 gene variant is associated with fasting glucose change after antihypertensive treatment
PROX1 Gene Variant is Associated with Fasting Glucose
Yan Gong,1* Caitrin W. McDonough,1 Amber L. Beitelshees,2 Jason H. Karnes,3 Jeffrey R. O’Connell,2
Stephen T. Turner,4 Arlene B. Chapman,5 John G. Gums,1,6 Kent R. Bailey,4 Eric Boerwinkle,7 Julie A.
Johnson,1,6 and Rhonda M. Cooper-DeHoff,1,6
1Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of
Florida, Gainesville, Florida; 2College of Medicine, University of Maryland, Baltimore, Maryland; 3Division of
Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee; 4College of Medicine, Mayo Clinic
Rochester, Rochester, Minnesota; 5School of Medicine, Emory University, Atlanta, Georgia; 6College of Medicine,
University of Florida, Gainesville, Florida; 7Center for Human Genetics, University of Texas at Houston,
STUDY OBJECTIVE To assess the relationship of the 33 single nucleotide polymorphisms (SNPs) previously
associated with fasting glucose in Caucasians in genome-wide association studies (GWAS) with glucoseresponse to antihypertensive drugs shown to increase risk for hyperglycemia and diabetes.
DESIGN Randomized, multicenter clinical trial. PATIENTS A total of 456 Caucasian men and women with uncomplicated hypertension. MEASUREMENTS AND MAIN RESULTS The Pharmacogenomic Evaluation of Antihypertensives Responses
study evaluated blood pressure and glucose response in uncomplicated hypertensive patients random-ized to either atenolol or hydrochlorothiazide (HCTZ) monotherapy, followed by combination therapywith both agents. Association of these SNPs with atenolol- or HCTZ-induced glucose response wasevaluated in 456 Caucasian patients using linear regression adjusting for age, sex, body mass index,baseline glucose, baseline insulin, and principal component for ancestry. The SNP rs340874 in the 5′region of PROX1 gene was significantly associated with atenolol-induced glucose change (p=0.0013). Participants harboring the C allele of this SNP had greater glucose elevation after approximately9 weeks of atenolol monotherapy (b = +2.39 mg/dl per C allele), consistent with the direction ofeffect in fasting glucose GWAS, that showed the C allele is associated with higher fasting glucose.
CONCLUSION These data suggest that PROX1 SNP rs340874, discovered in fasting glucose GWAS, may
also be a pharmacogenetic risk factor for antihypertensive-induced hyperglycemia. b-blockers andthiazides may interact with genetic risk factors to increase risk for dysglycemia and diabetes.
KEY WORDS pharmacogenomics, dysglycemia, adverse metabolic effects, atenolol, Hydrochlorothiazide,hypertension, antihypertensives. (Pharmacotherapy 2014;34(2):123–130) doi: 10.1002/phar.1355
PEAR was supported by the National Institute of Health Pharmacogenetics Research Network grant U01-GM074492 and
the National Center for Advancing Translational Sciences under the award number UL1 TR000064 (University of Florida);UL1 TR000454 (Emory University) and UL1 TR000135 (Mayo Clinic) and funds from the Mayo Foundation. This researchwas also supported by K23 HL091120 (ALB) and K23HL086558 (RCD).
RMC, ALB, ABC, JGG, EB, STT and JAJ received funding from NIH. RMC also received funding from the NIH Women’s
Health Initiative. JGG received funding from Janssen Pharmaceuticals, Inc., has Speaker’s Bureau appointment from Boehrin-ger-Ingelheim and is a consultant for Forest Pharmaceuticals and Boehringer-Ingelheim. EB received honoraria from the Foun-dation of Rome.
*Address for correspondence: Yan Gong, Department of Pharmacotherapy and Translational Research, University of Flor-
ida, PO Box 100486, 1600 South West Archer Road, Gainesville, FL 32610-0486; e-mail: gong@cop.ufl.edu.
Ó 2013 Pharmacotherapy Publications, Inc.
