Alimentary Pharmacology and Therapeutics
Inulin significantly improves serum magnesium levels in proton
pump inhibitor-induced hypomagnesaemia
M. W. Hess*, J. H. F. de Baaij*, M. Broekman†, T. M. Bisseling†, B. Haarhuis‡, A. Tan§, R. te Morsche†,
J. G. J. Hoenderop*, R. J. M. Bindels* & J. P. H. Drenth†
*Department of Physiology, Radboud
Institute for Molecular Life Sciences,
Radboud University Medical Center,
Nijmegen, The Netherlands.
†
Department of Gastroenterology and
Hepatology, Radboud University
Medical Center, Nijmegen, The
Netherlands.
‡
Department of Gastroenterology,
Bernhoven Hospital, Uden, The
Netherlands.
§
Department of Gastroenterology,
Canisius-Wilhelmina-Hospital,
Nijmegen, The Netherlands.
Correspondence to:
Prof. R. Bindels, Department of
Physiology (286), Radboud University
Medical Center, PO Box 9101, 6500
HB Nijmegen, The Netherlands.
E-mail: [email protected]
Publication data
Submitted 13 January 2016
First decision 26 January 2016
Resubmitted 29 February 2016
Resubmitted 18 March 2016
Accepted 18 March 2016
Mark W. Hess, Jeroen H.F. de Baaij
contributed equally to this work.
This article was accepted for publication
after full peer-review.
SUMMARY
Background
Proton pump inhibitors (PPI) are among the most widely prescribed drugs
to treat gastric acid-related disorders. PPI-induced hypomagnesaemia, a
defect in intestinal absorption of Mg2+, can be a severe side effect of
chronic PPI use.
Aim
To restore serum Mg2+ concentrations in PPI-induced hypomagnesaemia
patients by dietary supplementation with inulin fibres.
Methods
Eleven patients with PPI-induced hypomagnesaemia and 10 controls were
treated with inulin (20 g/day). Each trial consisted of two cycles of 14-day
inulin treatment followed by a washout period of 14 days. Patients continued to use their PPI. Serum Mg2+ levels served as the primary endpoint.
Results
Inulin significantly enhanced serum Mg2+ levels from 0.60 to 0.68 mmol/L in
PPI-induced hypomagnesaemia patients, and from 0.84 to 0.93 mmol/L in
controls. As a consequence 24 h urinary Mg2+ excretion was significantly
increased in patients with PPI-induced hypomagnesaemia (0.3–2.2 mmol/day).
Symptoms related to hypomagnesaemia, including muscle cramps and
paraesthesia, were reduced during intervention with inulin.
Conclusion
Inulin increases serum Mg2+ concentrations under PPI maintenance in
patients with PPI-induced hypomagnesaemia.
Aliment Pharmacol Ther
ª 2016 John Wiley & Sons Ltd
doi:10.1111/apt.13619
1
M. W. Hess et al.
BACKGROUND
Proton pump inhibitors (PPIs) are used by millions of
patients for treatment and prevention of peptic ulcers,
gastro-oesophageal reflux disease and NSAID-induced
mucosal damage.1, 2 There is accumulating evidence that
PPIs induce hypomagnesaemia.3, 4 In 2011, the Food
and Drug Administration issued a formal warning on
PPI-induced hypomagnesaemia.5 A systematic review
from 2012 on 36 cases concluded that PPI-induced
hypomagnesaemia represents a class effect as it occurs
with all PPIs but is absent with other gastric-suppressing
agents such as histamine-2 receptor antagonists.6 The
adverse effect results in a wide spectrum of symptoms
including, but not limited to, fatigue, vertigo, lightheadedness, numbness and gastrointestinal complaints.6–8
PPI-induced hypomagnesaemia occurs after prolonged
PPI use, resolves within days following interruption, but
resumption of treatment inevitably results in recurrence.6, 9 Nevertheless, many patients are dependent on
PPIs since they do not respond sufficiently to histamine2 receptor antagonists.10
Currently, there is no satisfying treatment strategy that
resolves PPI-induced hypomagnesaemia while maintaining the desired acid suppressing effect of PPIs. Oral Mg2+
supplementation is not sufficient to treat PPI-induced
hypomagnesaemia in 25% of PPI-induced hypomagnesaemia patients.5 This is the reason to search for alternative strategies that allow patients to continue PPI yet
protect them against hypomagnesaemia. Mg2+ loss probably results from intestinal malabsorption of Mg2+ as renal
Mg2+ retention is unaffected in PPI-induced hypomagnesaemia cases11, 12 PPIs raise luminal pH which interferes
with adequate Mg2+ uptake in the large intestine.13 A
strategy that centres on acidification of colon might contribute to a more efficient intestinal absorption of Mg2+.
