Download The relationship of fibroblast growth factors 21 and 23

Clin Chem Lab Med 2015; 53(10): 1569–1574
Yoshihiro Takedaa, Shu-ichi Fujitaa, Toshiyuki Ikemoto, Yoshikatsu Okada, Koichi Sohmiya,
Masaaki Hoshiga and Nobukazu Ishizaka*
The relationship of fibroblast growth factors
21 and 23 and α-Klotho with platelet activity
measured by platelet volume indices
DOI 10.1515/cclm-2014-1251
Received December 16, 2014; accepted February 12, 2015; previously
published online March 14, 2015
Abstract
Background: Subjects with high fibroblast growth factor
21(FGF21) and 23 (FGF23), endocrine hormones that
regulate insulin sensitivity and phosphate metabolism,
respectively, are reported to have a higher risk for adverse
cardiovascular outcome. Therefore, the relationship of
FGF21, FGF23, and α-Klotho (co-receptor for FGF23 signaling) with mean platelet volume (MPV) and platelet distribution width (PDW), two platelet volume indices that
reflect platelet activity, was investigated.
Methods: Data from 156 patients admitted to the cardiology department were analyzed. MPV and PDW were measured by an automatic blood counter, and serum FGF21,
FGF23, and α-Klotho concentrations were measured by an
enzyme-linked immunoassay.
Results: Log(FGF21) was significantly correlated with
serum triglycerides but did not differ according to the use
of non-use of antidiabetic or lipid-lowering drugs. MPV
and PDW were significantly correlated (R = 0.475, p < 0.001).
MPV was significantly correlated with log(FGF21)
(R = –0.167, p < 0.05) and log(FGF23) (R = 0.351, p < 0.001) but
not with log(α-Klotho). Linear regression analysis showed
a negative and positive association of log(FGF21) and
log(FGF23), respectively, with MPV that was independent
of possible confounders including sex, age, renal function, and antithrombotic drug use. In addition, log(FGF23)
a
Y. Takeda and S. Fujita contributed equally to this article.
*Corresponding author: Nobukazu Ishizaka, MD, Department of
Cardiology, Osaka Medical College, Takatsuki-shi Daigaku-machi
2-7, Osaka 569-8686, Japan, Phone: +81-72-683-1221,
Fax: +81-72-684-6533, E-mail: [email protected]
Yoshihiro Takeda, Shu-ichi Fujita, Koichi Sohmiya and Masaaki
Hoshiga: Department of Cardiology, Osaka Medical College, Osaka,
Japan
Toshiyuki Ikemoto and Yoshikatsu Okada: Central Clinical
Laboratory, Osaka Medical College, Osaka, Japan
was found to have a significant independent positive association with PDW.
Conclusions: Among cardiac patients, FGF21 had a negative association with MPV, whereas FGF23 had a positive
association. Future studies of serum FGF23/FGF21 concentrations and the incidence of thromboembolic disorders
are warranted.
Keywords: fibroblast growth factor 21 (FGF21); FGF23;
platelet activity; α-Klotho.
Introduction
Unlike other fibroblast growth factors (FGFs), FGF21 and
FGF23, together with FGF19, comprise a unique subfamily
that functions as endocrine hormones in the regulation of
various metabolic processes [1, 2]. FGF21 is expressed predominantly in the liver, and its signaling pathway functions in adipose tissue. FGF21 is elevated in obesity and
type 2 diabetes [3] and plays an important role in the regulation of insulin sensitivity and energy balance [4]. FGF23,
a bone-secreted hormone, plays a crucial role in maintaining the calcium-phosphate homeostasis together with coreceptor α-Klotho, which had originally been identified
as an antiaging gene [5–7]. In patients with renal failure,
FGF23 is increased and α-Klotho is decreased because
klotho is mainly expressed in the renal tubular epithelium
[8].
In addition to its metabolic actions, FGF23 promotes
cardiac hypertrophy and fibrosis [9, 10], which may be
clinically manifested as heart failure, and left ventricular
systolic and diastolic dysfunction [11–13]. Epidemiological
studies demonstrated that subjects with high FGF23 are
at increased risk of cardiovascular disease [14, 15]. Meanwhile, animal studies showed that FGF21 may exert cardio-protective effects [16, 17]; in humans, however, higher
FGF21 was also found to be associated with higher cardiovascular events [18, 19], which might be related to FGF21
resistance or a compensatory elevation of FGF21 [20].