PHARMACOTHERAPY Volume 34, Number 2, 2014
the association of these loci with glucose
disease for which drugs are prescribed and
response to atenolol (a b-blocker) and hydro-
places over one-third of Americans at substan-
tially increased risk for stroke, coronary heart
Identifying genetic predictors of b-blocker and
disease (including myocardial infarction), renal
failure, and heart failure.1 Two of the widely
guide clinicians to prescribe drugs that mitigate
the development of hyperglycemia and diabetes
b-blockers and thiazide diuretics,2 are associated
with decreased insulin sensitivity and hypergly-cemia.3 Short-term use of these drugs is associ-
ated with an increased incidence of impairedfasting glucose,4 and in numerous clinical trials,
long-term use has been shown to increase therisk of new-onset diabetes.5–7
The PEAR study (clinicaltrials.gov Identifier
There is considerable variability in glucose
NCT00246519) was a randomized, multicenter
changes after exposure to b-blockers and thia-
clinical trial examining the role of genetic vari-
zide diuretics.4 We have previously reported that
ability on blood pressure and adverse metabolic
reductions in blood pressure were not correlated
responses to HCTZ and atenolol.17 Men and
with changes in glucose elevation after b-blocker
women of any race between the ages of 17 and
and thiazide treatment.8 Although genetic poly-
morphisms likely explain a portion of this vari-
recruited to participate at University of Florida
ability, the few studies that have investigated the
(Gainesville, FL), Mayo Clinic (Rochester, MN),
pharmacogenomics of b-blocker and thiazide-
and Emory University (Atlanta, GA). Patients
induced glucose change have largely focused on
with diabetes were excluded from the study. The
glucose response to thiazide diuretics.9, 10
institutional review boards at each institution
Studies have shown that even for individuals
approved the protocol and each participant pro-
with normal fasting glucose, the diabetes risk
vided informed written consent before entry into
increases as fasting glucose levels increase.11, 12
In a study of more than 45,000 individuals
with a mean follow-up of 81 months, each mg/
4 weeks of washout of antihypertensive drugs.
dl increase in fasting glucose was associated
Participants were randomized to receive either
with a 6% higher risk for diabetes (hazard ratio
HCTZ 12.5 mg/day or atenolol 50 mg/day for
1.06; 95% confidence interval 1.05–1.07).11
3 weeks, followed by dose titration to 25 mg
There is evidence that drug-associated new-
and 100 mg/day, respectively, for systolic blood
onset diabetes and diabetes of other etiologies
pressure (SBP) greater than 120 mm Hg or dia-
may share common mechanisms.13, 14 Antihy-
stolic blood pressure greater than 70 mm Hg.
pertensive drugs such as b-blockers and thia-
In the atenolol treatment arm, 84% of the par-
zide diuretics could act as an environmental
ticipants underwent dose titration to atenolol
trigger to accelerate the onset of diabetes.5–7
100 mg and 99% of the participants in the
We believe that for nondiabetic individuals
HCTZ arm received titration to HCTZ 25 mg/
with genetic risk for higher fasting glucose, tak-
day. Blood pressure and metabolic responses to
ing antihypertensives with glucose-increasing
monotherapy were assessed after 9 weeks of
side effects may further increase their glucose
treatment. In the second part of the study, the
and put them at a greater risk for developing
alternate drug was added in those patients
diabetes. More specifically, we hypothesize that
with SBP above 120 mm Hg or diastolic blood
genetic variants associated with higher fasting
pressure above 70 mm Hg (> 90% for both
randomization arms), with dose titration after
increases induced by b-blockers and thiazide
diuretics. To date, 36 loci have been associated
9 weeks, as in the first portion of the study.
with fasting glucose in genome-wide association
Participants were asked to maintain their cur-
studies (GWAS) of nondiabetic Caucasians.15, 16
rent lifestyle behaviors throughout the study
To test our hypothesis, we analyzed data from
period. The current analysis focuses on the
the Pharmacogenomic Evaluation of Antihy-
glucose change after atenolol or HCTZ mono-
pertensive Responses (PEAR) study to assess
PROX1 VARIANT AND ANTIHYPERTENSIVE-INDUCED GLUCOSE ELEVATION Gong et al
rate in the remaining individuals in these lociwas 99.95%.