Natural bacterial fermentation of carbohydrates and
proteins generates short-chain fatty acids, which results
in an acidic environment that promotes Mg2+ solubility
and absorption.14 Inulin is a naturally occurring
oligosaccharide that upon fermentation by colonic bacteria results in a decrease of pH.15–19 In experiments with
rodents, inulin actually increased the intestinal uptake
Ca2+.20 Therefore, inulin may serve to increase serum
Mg2+ concentrations in patients with PPI-induced hypomagnesaemia.
In a series of n-of-1 crossover trials, we treated
patients with PPI-induced hypomagnesaemia with inulin
supplementation with the aim to evaluate changes in
serum Mg2+ concentrations under continuous PPI use.
2
By this approach we aimed to obtain scientifically robust
(‘level 1’) evidence of benefits and harms of inulin treatment for PPI-induced hypomagnesaemia.
METHODS
Series of n-of-1 trials
The trial protocol was approved by the local ethics
committee (METC Arnhem Nijmegen, the Netherlands)
and the study was performed according to the declaration of Helsinki. All patients provided written informed
consent. The trial was registered at clinicaltrials.gov
(NCT02518659). All study investigators had access to the
study data, reviewed and approved the final manuscript.
Cases with PPI-induced hypomagnesaemia were collected between 2012 and 2014 in the Radboud University
Medical Center (Nijmegen, the Netherlands), Canisius
Wilhelmina Ziekenhuis (Nijmegen, the Netherlands) and
Bernhoven Ziekenhuis (Oss, the Netherlands). To be
included patients should be chronic users of PPIs and
suffer from PPI-induced hypomagnesaemia. Patients with
uncontrolled diabetes were excluded from enrolment.
Healthy controls were recruited from the community
using advertisements in the local media. Patients with
PPI-induced hypomagnesaemia and healthy controls participated in an intervention trial which used orally
administered fructooligosaccharide inulin fibres. Participants were provided with portions of 20 g inulin (Synergy 1; Orafti-Beneo, Tienen, Belgium) to be consumed
with meals. Patients were asked to maintain their dietary
habits and to continue the use of PPIs.
Aim and objectives
We aimed to improve and to individualise treatment of
patients with hypomagnesaemia using a series of n-of-1
trials to decipher benefits and harms of inulin treatment
for PPI induced hypomagnesaemia. This study was
designed as a single-centre, controlled, multiple crossover
n-of-1 studies. Total study duration was 56 days, divided
into 4 periods of 14 days each (Figure 1). During days
0–14 and days 28–42 all participants were given inulin
in a dosage of 20 g/day, which is in the same range as
other studies.19 Each of the treatment phases was followed by a washout phase of 14 days.
Measurements
Primary endpoint is the study population treatment
effect of inulin compared to control by the serum Mg2+
concentration on day 0, 14, 28, 42 and 56. Secondary
Aliment Pharmacol Ther
ª 2016 John Wiley & Sons Ltd
Inulin improves PPI-induced hypomagnesemia
14
0
Controls (n = 10)
Inulin
Patients (n = 11)
Blood
28
Wash out
Blood
Blood
Urine*
42
Inulin
56
Wash out
Blood
Urine*
Mixed models analysis
Primary outcome: serum Mg2+ concentration
Secondary outcomes: serum Ca2+, K+
concentrations
Blood
Figure 1 | Design and time-schedule of the series of n-of-1 trials. Inulin supplementation is administered during days
0–14 and days 28–42, followed by 14 day washout periods. Blood is collected every 14 days for serum ion
determinations. *Urine is only collected in patients.
endpoints were serum Ca2+, K+ and Na+ concentrations
at the indicated time points. We evaluated 24-h urinary
Mg2+ and Ca2+ excretion in the PPI-induced hypomagnesaemia group on days 27/28 and days 41/42 immediately prior to blood withdrawals. During each of the four
treatment cycles of 14 days (inulin-washout-inulin-washout) patients were questioned for the presence of diarrhoea, flatulence, abdominal bloating, abdominal
cramping, nausea, boborygmi (bowel sounds) and presence of soft stools.