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1570 Takeda et al.: FGF21, FGF23, α-Klotho, and platelet indices
Mean platelet volume (MPV) and platelet distribution width (PDW) are parameters of platelet volume and
are considered to be useful and inexpensive-to-measure
biomarkers of platelet activity [21]. MVP and PDW are
reported to be increased in patients with diabetes [22, 23]
and cardiovascular and cerebrovascular diseases [24–26].
To the best of our knowledge, it has not been clarified
whether serum FGF21, FGF23, and/or α-Klotho concentrations are associated with the enhanced platelet activity
that may underlie thromboembolic disorders. To this end,
here we analyzed the relationship of FGF21, FGF23, and
α-Klotho with the platelet volume indices, MPV and PDW,
among cardiac patients.
Materials and methods
Study population
The current retrospective study was approved by the Ethics Committee of Osaka Medical College. Between December 2012 and December
2013, 156 cardiac patients who had provided written informed consent and for whom sufficient information regarding the data analysis
for the current study was available were enrolled in the current study.
Laboratory analysis
C-reactive protein (CRP) and B-type natriuretic peptide (BNP) were
measured by routine laboratory methods. The eGFR was calculated
by the following Modification of Diet in Renal Disease equation for
Japanese subjects: eGFR mL/min/1.73 m2) = 194 × [serum creatinine
(μmol/L)/88.4]–1.094 × (age)–0.287( × 0.739, when female) [27]. The patients
were classified into chronic kidney disease (CKD) stages 1–5 based
on eGFR levels or requirement for hemodialysis [28]. When patients
had renal dysfunction with the grade of CKD stage 3 or higher, they
were judged to have CKD. MPV and PDW were analyzed by automatic
blood counter (ADVIA 2120i Hematology System; Siemens). Serumintact FGF23 was measured using a two-step FGF23 enzyme-linked
immunosorbent assay (ELISA) kit (Kainos Laboratories, Tokyo,
Japan), serum soluble α-Klotho was measured using a solid-phase
sandwich ELISA kit (Immuno-Biological Laboratories, Gunma,
Japan) [8], and serum FGF21 was measured using sandwich ELISA
kit (Biovendor, Modrice, Czech Republic) according to the manufacturer’s instructions.
Statistical analysis
Baseline characteristics were assessed with standard descriptive statistics. Data were expressed as either mean±standard deviation or
median and interquartile range. Pearson and Spearman correlation
tests were used to assess the correlation between two variables when
variables were normally and non-normally distributed, respectively.
For multivariate analysis, stepwise multivariate linear regression was
used. Data analysis was performed by SPSS statistics version 22.0
(IBM, Armonk, NY, USA). A value of p < 0.05 was taken to be statistically significant.
Results
Patient characteristics
Among the 156 patients enrolled, 108 (69%) were male
and 15 (9.6%) had severe renal dysfunction (CKD stage
4 or 5) (Table 1). Ischemic heart disease was the most
prevalent underlying cardiac disorder, and about twothirds and one-third of patients, respectively, were taking
antiplatelet drugs and anticoagulants. Log(FGF21) was
Table 1: Clinical characteristics of the study patients.
Variables
Women/men
Age, years
Body mass index, kg/m2
Systolic blood pressure, mmHg
CKD stage, n of 1/2/3/4/5
Smoking history
Cardiovascular disease, n (%)
Ischemic heart disease
Arrhythmic disease
Cardiomyopathy
Peripheral artery disease
Valvular heart disease
Medication, n (%)
ACE inhibitors/ARB
β-Blockers
Calcium channel blockers
Any antiplatelet drugs
Any anticoagulants
Insulin
Sulfonylurea
DPP-4 inhibitors
Statin
Fibrate
Laboratory data
White blood cell count, × 109/L
Hemoglobin, g/L
Platelet count, × 109/L
Mean platelet volume, fL
Platelet distribution width, %
CRP, mg/L
BNP, ng/L
FGF21, ng/L
FGF23, ng/L
α-Klotho, ng/L
48/108
69.9±9.9
23.3±3.6
128±18
1/36/104/14/1
84 (53.8)
99 (63.5)
55 (35.3)
12 (7.7)
14 (9.0)
8 (5.1)
89 (57.1)
63 (40.4)
79 (50.6)
101 (64.7)
57 (36.5)
15 (9.6)
9 (5.8)
20 (12.8)
76 (48.7)
3 (1.9)
5.64 (4.68–6.87)
131 (120–144)
207 (171–241)
8.3 (7.8–8.7)
52.8 (48.6–57.7)
0.8 (0.4–2.0)
59.1 (24.1–150.6)
229 (108–399)
46.0 (32.8–67.3)
293 (197–445)
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Takeda et al.: FGF21, FGF23, α-Klotho, and platelet indices 1571
associated borderline significantly with CRP (R = 0.145,
p = 0.071) and significantly with triglycerides (R = 0.196,
p = 0.014) and log(α-Klotho) (R = –0.164, p = 0.041); meanwhile, log(FGF21) was not significantly correlated with
age, body mass index, systolic blood pressure, fasting
glucose, or eGFR. The FGF21 levels did not significantly
differ according to the use or non-use of insulin, sulfonylurea, dipeptidyl peptidase 4 (DPP-4) inhibitors, angiotensin-converting enzyme inhibitors/angiotensin receptor
blockers, or statin (data not shown).