The phenotype of interest for this subgroup
analysis was glucose change after monotherapy,calculated as glucose after 9 weeks of monothera-
py minus glucose at baseline (untreated). Fasting
blood samples were collected for glucose and insu-
the Infinium II assay and genotypes were called
lin before and after completion of atenolol or
using BeadStudio software and GenTrain2 call-
HCTZ monotherapy. Plasma glucose was mea-
ing algorithm (Illumina, San Diego, CA). Quality
sured using a Hitachi 911 Chemistry Analyzer
control procedures were performed as with
(Roche Diagnostics, Indianapolis, IN) at the central
Human CVD Beadchip data. After the quality
control procedures, the total SNP call rate in the
remaining individuals and SNPs was 99.86%.
automated enzymatic assay. Plasma insulin was
Principal component analysis was performed
measured using the Access Ultrasensitive Insulin
using Omni1M Quad GWAS data to assess the
immunoassay system (Beckman Coulter, Brea,
ancestral background. Participant’s self-identified
CA). Insulin sensitivity status was calculated using
race information was confirmed with principal
the homeostatic model assessment – insulin resis-
component analysis of the Omni1M Quad data
tance.18 All samples were tested in duplicate, and
data reported are means of the duplicate samples.
We limited our analysis in this study to the
We were able to obtain genotypes on 33 sin-
Caucasian patients enrolled in PEAR since SNPs
gle nucleotide polymorphisms (SNPs) from the
were selected from GWAS in Caucasians. To
36 loci associated with fasting glucose level in
exclude patients that were potentially nonfasting
at either visit, we regressed glucose response
against nongenetic covariates (age, sex, body
mass index , baseline glucose, and baseline insu-
(rs16913693 in IKBKAP, rs10747083 in P2RX2
lin) and then standardized the residuals into a
and rs2302593 in GIPR) or their proxies (SNPs
distribution with mean of 0 and standard devia-
with r2 > 0.8 with the index SNPs) were not
tion of 1. Participants with standardized residu-
als that were outside four standard deviationswere excluded from analysis (n=2). In theremaining 456 Caucasian participants, associa-
tions of the 33 SNPs with glucose response after
atenolol or HCTZ monotherapy were evaluated
ized gene-centric array including approximately
using linear regression that adjusted for signifi-
cant nongenetic predictors of glucose response,
genotyped using the Infinium II Assay (Illumina,
including baseline glucose, baseline insulin, age,
San Diego, CA). Genotypes were called using
sex and body mass index. The analyses also
GenomeStudio software version 2011.1 and the
adjusted for the first principal component for
Genotyping Module version 1.9 calling algo-
ancestry, which corresponds to European ances-
rithm (Illumina, San Diego, CA). Participants
try in PEAR individuals. Additive mode of inher-
were excluded if sample genotype call rates were
itance was assumed where the SNPs were coded
below 95% and SNPs were excluded if genotype
as 0, 1, and 2 in the linear regression model.
call rates were below 95%. Sample contamina-
To correct for multiple testing of 33 SNPs, we
tion was detected by checking sex mismatches
lowered the a level to 0.0015 (0.05/33) so that
using X chromosome genotype data and cryptic
the type I error (false positive) of the study is
relatedness was estimated by pairwise identity-
less than 0.05. Therefore SNPs with p values of
by-descent analysis implemented using PLINK
less than 0.0015 were considered statistically
(http://pngu.mgh.harvard.edu/purcell/plink/).
significant. For nominally significant (p<0.05)
Hardy–Weinberg Equilibrium was assessed with
SNPs with lower minor allele frequencies, we
a v2 test with one degree of freedom. After the
also explored a dominant model whereby het-
quality control procedures, the total SNP call
erozygotes and minor allele homozygotes were
PHARMACOTHERAPY Volume 34, Number 2, 2014
combined and compared with the common allele
+ 2.8 mg/dl (interquartile range: À 3.8 to
homozygotes. To evaluate the overall risk and
+ 7.0 mg/dl). The median glucose change after
benefit of antihypertensive treatments, we also
HCTZ monotherapy was + 2.0 mg/dl (interquar-
assessed the systolic blood pressure response for
tile range: À4.3 to + 6.8 mg/dl). Figure 1 dem-
onstrates the large interindividual variability in
response using linear regression, adjusting for
glucose response to atenolol and HCTZ mono-
baseline systolic blood pressure, age, sex, and
therapy in Caucasian hypertensive participants.
first principal component. All single SNP linearregression
SNPs associated with atenolol-induced glucose
PLINK.20 Other analyses were performed in SASversion 9.3 (Cary, NC).
Genotypes for the 33 previously identified
fasting glucose GWAS SNPs were available forPEAR participants from the two genotyping plat-
The baseline characteristics of the 456 Cauca-
sian PEAR participants assigned to atenolol
Hardy–Weinberg Equilibrium in Caucasians.