Laboratory procedures
Serum Mg2+, Ca2+, K+ and Na+ levels were determined
using a Hitachi Autoanalyzer according to the manufacturer’s protocol (Abbott Diagnostics, Ottignies/LouvainLa-Neuve, Belgium). Urinary Mg2+ concentrations
were determined with a colorimetric xylidyl-II blue kit
(Roche Diagnostics, Burgess Hill, UK) at 600 nm wavelength. Urinary Ca2+ concentrations were measured
with a colorimetric chromogenic/buffer dual-component
kit (Sigma Aldrich, Gillingham, UK) at 570 nm wavelength.
Statistical analysis
A mixed model analysis was performed using the SAS 9.2
software package (Cary, NC, USA). For each of the electrolytes (Mg2+, Ca2+, K+ and Na+) the mixed model was
used with fixed factors patient group (Control, Patients),
treatment (Inulin addition, No addition) and their interaction. To deal with the correlation of the repeated measured outcome within a single patient, a random
intercept was included in the model. The model assumes
that the effect of treatment can be different for the two
patient groups (interaction) and that correlations
between two measurements within a patient is the same
for each combination. Using the mixed model, the treatment effect, that is, the difference of the mean outcome
using inulin minus the mean outcome without inulin,
Aliment Pharmacol Ther
ª 2016 John Wiley & Sons Ltd
for both patient groups was estimated and tested. Averaged values were reported as mean S.E.M.
RESULTS
Demographics
Twenty-six patients (11 PPI-hypomagnesaemia patients
and 15 healthy non-PPI using controls) were contacted
for participation (Figure 1). All patients (6 male, 5
females, mean age 64 years-of-age, range 46-76 years-ofage) consented. We excluded five controls, due to intestinal complaints (n = 1), unwillingness to adhere to the
study protocol (n = 1), intercurrent illness (n = 1)
or loss of interest (n = 2). This resulted in a final study
population of 11 cases and 10 healthy controls (Table 1).
Patients with PPI-induced hypomagnesaemia used
omeprazole (n = 6), pantoprazole (n = 3) or esomeprazole (n = 2) and the doses ranged from 20 to 60 mg/day.
In all included patients, PPIs were temporarily stopped
at one stage in their disease to show that hypomagnesemia is caused by PPI use. However, all of them reinitiated PPI treatment for gastrointestinal protection.
During the study all patients continued their PPI
treatment.
Inulin increases serum Mg2+ concentrations
Proton pump inhibitor-induced hypomagnesaemia
patients had mean baseline serum Mg2+ concentration of
0.60 0.03 mmol/L, which increased to 0.68 0.03
mmol/L (P < 0.01) after the first course of 2 weeks of
inulin supplementation (Figure 2a). Similarly, the second
inulin course also enhanced serum Mg2+ concentrations
from 0.61 0.03 to 0.69 0.03 mmol/L (P < 0.01).
In controls, serum Mg2+ levels increased significantly
during the second course of 2 weeks (0.84 0.02
to 0.93 0.03 mmol/L, Figure 2c). To determine a
global treatment effect, we performed a mixed models
analysis was performed that demonstrated that inulin
3
M. W. Hess et al.
Table 1 | Basic demographics of the participants
Demographics
Age, years (range)
Sex, m:f (n)
Dose PPI (mg/day)
Type PPI
Length of PPI use, years (range)
Baseline serum electrolytes (mmol/L)
Mg2+
Ca2+
Na+
K+
Indication for PPI use (n)
Gastro-oesophageal reflux disease
Gastritis
Medication (n)
Calcium antagonists
Statins
A2R antagonists
ACE inhibitors
Beta blockers
Sulfonylureum derivates
Comorbidities (n)
Hypertension
Type 2 diabetes
Patients (n = 11)
Controls (n = 10)
64 (46–76)
6:5
62.2 6.3
o:6, p:3, e:2
8.1 (1.3–13.7)
49 (23–75)
5:5
–
–
–
0.60
2.27
141
3.99
0.03
0.04
1
0.14
0.85
2.36
141
4.30
10
1
–
–
5
4
4
2
3
2
0
0
0
0
0
0
8
4
0
0
0.03*
0.05
1
0.13
Results are represented as means SEM. o, omeprazole, p, pantoprazole, e, esomeprazole. Medication was included in the table
when used by multiple patients in the cohort. A2R, Angiotensin II receptor; ACE, angiotension converting enzyme.
