Functional Val66Met polymorphism of Brain-derived neurotrophic factor in type 2 diabetes with depression in Han Chinese subjects
Behavioral and Brain Functions
Functional Val66Met polymorphism of Brain-derived neurotrophic factor in type 2 diabetes with depression in Han Chinese subjects
Jian-Xin Zhou 0 1 3
He-Chao Li 0 1 3
Xue-Jun Bai 2 3
Bao-Cheng Chang 0 1 3
Chun-Jun Li 0 1 3
Pei Sun 0 1 3
Li-Ming Chen 0 1 3
0 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University , Tianjin , China
1 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health) , Metabolic
2 Center of Psychology and Behavior, Tianjin Normal University , Tianjin , China
3 Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University , Tianjin , China
Background: Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of major depression. Individuals with type 2 diabetes (T2DM) have a high prevalence of major depression and low levels of BDNF. We therefore explored whether the BDNF Val66Met polymorphism is associated with co-morbid depression and whether depression affects the serum levels of BDNF in a Han Chinese subjects with T2DM. Methods: A Total of 296 T2DM patients and 70 healthy volunteers (Health control, HC group) were recruited in this study. T2DM patients were divided into two subgroups: depressive diabetes group (DDM group, n = 64) and non-depressive diabetes group (NDDM group, n = 232), according to the presence or the absence of depression assessed by Center for Epidemiologic Studies Depression Scale (CES-D) and Patient Health Questionnaire-9 (PHQ-9). Val66Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). Serum BDNF levels were measured by ELISA kit. Results: In this study, 21.6% (64/296) patients with T2DM had depression. The BDNF Val66Met genotype distributions were statistically different among the three groups (2 = 7.39, p < 0.05). DDM group carried the highest frequencies of Met allele (53.9%) compared to HC group (39.3%) and NDDM group (38.8%). Subjects with Met/Met had lowest serum BDNF levels (76.59 5.12 pg/ml, F = 7.39, p < 0.05) compared to subjects with Val/Met (79.04 5.19 pg/ml) and Val/Val (83.83 3.97 pg/ml). Within T2DM group, it was also observed that the serum BDNF levels in DDM group were significantly lower than those in NDDM group (76.67 5.35 vs. 79.84 3.97 pg/ml, p < 0.05). In type 2 diabetes subjects, BDNF serum levels were significant correlations with genotypes (r = 0.346, p < 0.01), depression scores (r = 0.486, p < 0.01) and HbA1c (r = 0.168, p < 0.05). After adjustment for gender, HbA1c, BMI and numbers of complications, BDNF Val/Met genotype distributions (OR = 2.105, p < 0.05) and decreased serum BDNF levels (OR = 0.835, p < 0.01) were independently associated with depression in T2DM. Conclusions: The BDNF Val66Met polymorphism might be implicated in the pathogenesis of depression in T2DM by decreasing serum BDNF levels in Han Chinese Subjects.
Type 2 diabetes (T2DM); Depression; Brain-derived neurotrophic factor (BDNF); Polymorphism
Depression and type 2 diabetes (T2DM) are two of the
most prevalent and devastating diseases. There is a strong
association between T2DM and depression [1,2].
Epidemiological data indicates that approximately 26-30%
of diabetic patients suffer from differential severity of
depression, excessive above that of the normal
population [3,4]. Moreover, the mortality rate is significantly
higher among patients with T2DM and depression
than among patients with diabetes without depression
. Therefore, it is important to study the etiology of
depression with T2DM.
Brain-derived neurotrophic factor (BDNF) is a member
of the neurothophic factor family, which plays a key role in
regulating survival, growth and maintenance of neurons
. It has been suggested that reduction in BDNF
expression is a pathogenic factor common to Alzheimers disease
and major depression [7,8]. For example, a study by Karege
et al. have reported that major depressive patients exhibited
significantly lower levels of serum BDNF compared with
normal controls [9,10], whereas the use of antidepressants
led to an up regulation of BDNF in the hippocampus of
subjects with major depression . The association
between BDNF and depression is also supported by animal
studies in which infusion of recombinant BDNF exerted
antidepressant effect .