(n=232) and HCTZ treatment (n=224) are pre-
An SNP in the 5′ untranslated region of the
sented in Table 1. The participants had a mean
prospero homeobox 1 gene (PROX1), rs340874,
was significantly associated with glucose change
44% were overweight and obese, respectively. The
145.0 Æ 9.4/92.9 Æ 5.5 mm Hg. The mean base-
Atenolol Monotherapy
line glucose in both treatment groups was in the
normal range, with a median of 90 mg/dl and
interquartile range of 84–96 mg/dl.
After an average of 9 weeks of atenolol mono-
Table 1. Baseline Characteristics of Caucasian Partici-
glucose change (mg/dL) HCTZ Monotherapy
BMI = body mass index; HOMA-IR = homeostatic model assess-
glucose change (mg/dL)
aNumeric characteristics were presented as mean Æ standard devia-tion and categorical variables were presented as number and per-
Figure 1. Distribution of glucose change (mg/dl) after
atenolol (A) and hydrochlorothiazide monotherapy (B).
PROX1 VARIANT AND ANTIHYPERTENSIVE-INDUCED GLUCOSE ELEVATION Gong et al
Table 2. Fasting Glucose SNPs Associated with Glucose Response to Atenolol or HCTZ Monotherapy in PEAR CaucasianHypertensive Patients (with p<0.05)
MAF = minor allele frequency; SE = standard errorLocation: NCBI build 36 base pair position. Beta indicates the glucose response (in mg/dl) for each glucose increasing allele. p values werelinear regression p adjusted for baseline glucose, baseline insulin, age, sex, body mass index and principal components for ancestry.
aAlleles were presented as major/minor alleles.
bp value that reached Bonferroni-corrected significance level. PROX1 rs340874
b = +2.4 mg/dl; Table 2). Participants with T/T,
T/C and C/C genotypes had mean glucosechanges of À 0.46, + 1.77, and + 3.19 mg/dl,
respectively (Figure 2). The systolic blood pres-
sure reduction was not statistically different
among the three genotype groups (À12.6 mm
-induced
À9.3 mm Hg for C/C individuals, respectively,
p=0.15), although the trend was such that those
with the greatest glucose increase also had a
smaller reduction in blood pressure.
An intronic SNP in ARAP1 gene (ArfGAP with
RhoGAP domain, ankyrin repeat and PH domain1), rs11603334, was nominally associated with
Figure 2. Fasting glucose SNP PROX1 rs340874 associated
b = + 2.7 mg/dl) (Table 2). Participants with
with glucose response to atenolol monotherapy among
the A allele had a higher glucose increase after
Caucasian hypertensive patients. Error bars represent
+ 0.7 mg/dl for A/A, A/G, and G/G individuals,respectively (Figure S1). There was no statisti-
therapy, patients with A/A, A/T, and T/T geno-
cally significant difference in reduction of sys-
tolic blood pressure during the same treatment
response of + 9.1, + 3.1, and + 0.6 mg/dl,
period: A/A: À9.5 mm Hg, A/G: À9.9 mm Hg,
respectively (Figure S2). There was no signifi-
cant difference in systolic blood pressure reduc-
Two other SNPs showed a trend toward asso-
tion among the genotypes: À9.7, À6.7, and
ciation with glucose change after atenolol mono-
À8.0 mm Hg for A/A, A/T, and T/T, respectively
therapy. These SNPs included rs11039149, an
intronic SNP in NR1H3 (p=0.057, b = + 1.6 mg/
rs10830963 and ADCY5 rs11708067) showed a
dl) and rs4869272, an intergenic SNP between
trend toward association with glucose change
PCSK1 and MIR583 (p=0.058, b = + 1.5 mg/dl)
SNPs associated with HCTZ-induced glucose
To our knowledge, this is the first study to
test fasting glucose GWAS loci on drug-induced
An intronic SNP rs11920090 in SLC2A2 (sol-
glucose change. Among 33 SNPs previously doc-
ute carrier family 2, member 2) gene was the
umented to be associated with fasting glucose
levels in Caucasians, one SNP achieved statistical
significance for association with glucose change
b = + 3.1 mg/dl) (Table 2). After HCTZ mono-
after approximately 9 weeks of atenolol mono-
PHARMACOTHERAPY Volume 34, Number 2, 2014
therapy. Two other SNPs were nominally associ-
direction of effects appeared to be opposite of
ated with glucose change after exposure to ate-
the fasting glucose GWAS effects. In the prior
fasting glucose GWAS, individuals with the G
The effect sizes of these SNPs on the atenolol