*P < 0.01.
increased serum Mg2+ concentrations with 0.10 mmol/L
(P < 0.01) in patients and with 0.06 mmol/L (P < 0.01)
in controls.
Inulin restores urinary Mg2+ excretion
Urinary Mg2+ excretion analysis of PPI-induced hypomagnesaemia patients prior to and after the second inulin course demonstrated that eight cases had baseline
urinary Mg2+ concentrations below the threshold of
quantification (<0.2 mmol/L), while the remaining
cases (n = 3) had a mean of 0.29 0.05 mmol/24 h
(Figure 2b). After 14 days of inulin urinary Mg2+ excretion increased to a mean of 2.20 0.56 mmol/24 h
(P < 0.01).
Inulin and electrolyte homeostasis
To determine the specificity of the effect of inulin supplementation on electrolyte homoeostasis, serum Ca2+,
Na+ and K+ levels were determined. During the first inulin course, serum Ca2+ concentrations increased in
patients (2.27 0.04 to 2.41 0.04 mmol/L; P < 0.01,
Figure S1a). Similarly, the control group showed a
4
significant increase in serum Ca2+ concentrations only in
the second treatment period (P < 0.05, Figure S1c).
Mixed models analysis with data from both 2-week treatment courses demonstrated an increase in serum Ca2+
levels with 0.09 mmol/L in the PPI-induced hypomagnesaemia group. Urinary Ca2+ excretion increased significantly from 1.23 0.30 to 2.40 0.28 mmol/24 h in
PPI-induced hypomagnesaemia patients (P < 0.01, Figure S1b). Serum K+ levels increased in PPI-induced
hypomagnesaemia cases during the second inulin course
(Figure S2a). The overall mean treatment effects for inulin on serum K+ were significant for patients with a net
increase in 0.26 mmol/L (P < 0.01), as determined by
mixed models analysis (Figure S2a,b). Finally, inulin did
not affect serum Na+ concentrations in both patients
and control (Figure S2c,d).
Symptoms
Seven patients with PPI-induced hypomagnesaemia
reported symptoms likely attributed to hypomagnesaemia
(Table 2). Most frequently reported were paraesthesia in
hands and feet, muscle cramps, generalised weakness,
Aliment Pharmacol Ther
ª 2016 John Wiley & Sons Ltd
Inulin improves PPI-induced hypomagnesemia
PPI-induced hypomagnesemia patients
(a)
Inulin
8
Inulin
*
Inulin
*
*
Urine Mg2+ (mmol/24 h)
Serum [Mg2+] (mmol/L)
1.0
PPI-induced hypomagnesemia patients
(b)
0.8
0.6
0.4
6
4
2
0.2
0
0
14
28
42
56
Time (days)
(c)
27/28
41/42
Time (days)
Controls
Inulin
1.2
Inulin
Serum [Mg2+] (mmol/L)
*
1.0
0.8
0.6
0.4
0
14
28
42
56
Time (days)
Figure 2 | Effects of inulin on serum Mg2+ and 24 h urinary Mg2+ excretion. The serum Mg2+ concentration is shown
during 56 days in cases (a) and controls (c). The dotted line represents the lower cut-off value for normal serum
Mg2+ levels. (b) Depicts the urinary excretion of Mg2+ before (day 27/28) and the end (day 41/42) of the second
14-day period of inulin supplementation. Values depict means S.E.M. in mmol/L, with significant effects highlighted
by *, with P < 0.01.
tetany of hands, cardiac arrhythmia and nausea/vomiting. Inulin improved these symptoms. Three patients
reported remission of paraesthesia in hands and feet, two
patients found that muscle cramps improved or disappeared. Tetany of hands disappeared in a single patient,
while weakness improved in another.
Introduction of inulin was associated with onset of
intestinal symptoms such as bloating, increased flatulence
(19 patients) and boborygmi (16 patients), which
improved within the first week of therapy. Other commonly reported symptoms were soft stools and transient
diarrhoea (Table 2). One control patient prematurely
stopped treatment because of severe diarrhoea after
5 days of inulin use.
