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Genetic
variation in histamine pathway has been associated with disease. In a group of
195 patients, many of these with a variety of underlying diseases, three
genetic polymorphisms were analyzed in the histamine receptor H1 gene (HRH1), the histamine receptor H2 gene (HRH2) and the histamine
N-methyltransferase gene (HNMT), to
establish a potential relationship between these polymorphisms and blood
histamine levels, white blood cell count, serum cytokines and C reactive
protein levels.
Our
results show a significantly higher proportion of HRH1-17GG genotype in those patients with TNF-alpha levels above
the normal value (more than 8.1 pg/mL), whereas in patients with normal levels
of serum TNF-alpha (less than 8.1 pg/mL), there is a significant disproportion
of the HRH1-17GA/AA genotype. The HRH1-17GG genotype is associated with
high levels of serum TNF-alpha and a high percentage of blood monocytes
compared to the GA genotype. The HRH2-1018GA
genotype is overrepresented in those subjects with hs-CRP levels above 3 mg/dL,
while in the group with hs-CRP levels below 3 mg/dL there is a higher
proportion of subjects with the HRH2-1018
GG genotype. Those subjects with the HRH2-1018GA
genotype also have significantly higher levels of serum hs-CRP and a lower
percentage of blood monocytes compared to the GG genotype. The HNMT105 CT/TT genotype is associated
with a significant increase in the levels of blood histamine, and the HNMT105 CC genotype is associated with
increased IL8 serum levels.
In
conclusion, the three histamine-related polymorphisms analyzed in the present
study are associated with inflammatory mediators and markers of allergic
processes.
Keywords: Histamine, Histamine receptors,
Polymorphisms, Genomic, Blood cells, Cytokines.
Abbreviations: HRH1: Histamine Receptor H1; HRH1: Histamine
Receptor H2; HNMT: Histamine N-Methyltransferase; HA: Histamine; IL1B:
Interleukin 1 beta; IL4: Interleukin 4; IL5: Interleukin 5; IL6: Interleukin 6;
IL8: Interleukin 8; IL10: Interleukin10; IL13: Interleukin 13; H1: Histamin
Receptor 1; H2: Histamin Receptor 2; H3: Histamine Receptor 3; H4: Histamine Receptor
4; HDC: Histidine Decarboxylase; HMT: Histamine N-methyltransferase; DAO:
Diamine Oxidase; IgA: Immunoglobulin A; IgG: Immunoglobulin G; IgM:
Immunoglobulin M; IgE: Immunoglobulin E; hs-CRP: high sensitive C-Reactive
Protein; TNF-alpha: Tumor Necrosis Factor alpha.
INTRODUCTION
Histamine, 4-imidazolyl-2-ethylamine, is an ancestral biogenic amine
present in many living tissues as a normal constituent of the body, with
multiple effects in several organs of mammals and invertebrates. In humans, HA
is found in different concentrations in the majority of the organs of the human
body, being synthesized and released by different human cells, especially
basophils, mast cells, platelets, neurons, lymphocytes, and enterochromaffin
cells, and it is stored in vesicles or granules released on stimulation [1-5].
Histamine exerts its effects on target cells through four different types of
receptors: H1, H2, H3 and H4. These receptors belong to the G protein-coupled
receptor 1 family and they differ in their location, second messengers, and
histamine-binding characteristics [6].
The human H1 receptor gene is located on chromosome 3p25 and encodes
for a 487 amino acid G protein, being expressed in a wide variety of tissues,
including the gastrointestinal tract, central nervous system, airway and
vascular smooth muscle cells, endothelial cells, chondrocytes, monocytes,
neutrophils, dendritic cells, and T and B lymphocytes. H1 receptor is involved
in numerous physiological processes, including thermal regulation, memory and
learning, and control of the sleep-wake cycle, food intake, and emotional and
aggressive behaviors. It mediates the contraction of smooth muscles, the
increase in capillary permeability, the catecholamine release from adrenal
medulla, participates in neurotransmission in the central nervous system, and
exerts modulatory effects in the immune system [6-9]. Histamine acting through
the H1 receptor is involved in the development of various aspects of the
antigen-specific immune response and also has a role in autoimmune diseases and
malignancy [10]. It is also responsible for many symptoms of allergic
inflammation. Antagonists for this receptor exert anti-inflammatory properties
and are the first choice to treat allergic conditions [8,9].
Histamine H2 receptor has a widespread distribution, being found in the
gastrointestinal tract, in the stomach parietal cells; in cardiomyocytes of the
heart; in vascular smooth muscle cells; in endothelial cells; in the central
nervous system; and in cells of the immune system. It mediates gastric acid
secretion and also appears to regulate gastrointestinal motility, heart
contraction, cell proliferation and differentiation, and immune response. The
human H2 receptor gene is located on chromosome 5q35 and encodes for a 359
amino acid G protein. H2 activation negatively regulates basophils and mast
cells, and inhibits antibody synthesis, T cell production, cell-mediated
cytolysis and cytokine production. H2 receptors are present on Th2 cells and
their activation increases the synthesis of cytokines such as IL4, IL5, IL10
and IL13. Furthermore, histamine-induced T cell suppressor activity is mediated
through H2 receptors [6-9,11].