The human BDNF gene has been mapped to
chromosome 11p13 and a common single nucleotide
polymorphism (SNP) consisting of a missense change (G196A), which
produces a valine (Val) to methionine (Met) change, has
been identified in the coding exon of the BDNF gene at
position 66 (Val66Met) . The Val66Met polymorphism
in the BDNF gene has been shown to impact intracellular
trafficking and activity-dependent secretion of BDNF .
Clinical studies demonstrate that the Met allele is
associated with decreased hippocampal volume in both normal
and depressed patients and with decreased executive
function and cognition [13,14] Hong et al. first reported that
BDNF Val66Met polymorphism was associated with major
depressive disorders in a Caucasian population .
Subsequently, increasing clinical studies have confirmed that the
Met allele was more commonly found among individuals
with mood disorders [16-18]. In line with these clinical
findings, animal study showed that a variant BDNF mouse
(BDNF Met/Met) reproduced the phenotypic hallmarks of
humans with this variant allele, and exhibited increased
anxiety-related behaviors . Paradoxically, Tsai SJ et al.
reported a higher incidence of depression in Val, not
Met carriers . Currently, it is still unclear what the
consequences of the Val66Met polymorphism are on the
brain function, as both alleles have been associated with
different disease processes, including emotion response
, esoghageal hypersensitivity , individual's sexual
activities  and depression [15,24,25]. Of interest, several
studies have shown that the degree of therapeutic response
to antidepressants is associated with the BDNF Val66Met
polymorphism, suggesting that BDNF gene may be a
good candidate gene for the pharmacogenetic study of
Furthermore, a decrease in BDNF concentration has
been strongly linked to T2DM. BDNF was reported to
improve glucose metabolism insulin sensitivity, and reduce
food consumption . The direct role of BDNF in
metabolism is supported by studies on BDNF-deficient mice,
which developed diabetes and obesity in early adulthood
. Animals studies have also shown that BDNF has
important effects on the regulation of eating behavior 
and modulation of the secretion and activities of insulin,
leptin, ghrelin and pro-inflammatory cytokines associated
with energy homeostasis. These findings suggest that
BDNF may also play a pathogenic role in the development
of obesity and T2DM in humans. More recent
epidemiologic studies  showing T2DM patients develop more
depression and at the same time have lower serum BDNF
levels compared to non-diabetic individuals [28,31,32],
posed an interesting question whether the higher rate of
depression in diabetes may be in part mediated by decreased
BDNF levels. However, the clinical significance of the effect
of BDNF levels on depression and the impact of Val66Met
polymorphism remain unclear in T2DM patients with
depression. Thus, BDNF genetic studies of patients with and
without depression may shed light on the potential genetic
link between depression and T2DM. We therefore
hypothesized that a genetic variation (Val to Met substitution) in
BDNF leading to a reduction in serum BDNF levels in
T2DM may contribute to depression and diabetes. In this
study, we investigated whether the Val66Met polymorphism
and serum BDNF levels are different in Han Chinese
subjects who suffered from T2DM with or without depression.
Subjects and Methods
All subjects were of Chinese origin (Han Chinese) and
lived in the same region at the time of the study. A total
of 296 T2DM patients from Metabolic Disease Hospital of
Tianjin Medical University were recruited into this study.
T2DM was diagnosed according to the 1999 WHO criteria.
In the ethnicity, age and gender-matched control group, 70
healthy people without mental illness, family history of
psychiatric disorders and T2DM were recruited from the same
area. All T2DM subjects were divided into two subgroups:
depressive group (DDM group, n = 64) and non-depressive
group (NDDM group, n = 232), depending on presence or
absence of depression. This study was approved by the local
ethics committee review board and was conducted using
Good Clinical Practice in accordance with the Declaration
of Helsinki. All subjects gave written informed consent
before entering the study.