Aliment Pharmacol Ther
ª 2016 John Wiley & Sons Ltd
DISCUSSION
The primary finding of this study is that inulin increases
serum Mg2+ concentrations in patients with PPI-induced
hypomagnesaemia. Fourteen days of inulin supplementation was sufficient to raise Mg2+ levels in patients maintaining PPI intake. Inulin restored serum Mg2+
concentrations to the low-normomagnesemic range in
PPI users. As a consequence, hypomagnesaemia-related
symptoms improved. Inulin may thus represent an
attractive treatment option in patients with PPI-induced
hypomagnesaemia that cannot stop PPI use.
The typical approach of PPI-induced hypomagnesaemia consists of PPI withdrawal. However, alternative
options such as histamine-2 receptor antagonists are
5
M. W. Hess et al.
Table 2 | Symptoms of the participants
Before inulin intake
Muscle cramps
Paresthesia in hands/feet
Generalised weakness
Tetany of hands
Cardiac arrhythmia
Nausea/vomiting
Flatulence
Boborygmi
Soft stools
Transient diarrhoea
After inulin intake
Patients (n = 11)
Controls (n = 10)
Patients (n = 11)
Controls (n = 10)
5
4
2
2
1
1
1
–
–
4
–
–
–
–
–
–
–
–
–
–
3
1
1
1
1
–
11
8
7
4
–
–
–
–
–
–
4
4
3
2
Values represent number of patients.
often ineffective.6, 21 Oral Mg2+ supplementation results
in side effects such as diarrhoea and are insufficient to
raise Mg2+ levels in PPI users.22 Inulin is able to increase
serum Mg2+ in PPI-induced hypomagnesaemia patients
and in healthy controls, but the magnitude of increase in
patients exceeded that of controls by a factor two. These
results are in line with previous observations documenting that inulin fibres enhance Mg2+ absorption in human
volunteers.19, 23 The dose of 20 g/day is based on previously published studies that used inulin to increase
intestinal absorption of Ca2+ or Mg2+. The commonly
used dose in this type of experiments ranges between 10
and 40 g/day.19 Our dose of 20 g/day is in the centre of
this spectrum.
The beneficial effects of inulin supplementation were not
restricted to Mg2+ but extended to other electrolytes such as
Ca2+ and K+. Although serum Ca2+ and K+ levels were in
the normal range in our study population, there have been
reports of hypocalcaemia and hypokalaemia associated with
PPI use.6 We observed an increase in serum Ca2+ and K+
levels that stayed within the normal range.
In line with earlier studies in healthy patients using
PPI, our PPI-induced hypomagnesaemia patients had
marginally decreased 24-h urinary Ca2+ excretion.24
Low-serum Mg2+ suppresses parathyroid hormone secretion which reduces Ca2+ absorption and puts patients at
risk for bone-fractures and/or osteoporosis.25 Inulin
raised renal Ca2+ excretion in our population, resulting
from stimulated intestinal Ca2+ absorption which is
reflected in a net increase Ca2+ serum level. As such, this
effect may contribute to the protection against osteoporosis in chronic PPI users.26
The fact that inulin increases serum Mg2+, Ca2+ and
+
K in this trial suggests a general mechanism of action.
6
A plausible hypothesis proposes that colonic fermentation of inulin drives short-chain fatty acid production
that lowers intestinal pH and ultimately improves the
solubility of minerals.18, 27 Ingestion of fermentable
oligosaccharides increases true fractional Mg2+ and Ca2+
absorption in humans.28, 29 Gut microbiota are present
in the colon and caecum, overlapping with the main
regions of Mg2+ absorption.30 Additionally, the main
intestinal Mg2+ channel, TRPM6, is more active in acidic
pH range.31 These findings may explain why the effects
of inulin on Mg2+ absorption are stronger than on the
uptake of other ions.
The use of inulin comes with gastrointestinal complaints such as flatulence and boborygmi. However, these
side effects were mainly reported within the first 2–
3 days after the start of the inulin treatment. These
events reflect a transient adaptation to inulin treatment
and disappeared with prolonged treatment. Therefore,
we consider the 20 g/day dose as well-tolerated in PPI
patients. This is supported by the fact that all the PPIinduced hypomagnesaemia patients completed the full
56-day trial period.