allele of ARAP1 rs11603334 had higher fasting
or HCTZ-associated glucose change were in the
glucose levels (b = 0.019 mmol/L or 0.34 mg/dl
range of 2–3 mg/dl per allele, which is approxi-
per allele).15 In this study, however, patients
mately 10 times greater than the effect sizes
with the G allele had a smaller glucose increase
observed in the fasting glucose GWAS.15, 16 This
after atenolol monotherapy. In fasting glucose
is consistent with numerous studies indicating
GWAS, the T allele of SLC2A2 rs11920090 was
that pharmacogenetic effect sizes are larger than
associated with higher glucose levels, with a b of
+ 0.02 mmol/L or + 0.36 mg/dl.16 In this study,
however, the T allele was associated with a
is an early specific marker for developing liver
smaller increase in glucose after HCTZ mono-
and pancreas in foregut endoderm. In an in vitro
therapy. The associations of these two SNPs
were not consistent with our original hypothesis.
repressor of hepatocyte nuclear factor 4a (HNF4
One possible explanation is that the patients
a) that may play a key role in the regulation of
may have other variants (for which we did not
bile acid synthesis and gluconeogenesis in the
test) that might influence the glucose response
liver.25 HNF4A, which is the gene that encodes
in the opposite direction from these two SNPs.
HNF4 a, is responsible for a type of diabetes
For this study, we evaluated only the associa-
called maturity-onset diabetes of the young
tions of single SNPs (previously identified in
(MODY).26 A genetically heterogeneous mono-
fasting glucose-associated GWAS) with glucose
genic form of noninsulin-dependent diabetes
change to antihypertensive treatment. It is our
mellitus, MODY is characterized by onset usu-
long-term goal to evaluate combined effect of
ally before age 25 and often in adolescence or
multiple variants in a model to predict which
childhood and by autosomal dominant inheri-
patient population would benefit from antihy-
tance. In GWAS studies and meta-analyses of
pertensive treatment without adverse metabolic
fasting glucose homeostasis and risk of type 2
side effects, including increased glucose.
The mechanisms by which atenolol and HCTZ
rs340874 C allele had higher fasting glucose
increase glucose are not well understood. This
level (b = + 0.013 mmol/L or + 0.23 mg/dl per
study identifies one SNP (PROX1 rs340874 C
allele, p=6.6*10À6) and were at higher risk of
allele) that is associated with higher glucose
developing type 2 diabetes (odds ratio 1.07,
increase after short term exposure (approxi-
p=7.2*10À10).16 In our study, hypertensive
mately 9 weeks) to atenolol monotherapy; this
Caucasians harboring the C allele of this SNP
same SNP was also previously associated with
had greater glucose elevation after approximately
These data suggest that administration of ate-
2.39 mg/dl per allele) and a trend for less pro-
nolol in individuals already predisposed to
nounced blood pressure reduction. If replicated,
higher fasting glucose by their PROX1 genotype
these data suggest that hypertensive Caucasians
might provoke an exaggerated glucose elevation.
with the C allele of this SNP should avoid treat-
Due to the long-term nature of antihypertensive
ment with atenolol where possible, given that
therapy and the wide use of b-blockers, it is
even modest elevation in glucose could increase
imperative to further investigate the underlying
the long-term risk for diabetes (6% higher risk
mechanisms of the adverse metabolic effects
of diabetes for each mg/dl increase),11 the long-
associated with these agents. We anticipate that
term nature of antihypertensive therapy and the
studies of larger sample size will enable us to
high allele frequency of this SNP (48% minor
find additional genetic variants. Hence, our goal
is to identify multiple genetic variants that could
Two SNPs achieved nominal p values of less
be considered in a risk model for increased glu-
than 0.05 but did not meet the requirement for
cose when considering the initiation of antihy-
statistical significance after considering multiple
This study is not without some limitations.