The Center for Epidemiologic Studies Depression Scale
(CES-D) Chinese edition  was used to assess depressive
symptoms. This scale is the most widely used depression
screening scale. The Chinese version of the CES-D scale
shows good reliability and validity across all ages in urban
and rural population . This scale consists of 16 negative
affect and 4 positive affect items, such as "I felt depressed",
"I felt lonely", and "I was happy". Participants were asked
about the number of days on which they experienced
depressive symptoms during the previous week. Each item
was accompanied by a standard four-point Likert scale of
potential responses: 1 = none, 2 = one or two days a week,
3 = three or four days per week, and 4 = five days or more
per week. Higher scores on the CES-D indicate more
depressive symptoms. In the scale, four items that describe
positive effects were reversed before conducting our
analysis. Radloff has suggested that a score of 16 should be the
cut-off point for the scale , while other studies have
adopted 21 or 22 as the cut-off point . Given the
complexity of the cutoff point selection, this study used CES-D
scale combined with another scale named Patient Health
Questionnaire-9 (PHQ-9)  to assess to be depressed
together. Participants rated the frequency of experiencing
nine symptoms during the previous two weeks: 0) not at
all, 1) on several days, 2) on more than half of the days, and
3) nearly every day. The PHQ-9 scores range from 0 to 27,
with higher scores indicating high severity of symptoms.
The CES-D scale score cut-off point was set to 16, and the
PHQ-9 scale was set to 5. The recruited subjects were
asked to complete the 2 questionnaires by themselves at
different days. Subjects meeting the criteria of both scales
were defined as depression.
BDNF polymorphism analyses
Genomic DNA was extracted from peripheral whole
blood of subjects by proteinase K digestion.
BDNFVal66Met polymorphism was performed by polymerase
chain reaction-restriction fragment length polymorphism
(PCR-RFLP). DNA fragments of interest were amplified
by polymerase chain reaction (PCR) with the primers
5'ACTCTGGAGAGCGTGAAT-3' and 5'-ATACTGTCAC
ACACGCTC-3' designed by Oligo 6.0 primer analysis
software. A total volume of 25 l PCR reaction contains
2 l of genomic DNA, 2.5 l of 10 PCR buffer, 2 l of
dNTP, 1 l of each primer, 16.2 l of distilled water and
0.3 l of Taq polymerase. The PCR conditions were as
follows: predegeneration at 94C for 5 min, 35 cycles of 30s
at 94C, annealing at 55C for 30s and extending at 72C
for 1 min. The thermal cycle was completed with 72C for
10 min. The Val66Met polymorphism was differentiated
with the NlaIII restriction enzyme and the product was
electrophoresed in 2% agarose gels and stained with
ethidium bromide and visualized on a UV trans-illuminator.
Measurement of serum BDNF, glycosylated haemoglobin
A1c, blood urea nitrogen, Cr: creatinine, UMA:urine
Blood samples were drawn into glass tubes without
anticoagulants, which were immediately spun at 3000 rpm
for 10 min at 4C. Serum was isolated and stored at 20C.
The serum BDNF levels were measured by commercial
ELISA kit (Adlitteram diagnostic laboratories, USA). After
thawing, samples were centrifuged at 10,000 g for 10 min
at 4C for complete platelet removal. All samples and
standards were measured in duplicate, and the coefficient of
variation was less than 5%.
Plasma levels of blood urea nitrogen (BUN), Cr: creatinine
(Cr) and urine micro- albumin (UMA) were measured using
routine laboratory methods. Plasma glycosylated
haemoglobin A1c (HbA1c) were measured using High-performance
liquid chromatography (HA-8160).
Statistical analyses were performed using the SPSS
Windows version 18.0. Genotype and allele frequency
distributions were compared using the 2 test.
HardyWeinberg equilibrium was computed to the expected
genotype distributions. Data was expressed as mean SD.
The means for variables between the two groups were
compared by a two-tailed unpaired Students t-test.
Statistics among the three groups were analyzed by
one-way ANOVA followed by post hoc individual
comparisons with the SNK test and chi-square analysis for
categorical variables. The associations of BDNF
polymorphism and serum levels with the relevant clinical
parameters and depression scale scores were analyzed
by Pearson correlation and multiple step logistic
regression. In both Pearson correlation and multiple step
logistic regression, Met/Met + Met/Val were delegated
by 1 and Val/Val was delegated by 2. All reported p
values were two-tailed, and p values of < 0.05 were
considered statistically significant.