Our study comes with strength and limitations. The
introduction-withdrawal design included two cycles of
inulin-based treatment. Such a design delivers evidencebased results and is easily translatable to a large variety
of settings within daily clinical practice.32 The clinical
effect on Mg2+ serum levels during both cycles was
highly reproducible in and between patients suggesting a
true treatment effect. The washout time was determined
on basis of a previous systematic review that indicated
that the PPI-induced hypomagnesaemia is reversible in a
few (<5) days.6 As such we avoided a carry-over effect
that was documented by the finding that serum Mg2+
Aliment Pharmacol Ther
ª 2016 John Wiley & Sons Ltd
Inulin improves PPI-induced hypomagnesemia
returned to baseline levels within 14 days in all patients.
PPI-induced hypomagnesaemia is a rarely reported side
effect of PPI use and a recent review identified 36 globally published cases of PPI-induced hypomagnesaemia.6
It is, therefore, difficult to conduct group-RCTs to determine its effectiveness. N-of-1 trials may provide a way of
gathering scientifically robust evidence of effectiveness in
small patient groups. N-of-1 trials are randomised, controlled, multiple crossover trials in single patients, in
which data are contributed over several treatment cycles.
Evidence from several n-of-1 trials can be aggregated to
produce population treatment effect estimates. We used
a multiple crossover n-of-1 trial so that each patient
acted as own control and contributed multiple cycles of
data. A limitation of this design is the absence of blinding. We were able to trial 11 patients who were able to
cycle through all treatment periods. Effects were consistent between treatment periods which suggests that the
robustness of the design.
In conclusion, we demonstrated that inulin stimulates
intestinal mineral uptake. Although not all patients
reached normal serum Mg2+ levels after inulin treatment,
serum Mg2+ levels increased sufficiently to improve
hypomagnesaemia-related symptoms. Therefore, inulin
provides a novel treatment for patients with PPI-induced
hypomagnesaemia that do not respond to regular Mg2+
supplementation. Future randomised trials are necessary
to examine the effects in larger patient groups. Its effect
may extend to other hypomagnesaemic populations such
as type-2 diabetics.33
SUPPORTING INFORMATION
Additional Supporting Information may be found in the
online version of this article:
Figure S1. Effects of inulin on serum Ca2+ and 24-h
urinary Ca2+ excretion. The serum Ca2+ concentration is
shown during 56 days in cases (a) and controls (c). The
dotted line represents the lower cut-off value for normal
serum Ca2+ levels. (B) The urinary excretion of Ca2+
before (day 27/28) and the end (day 41/42) of the second 14-day period of inulin supplementation (dotted line
represents lower cutoff value for normal urinary Ca2+
excretion. Values depict means S.E.M. in mmol/L,
with significant effects highlighted by *, with P < 0.01.
Figure S2. Effect of inulin treatment on serum K+ and
Na+. The serum Na+ and K+ concentrations during the
study period of 56 days are shown. The top row shows
the values for K+ in cases (a) and controls (b) The dotted line represents the lower cut-off value for normal
serum K+ levels. The bottom row shows the values for
Na+ in controls (c) and cases (d) and the dotted line
represents the lower cutoff value for serum Na+. Values
depict means S.E.M. in mmol/L, with significant
effects highlighted by *, with P < 0.01.
AUTHORSHIP
Guarantor of the article: Joost PH Drenth.
Author contributions: MH, JdB, MB, TB, JH, RB and JD
were involved in study design. MH, MB, TB, BH and AT were
involved in patient data acquisition. MH, JdB, JH, RB and JD were
involved in data analysis and interpretation. MH, MB, TB, BH and
AT were involved in clinical monitoring. MH, JdB, JH, RB and JD
were involved in writing of the manuscript. JdB, JH, RB and JD
were involved in supervision. All authors approved the final version
of the manuscript.
ACKNOWLEDGEMENTS
We are deeply indebted to the participants of the inulin trial. The
authors thank the contributing physicians staff of the Radboud university medical center, namely F. Hoentjen MD, M. Goerres MD, J.
Kersten MD, E. Klappe MD. We kindly thank A. Lameris, M. Blanchard, L. Bernts, D. Viering, J. Salomon, T. Wijnands and for their
(technical) support and expertise.
Declaration of personal interests: All authors declare that no financial and nonfinancial competing interests exist.
Declaration of funding interests: This study was funded through a
grant of the Radboud University Medical Center and was further
supported by grants from the Netherlands Organization for Scientific Research (VICI 016.130.668) and the EURenOmics project from
the European Union seventh Framework Programme (FP7/2007–
2013, agreement no. 305608).
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