associated with the atenolol-induced glucose
The PEAR study was designed primarily as a
response, and SLC2A2 rs11920090, associated
blood pressure response study. For blood pres-
with the HCTZ-induced glucose response, the
sure lowering, 9 weeks of treatment is sufficient
PROX1 VARIANT AND ANTIHYPERTENSIVE-INDUCED GLUCOSE ELEVATION Gong et al
to observe maximal blood pressure lowering.
therapy in hypertension. Circulation 2008;117:2706–15; dis-
Regarding the glucose response, data from the
7. Barzilay JI, Davis BR, Cutler JA, et al. Fasting glucose levels
large hypertension study ALLHAT27 provides
and incident diabetes mellitus in older nondiabetic adults ran-
evidence that glucose continues to rise over the
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long term, particularly in patients without diabe-
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tes when antihypertensive treatment begins.
Importantly, fasting glucose and the incidence of
8. Smith SM, Gong Y, Turner ST, et al. Blood pressure responses
new onset diabetes continued to rise over the
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entire 5-year study period. This suggests that the
9. Maitland-van der Zee AH, Turner ST, Schwartz GL, Chapman
duration of exposure is very important regarding
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tant than dose, which is titrated to blood pres-
sure response early in therapy. Therefore, the
10. Karnes JH, McDonough CW, Gong Y, et al. Association of
PEAR study likely underestimated the glucose
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These data suggest that variants discovered in
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fasting glucose GWAS provide pharmacogenetic
13. Wang TJ, Larson MG, Vasan RS, et al. Metabolite profiles
risk factors for atenolol or HCTZ-induced hyper-
and the risk of developing diabetes. Nat Med 2011;17:448–53.
glycemia. These drugs may interact with genetic
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risk factors to increase the risk for dysglycemia
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of these associations are needed. After validation
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in other independent populations, the clinical
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We acknowledge and thank the valuable contribu-
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19. Keating BJ, Tischfield S, Murray SS, et al. Concept, design
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Frederic Rabari-Oskoui, Dan Rubin, and Siegfried
array for large-scale genomic association studies. PLoS ONE2008;3:e3583.
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PHARMACOTHERAPY Volume 34, Number 2, 2014
26. Yamagata K, Furuta H, Oda N, et al. Mutations in the hepato-
Figure S1. Fasting glucose SNP ARAP1 rs11603334 nominally asso-
cyte nuclear factor-4alpha gene in maturity-onset diabetes of
ciated with glucose response to atenolol monotherapy among Cau-
the young (mody1). Nature 1996;384:458–60.
casian hypertensive patients. Error bars represent standard errors
27. The ALLHAT Officers and Coordinators for the ALLHAT
Collaborative Research Group. Major outcomes in high-risk
Figure S2. Fasting glucose SNP SLC2A2 rs11920090 nominally
hypertensive patients randomized to angiotensin-converting
associated with glucose response to hydrochlorothiazide monother-
enzyme inhibitor or calcium channel blocker vs diuretic: the
apy among Caucasian hypertensive patients. Error bars represent
antihypertensive and lipid-lowering treatment to prevent heart
attack trial (ALLHAT). JAMA 2002;288:2981–97.
Table S1. Fasting glucose GWAS SNPs included in this analysis. Table S2. Other fasting glucose SNPs and association with ateno-lol-induced glucose change.
Table S3. Other fasting glucose SNPs and association with HCTZ-induced glucose change.
The following supporting information is available in the online
EN SEANCE DU CONSEIL COMMUNAL DU MARDI 29 SEPTEMBRE 2009 A 20H00’ Présents: M.M. PIETTE Luc, bourgmestre ; DUMONT, ANCION, BOCART, Mme FAELES-VAN ROMPU, échevins ;DEKONINCK, Président de CPAS. MOUTON, GAILLARD, de WOUTERS, RONDIAT, COLOT, Mme PUISSANT-BONATO,Mme GILLES, Mme GAUX-LAFFINEUR, Mme MARCHAL-VAN DER SCHUEREN, Mme FALLAY-BATTEL, M. PLUYMERS, conseillers ; Et Mme SEPTON François
Upcoming Events COMMUNITY & SOCIAL ENGAGEMENT from 5 November, on Tuesdays 11:30am-3:30pm The Volunteer Desk will be open once again. This service offers Bocconi students, faculty and staff the opportunity to get to know and approach Milanese organizations committed to social issues, dedicating part of their time to concrete activities. The service is managed thanks to a collabor