Participants and clinical characteristics in DDM group
In this study, we totally recruited 296 T2DM Han Chinese
patients and 70 age- and gender-matched healthy subjects
(mean age: 53.2 5.5 vs. 55.2 6.5 years, gender ratio:
M/F 34/36 vs. 148/148) with the same ethnicity. Within
the T2DM group, 64 patients (21.6%) had depression
with 19 (12.8%) males and 45 (30.4%) females. In addition
to a higher female/male ratio, the DDM group had higher
HbA1c, BMI, educational levels and with more diabetic
complications than the NDDM group (Table 1). There
were no statistical differences in age, duration and marital
status between the DDM group and the NDDM group
(data not shown).
Table 1 Characteristics of NDDM and DDM group
Table 3 Genotype distributions of BDNF Val66Met
Education Level (%)
Junior middle school
Senior middle school
Disease duration (year)
The number of
p = 0.337
p = 1.000
p = 0.199
p = 0.847
p = 0.234
p = 0.004
p = 0.017
Data expressed as mean S.D. or frequency [n (%)], BMI: body mass index;
HbA1c: glycosylated haemoglobin A1c, p value < 0.05 for
Association of BDNF Val66Met polymorphism with type 2
diabetes and depression
To assess whether BDNF Val66Met polymorphism
contributed to depression in T2DM, 70 healthy subjects, 64
T2DM with depression and 232 T2DM without depression
were genotyped. The genotype distributions of BDNF
Val66Met followed Hardy-Weinberg equilibrium among
the groups, were summarized in Table 2. The genotype
distributions and allele frequencies of BDNF Val66Met were
summarized in Table 3. Our study indicated that BDNF
Val66Met polymorphism had no association with T2DM.
However, within the T2DM group, there were statistical
differences in genotype distributions and allele frequencies
between the NDDM group vs. DDM group, p < 0.05. The
DDM group carried higher frequencies of Met allele
(53.9%, p < 0.05) compared to NDDM group (38.8%).
Association of serum BDNF levels and BDNF genotypes
To explore whether serum BDNF levels was associated
with BDNF Val66Met polymorphism, we divided the
participants into 3 groups according to genotype distribution:
Val/Val group, Val/Met group and Met/Met group.
Our study revealed that there were significantly
genotyperelated differences in serum BDNF levels among 3 groups
(F = 7.39, p < 0.05, Table 4). Interestingly, Val/Val carriers
Table 2 Hardy-Weinberg equilibrium of BDNF Val66Met
Group n 2 p
A is the actual number of genotypes; T is the expected number of genotypes.
HC: Healthy control, NDDM: type 2 diabetes without depression group, DDM:
type 2 diabetes with depression group.
Data expressed as frequency [n (%)], p value < 0.05 for statistical significance,
chi-square analysis used to identify differences in genotype frequencies
between groups. HC: Healthy control, NDDM: type 2 diabetes without
depression group, DDM: type 2 diabetes with depression group.
had the highest serum BDNF levels and Met/Met carriers
had the lowest serum BBNF levels.
Association of serum BDNF levels in patients with T2DM
There were significant differences in serum BDNF levels in
HC, NDDM and DDM groups (F = 24.94, p < 0.01, Table 5).
NDDM subjects had significantly lower serum BDNF
levels compared to HC (p < 0.05), but had significantly
higher serum BDNF levels when compared to DDM
subjects (p < 0.05).
Association of BDNF Val/Met polymorphism and serum
levels with T2DM clinical characteristics and depression
Among type 2 diabetes subjects, multiple stepwise
regression analysis revealed that when BDNF Val/Met genotypes
against depression scores, gender, BMI, HbA1c, BUN, Cr
and numbers of complications, were independently
correlated with depression scores (OR = 1.952, p < 0.05) and
HbA1c (OR = 1.786, p < 0.05), indicating that the Met allele
contributed to both the risk of development depression and
diabetes. Moreover, Pearson correlation analysis showed
that when BDNF serum levels were tested for simple
linear correlations against genotypes, depression scores,
gender, BMI, HbA1c, BUN, Cr and numbers of
complications, significant inverse correlations were found with
genotypes (r = 0.346, p < 0.01), depression scores (r = 0.416,
p < 0.01) and HbA1c (r = 0.168, p < 0.05), indicating that
low BDNF concentrations may be a pathogenic factor
associated with both depression and T2DM. Furthermore,
after adjustment the presence or absence risk factors for
depression including gender, HbA1c, BMI , BUN(mol/l),
Cr(mol/l) and numbers of complications, BDNF Val/Met
genotype distributions (OR = 2.105, p < 0.05) and decreased
Table 4 Serum BDNF levels in three genotypes
Data expressed as mean S.D., p value < 0.05 criteria for statistical significance.