Histamine H3 receptor is expressed at high levels on histaminergic
neurons in the central nervous system, particularly in the basal ganglia,
cortex, hippocampus and striatum. It is also expressed at lower densities in
the gastrointestinal, bronchial and cardiovascular systems. H3 receptor is a
presynaptic autoreceptor, controlling the synthesis and release of histamine in
the brain, as well as the release of a variety of other transmitters. H3
receptor has multiple functions, including roles in cognition, sleep-wake
status, energy homeostasis and inflammation [6-9,12,13]. The human gene encoding
this receptor is localized to chromosome 20q13.33 and encodes for a 445 amino
acid G protein.
Histamine H4 receptor is expressed at high levels in spleen, thymus,
medullary cells, bone marrow and peripheral hematopoietic cells, including
eosinophils, basophils, mast cells, T lymphocytes, leukocytes and dendritic
cells. It is also expressed in a wide variety of peripheral tissues, including
heart, kidney, liver, lung, pancreas, skeletal muscle, prostate, small
intestine, spleen, testis, colon, fetal liver and lymph node. H4 receptors have
an important role in inflammation, hematopoiesis and immunity [6-9,14,15]. The
human gene encoding the H4 receptor is localized to chromosome 18q11.2 and
encodes for a 390 amino acid G protein.
Histamine, through binding to histamine receptors, is the major
mediator of the acute inflammatory and immediate hypersensitivity responses,
but also seems to be implicated in chronic inflammation and in the regulation
of several essential events in the immune response. Histamine and its receptors
are also implicated in the pathogenesis of inflammatory and autoimmune
diseases. Histamine can selectively recruit the major effector cells into
tissue sites and affect their maturation, activation, polarization, and other
functions, leading to chronic inflammation. Histamine also regulates monocytes,
dendritic cells, T cells and B cells. Several investigations agree that
histamine is able to influence T cell response, enhancing T helper 1 type
response by triggering the H1 receptor, whereas both T helper 1 and T helper 2
type response is negatively regulated by H2 receptors, through the activation
of different biochemical intracellular signals [16-19].
Histamine is synthesized from the amino acid histidine by the enzyme
histidine decarboxylase (HDC). In mammals, histamine is metabolized by two
major pathways: N(tau)-methylation via histamine N-methyltransferase (HMT), and
oxidative deamination via diamine oxidase (DAO). HMT is expressed in human
kidney, liver, spleen, prostate, ovary, colon, and spinal cord. Enzymatic
activity of HMT has been shown to be regulated by inheritance, and
inter-individual variation of HMT activity has been demonstrated in some
populations. DAO is the main histamine-degrading enzyme in peripheral tissues
(gut, connective tissues) and in invertebrates.
Genetic variation in histamine receptors and histamine-synthesizing and
-metabolizing enzymes is associated with differences in histamine metabolism,
altered enzyme activities, and risk of disease [20]. Genetic studies have found
that polymorphisms in the HDC gene
are associated with Tourette syndrome, asthma, rhinitis and neoplasms [21]. A
common polymorphism in the HNMT gene,
corresponding to variant rs11558538, results in a Thr105Ile substitution that
regulates enzyme activity. The less common T allele (encoding Ile) is
associated with decreased HMT enzyme activity [22,23] and with different
pathological conditions [24-26]. Genetic variation in histamine receptors has
been associated with diverse diseases and pathological states. Polymorphisms in
the HRH1 and HRH2 histamine receptor genes have been correlated in several
studies with schizophrenia, antipsychotic-induced weight gain, cardiovascular
disease, pharmacogenetics of clozapine, Parkinson disease, neoplasms, acetylsalicylic
acid hypersensitivity, among others [20,27-32].
To help and advance in the knowledge of histamine genomics, we analyzed
in a group of 195 patients three genetic polymorphisms in the HRH1 gene (rs901865; -17A>G), the HRH2 gene (rs2067474; -1018G>A) and
the HNMT gene (rs11558538;
Ile105Thr), to establish a potential association between histamine
polymorphisms and blood histamine, IgA, IgG, IgM, IgE, hs-CRP, TNF-alpha, IL1B,
IL6, IL8, and IL10 serum levels, as well as leukocyte, lymphocyte, neutrophil,
monocyte, eosinophil and basophil counts.
MATERIAL
AND METHODS
The study
sample included 195 unrelated Caucasian patients from the EuroEspes Biomedical
Research Centre, in Galicia, Spain. The participants provided written informed
consent and the study was performed according to Applicable Regulatory
Requirements, the ethical code of the World Medical Association (Declaration of
Helsinki) and approved by the EuroEspes Biomedical Research Centre Review
Board. The study population was a mixture of healthy subjects and patients with
different pathologies (Table 1).