Among metabolic data, fasting glucose was significantly correlated with PDW (R = 0.182, p = 0.026). Among
149 patients for whom HbA1c data were available, HbA1c
had a significant correlation with MPV (R = 0.182, p = 0.026)
and PDW (R = 0.170, p = 0.038). HbA1c was also associated
significantly with log(FGF23) (R = 0.182, p = 0.027) and borderline significantly with log(FGF21) (R = –0.148, p = 0.071).
Relationship between MPV and FGF21,
FGF23, and α-Klotho
MPV was significantly correlated negatively with
log(FGF21) and positively with log(FGF23) (Figure 1).
Although MPV and PDW were significantly correlated
(R = 0.475, p < 0.001), the association between PDW and
log(FGF21) or log(α-Klotho) was found to be non-significant (Figure 2). When the data were assessed in tertiles
of FGF21 and FGF23, the mean MVP value seemed to
decrease and increase, respectively, with higher tertiles of
log(FGF21) and log(FGF23) (Figure 3A). This tendency was
not observed for the mean PDW value (Figure 3B).
In univariate linear regression analysis, age,
log(FGF21), and log(FGF23) were found to have a significant association with MPV (Table 2). We used
antithrombotic drugs as a possible independent variable because several previous reports have shown a
relationship between such drugs and platelet indices
[29, 30]. In the multivariate model, the relationship of
FGF21 and FGF23 with MPV remained significant after
taking antithrombotic drug use into account (Table 2).
In the stepwise multivariate analysis performed by
entering variables that were used in univariate analysis,
the association of MVP with log(FGF21) and log(FGF23)
retained statistical significance. When PDW was used
as the dependent variable in the same multivariate
model, log(FGF23), but not log(FGF21), was found to be
a significant factor.
Figure 1: Correlation between FGF21, FGF23, and α-Klotho and MPV.
The correlations of FGF21 (A), FGF23 (B), and α-Klotho (C) with MPV is shown.
Figure 2: Correlation between FGF21, FGF23, and α-Klotho and PDW.
The correlations of FGF21 (A), FGF23 (B), and α-Klotho (C) with PDW is shown.
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1572 Takeda et al.: FGF21, FGF23, α-Klotho, and platelet indices
Figure 3: Mean values of MPV and MPV according to tertiles of FGF21 and FGF23.
The mean MPV (A) and PDW (B) value for each tertile of FGF21 and FGF23 is shown.
Table 2: Linear regression analysis of factors associated with MPV and PDW.
Dependent variable
MPV
Sex (male = 1)
Age
Systolic blood pressure
Any antiplatelet drug
Any anticoagulants
CKD stage
Fasting glucose
Triglycerides
Log(FGF21)
Log(FGF23)
Log(α-Klotho)
PDW
Sex (male = 1)
Age
Systolic blood pressure
Any antiplatelet drug
Any anticoagulants
CKD stage
Fasting glucose
Triglycerides
Log(FGF21)
Log(FGF23)
Log(α-Klotho)
Univariate
Multivariate (stepwise)
Std β
p-Value
Std β
p-Value
0.08
0.23
–0.10
–0.07
0.07
0.08
0.09
–0.11
–0.17
0.35
0.05
0.321
0.005
0.224
0.369
0.398
0.292
0.286
0.184
0.037
< 0.001
0.570
0.16
–
–0.17
–
–
–
–
–
–0.18
0.40
–
0.036
0.17
0.05
–0.01
0.02
–0.04
0.09
0.17
–0.01
–0.13
0.14
–0.04
0.034
0.562
0.857
0.840
0.627
0.287
0.030
0.950
0.115
0.088
0.625
0.20
–
–
–
–
–
0.17
–
–
0.16
–
Then we analyzed the patient with (n = 119) or without
(n = 37) CKD. When only patients with CKD were analyzed,
stepwise regression analysis showed that log(FGF23) was,
but log(FGF21) was not, selected as a factor that had significant association with MPV with standardized correlation coefficient of 0.36 (p < 0.001). Meanwhile, neither
log(FGF21) or log(FGF23) had significant association
with PDW (data not shown). When only patients without
CKD was analyzed, neither log(FGF21) nor log(FGF23)
was selected as significant predictor for MPV (data not
shown). Meanwhile, log(FGF23) was selected as a factor
0.021
0.017
< 0.001
0.011
0.031
0.047
that had significant association with PDW with standardized correlation coefficient of 0.34 (p = 0.039).