*p < 0.05 vs. Val/Val group, # p < 0.05 vs. Val/Met group.
Table 5 Serum BDNF levels in T2DM and depression subjects
Data expressed as mean S.D., p value < 0.05 criteria for statistical significance.
* P < 0.05 vs. HC group, # P < 0.05 vs. NDDM group.
serum levels of BDNF (OR = 0.835, p < 0.01) were also
independently associated with depression in T2DM (Table 6).
In the present study, we investigated the association of
BDNF Val66Met polymorphism with depression in T2DM
of Chinese Han subjects. Our results show that, for Chinese
subjects, there is a positive association between BDNF
Val66Met polymorphism and comorbid depression in
T2DM patients and Met allele carriers are susceptible
to suffer from depression. Our data also show that the
serum BDNF levels are decreased in T2DM patients
carrying either 66Met/Met homozygote or 66Val/Met
heterozygote compared to those carrying 66Val
homozygote. We also found a significant inverse association
between BDNF levels and HbA1c.
The functional Val66Met polymorphism of BDNF has
been studied for its possible associations with depression,
but reports were contradictory. Hong et al. first reported
that BDNF Val66Met polymorphism was associated
with major depression disorders in a Caucasian population
[13,15]. Subsequently, increasing clinical studies have
confirmed that the Met allele was found more often among
individuals with mood disorders [16-18]. Paradoxically, Tsai
SJ et al. reported a higher incidence of depression in Val,
not Met carriers . In contrast, the meta-anlysis done by
Number of complications(n)
Verhagen et al. did not detect any significant genetic
association between the BDNF Val66Met polymorphism and
major depression disorders . Differences between our
study and previous study findings of an association between
the BDNF Val66Met polymorphism and depression may
be due to ethnic variances and alternative definitions for
depression. In this study, we were among the first to
identify that there is no association between BDNF
Val66Met polymorphism and T2DM in Chinese
subjects. Yet, we have demonstrated a significant
association between the BDNF Val66Met polymorphism and
depression within the T2DM group. We found that
DDM group carried a higher frequency of Met allele
(53.9%). After adjustment for age, gender, BMI and
HbA1c, BDNF Val/Met genotypes were still independently
correlated with depression scores (OR = 1.952, p < 0.05).
Our study provides further evidence that the BDNF
Val66Met polymorphisms may be a good therapeutic
candidate gene for T2DM patients with depression in
The prevalence of depression is increasing at a
significantly greater rate in patients with T2DM as compared
with people without diabetes . How could the BDNF
Val66Met polymorphism influence depression in the
T2DM subjects? Probable explanation is that the Val66Met
polymorphism in the BDNF gene has been shown to
impact secretion of BDNF . A number of studies
have suggested that the Met allele is associated with
poorer episodic memory performance, a symptom often
observed in subjects with MDD. Furthermore, it has been
shown that the Met allele is associated with reduced
hippocampal activity . Studies in animal models
have shown that the presence of the Met allele alters
the sorting and secretion of proBDNF, such that less
Table 6 Analysis of risk factors for depression in type 2 diabetes patients
These variables were tested by multiple step logistic regression analysis. HbA1c: glycosylated haemoglobin A1c , BMI: body mass index, SBP: systolic blood
pressure, DBP: diastolic blood pressure, BUN: blood urea nitrogen, Cr: creatinine, UMA:urine micro- albumin, BDNF: Brain-derived neurotrophic factor.
regulated secretion is likely to occur in carriers of at
least one Met allele . In this study, the serum
BDNF levels are significantly lower in T2DM patients
carrying either 66Met homozygote or 66Val/Met
heterozygote compared with that carrying 66Val
homozygote, indicating that this homozygosity for the 66Met
allele confers an increased risk for depression in T2DM
patients through mechanism involving reduced BDNF
production and secretion. The study by Ribeiro et al. has
also shown that Val66Met variants were associated with
depression, presuming that the variants might affect the
genesis and secretion of BDNF [13,15]. Moreover, Krabbe
et al. discovered that the lower level of BDNF accompanied
T2DM established a negative correlation between BDNF
levels and fasting blood glucose. In other words, as fasting
blood glucose progressively increased, the output of BDNF
from the brain is progressively decreased. Collectively, the
decreased BDNF may be a pathogenetic factor involved not
only in depression, but also in T2DM . In this study,
we also found that BDNF serum levels were inversely
correlated with HbA1c as a reflection of the average level
of blood glucose over the previous 3 months. Therefore,
we suggest that the decreased levels of BDNF can not be
solely ascribed to Val66Met variants and the influence of
elevated glucose level should also be considered.
Regarding other potential factors involved in T2DM
with depression, we also found that HbA1c, BUN, Cr and
the number of complications were independent risk factors
for comorbid depression in T2DM patients, confirming
that diabetes and depression interacted with each other .
First, depression may have resulted from the biologic stress
of living with diabetes. This is because the biochemical
changes associated with diabetes such as stress,
inflammation, hyperglycemia and activations of the hypotha-lamic
pituitary adrenal axis which induce arousal of the nervous
system and may lead to the development of depression
. Moreover, depression may also results from the
burden of living with T2DM such as poor diet, physical
inactivity and taking insulin or from the psychological stress while
coping with diabetes [41,42]. Furthermore, poor glycemic
control is associated with elevated plasma concentrations
cortisol and greater sensitivity to stress, possibly leading to
concurrent diabetes and depression. Poor glycemic control
may also adversely affects mood, and further aggravates
depression. On the other hand, depression also contributes
to the development of diabetes. Prospective studies have
observed that many unhealthy lifestyles occur in patients
with depression, such as binge eating and lack of exercise,
which also increase diabetes risk . Depression induces
increased production of corticosteroids and catecholamine
by affecting neuroendocrine system, especially the
function of hypothalamus-pituitary-adrenal axis and central
nerve, which, in turn, influence blood glucose
indirectly . Taken together, these studies provide some
evidences to support the strong association between
T2DM and depression.
There are two other issues noted in our study that
might contribute to the development of depression in
T2DM. First is the gender difference in the prevalence
of depression occuring in 30.4% in women and 12.8% in
men, in line with the findings from a previous study .
Interactions between the BDNF Val66Met polymorphism
and environments may differ between men and women.
Although the amount of life events men and women
experience is rather similar, several studies have indicated
that women subjectively experience more stress and have
an increased stress response even they have the same
BDNF Val66Met polymorphism . The gender-related
influence of the BDNF Val66Met polymorphism in
depression may be due to sexual dimorphism in brain structures
involved in the neurobiology of depression, particularly, the
hippocampus. Male and female hippocampi have been
documented to differ significantly in their anatomical
structure, their neurochemical make-up and their
reactivity to stressful situations . The second is that
education levels are related to depression. Consistent
with our study, Abolfotouh el al suggested that lower
education levels are associated with an increased incidence
of depression .Whereas other studies provided evidence
that the higher educated people are more likely to develop
In conclusion, our current study demonstrated that the
presence of the functional BDNF Val66Met polymorphism
was associated with depression in T2DM by decreasing
the serum BDNF levels, suggesting that increased BDNF
levels may be a therapeutic potential in depression patients
with T2DM. Limitations of the present study are that our
sample was not large for a genetic polymorphism, and we
did not perform any interventions on our patients. A large
primary study will be necessary to confirm our study and
validate the therapeutic response in the depression with
T2DM patients who carry Met allele.
The authors have declared that they have no conflicts of interests.
Chen LM and Zhou JX conceived the study, analyzed data and wrote the
manuscript. Bai XJ and Li HC acquired and analyzed data, and Chang BC, Li
CJ and Sun P wrote the manuscript. All authors read and approved the final
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