Discussion
We demonstrated that FGF21 and FGF23, respectively,
were negatively and positively associated with MPV, a biomarker of platelet activity, independent of sex, age, blood
pressure, antithrombotic use, renal function, fasting
glucose, and triglycerides. FGF23 also had a positive
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Takeda et al.: FGF21, FGF23, α-Klotho, and platelet indices 1573
association with PDW. α-Klotho did not have a significant
association with MPV or PDW. Higher FGF21 was independently associated with lower MPV, suggesting lower platelet activity among patient with relatively higher levels of
FGF21.
Until now, the risk of thrombotic diseases in terms
of serum FGF23 has not been specifically addressed.
An association between FGF23 and the platelet activity
markers, MPV and PWD, if present at all, may have several
physiological consequences. First, considering that FGF23
increases with advancement of renal dysfunction [8] and
MPV is reported to increase with progression of CKD [31],
FGF23 might be involved in the increased risk of systemic
thromboembolism seen among patients with CKD [32].
In the current study population, however, neither MPV
nor PDW was associated with renal function (CKD stage),
which might be related to the fact that patients with severe
renal dysfunction (CKD stages 4/5) comprised < 10% of the
study population (Table 2). Second, low bone mineral
density (BMD) has been reported be associated with
high MPV [33] and increased risk of thromboembolic diseases [34]. Considering that FGF23 is involved in bone
mineral metabolism, FGF23 might be involved in the
increased thromboembolic risk in osteoporosis. Because
the reported association between FGF23 and BMD seems
to vary according to the study population [35, 36], BMD
should also be quantified among cardiac patients.
Little information is available about the relationship
between serum FGF21 and thromboembolic risk, although
high FGF21 levels have been found to be associated with
cardiovascular disease and stroke [19]. Several recent
studies showed that adiponectin is inversely associated
with platelet activation [37, 38]. FGF21 might increase with
adiponectin [39], although the relationship may not be
straightforward [40, 41]. To examine the possibility that
adiponectin, but not FGF21, is associated inversely with
MPV in the study population, circulating adiponectin
levels should be assessed in future studies.
There are several limitations to the current study. First
is the heterogeneity of the study population: the patients
enrolled had various cardiovascular conditions and were
taking various drugs that may potentially alter the FGF21/
FGF23 and α-Klotho concentrations and platelet activity.
Second, the cross-sectional nature of the study means
that whether modulation of FGF21/FGF23 and α-Klotho
may have therapeutic implications cannot be concluded.
A third limitation is the relatively small sample number.
Log(FGF23), but not log(FGF21), was independently associated with PDW among patients without CKD and with
MPV among patients with CKD. However, the number of
CKD (n = 119) and non-CKD (n = 37) subjects were small;
therefore, whether relation between FGF21/FGF23 and
platelet indices really differ according to the CKD status
should be analyzed in future studies. Fourth, we did not
assess the expression of β-Klotho, which may act as a coreceptor for FGF21 signaling.
In summary, cardiac patients with higher serum
FGF23 and lower FGF21 levels had high MPV, and presumably increased platelet activity, and this relationship was
independent of sex, age, fasting glucose, triglycerides,
and renal function. Future studies of high FGF23 and low
FGF21 serum levels and the incidence of thromboembolic
disorders are warranted.
Author contributions: All the authors have accepted
responsibility for the entire content of this submitted
manuscript and approved submission.
Financial support: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played
no role in the study design; in the collection, analysis, and
interpretation of data; in the writing of the report; or in the
decision to submit the report for publication.
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