Venous blood samples were taken from overnight fasting subjects in
supine position. Samples for the analysis of serum interleukin 10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), interleukin 1β (IL1β), interleukin 6 (IL6), interleukin 8 (IL8), immunoglobulins (IgA, IgG, IgM, IgE)
and high sensitive C-reactive protein (hs-CRP) were collected in BD
Vacutainer serum separation tubes. Samples for white cell count (total leukocytes
and subpopulations) were collected into EDTA-containing tubes. White blood
cells were analyzed immediately after venipuncture. Serum tubes were allowed to
clot at room temperature during 30 minutes before processing and centrifuged at
3,000 rpm, at 4°C, for 10 minutes. After refrigerated centrifugation, serum was
removed from blood cells and placed in an appropriate sample container to store
at -80ºC until analysis.
Determination of serum immunoglobulins (IgA, IgG, IgM) and hs-CRP
levels was performed by immunoturbidimetric assay, using an automated
biochemical analyzer, Cobas Mira Plus (ABX Diagnostics Inc.). IgE was measured
by the immunochemiluminiscence method using an automated immunoassay system,
Immulite 1000, Siemens Healthcare Diagnostics.
Determination of the absolute number and percentage of leukocytes,
lymphocytes, neutrophils, monocytes, eosinophils and basophils was carried out
by the electrical impedance method, using a Coulter ACT5 Diff CP hematology
analyzer from Beckman Coulter Inc. (Fullerton, CA, USA). The leukocyte
differential count was performed using absorbance cytochemistry and volume
technology.
Measurement of TNF-alpha, IL1B, IL6, IL8, and IL10 was performed by
immunochemiluminiscent assay, using the automated immunoassay system Immulite
1000, Siemens Healthcare Diagnostics.
Venous blood samples for histamine determination were diluted with
water (1:1 v/v), homogenized and centrifuged at 3,000 rpm for 10 min at 4o
C. The pellet was discarded and the supernatant was treated with 100 μl/ml 60%
perchloric acid and mixed vigorously; then, the mixture was centrifuged for 20
min at 12,500 rpm. The supernatant was stored at -40o C until
histamine determination. Histamine was measured by high-performance liquid
chromatography (HPLC), as previously described [33]. The chromatographic system
consists of four independent isocratic pumps (Agilent 1100 series G13110A), a
stainless-steel column packed with a cation exchanger (TSK gel SP-2SW, 5 μm;
TosoHaas Corporation) and a fluorometric detection system (Agilent 1100 G1321A
FLD). Samples of 20 μl were injected directly into the HPLC column. Histamine
is expressed as ng/mL of whole blood. The HPLC method is based on the
extraction of histamine with perchloric acid, followed by direct HPLC analysis
with on-line derivatization with o-phthaldialdehyde and fluorescence detection,
setting the excitation wavelength at 360 nm and the emission at 450 nm.
Molecular genetic analysis was carried out from subjects’ blood samples
after the appropriate informed consent. DNA was isolated by conventional
procedures from a blood leukocyte-rich fraction using a commercial kit, QIAamp
DNA Mini Kit (QIAGEN), following the kit handbook recommendations. Genotyping
was performed blindly for 3 polymorphisms in 3 genes: HRH1 rs901865, HRH2
rs2067474 and HNMT rs11558538, all of
these reported to be associated with pathological conditions. The polymorphisms
analyzed were identified by allelic discrimination, on an ABI PRISM 7300
Sequence Detection System, using a commercially available kit (Applied
Biosystems).
Statistical analysis was performed using SPSS® version 20
(IBM Analytics). Subject demographics
and mean clinical measurements were calculated by descriptive statistics. The
association between polymorphisms and blood and serum biochemical markers was
assessed by crosstabs analysis, chi-square test and Fisher’s exact test. For
this analysis, subjects were divided into two groups, those with biochemical
values within normal limits and those with levels above normal values.
Differences in biochemical factors as a function of genotypes were performed by
non-parametric independent sample Mann-Whitney U Test, assuming that the
population does not follow a normal distribution. Given the small observed
frequency of the AA genotype in the HRH1-17A>G
polymorphism and also the TT genotype in the HNMT Ile105Thr polymorphism, combined frequencies for these
genotypes were used (GA and AA; CT and TT). The level of significance for all
statistical tests was α= 0.05.
RESULTS
A total of 195 subjects were included in the study. Table 1 presents their demographic and
clinical characteristics. The majority of the subjects had underlying diseases,
including neurological and vascular disorders, neoplasms, psychiatric diseases
and metabolic conditions. Only 14% (n=28) of the subjects were considered
healthy subjects.
Genotype distribution for rs901865, rs2067474, and rs11558538 was
consistent with the Hardy-Weinberg Equilibrium
(H-W) (Table 2).
The group of subjects with the HRH1-17GG
genotype had significantly higher levels of serum TNF-alpha (7.5 ± 2.1 vs. 6.0 ± 1.4 pg/mL; p<0.005), and a
significant increase in the percentage of blood monocytes (7.6 ± 2.1 vs. 7.0 ± 2.0 %; p<0.05) when
compared with GA/AA subjects. HRH1-17A>G
genotype distribution was significantly associated with serum TNF-alpha levels.
In this sense, subjects were divided according to biochemical values, those
within the
normal limits and those above the normal values. A significant
over-representation of the GG genotype was observed in subjects with serum
TNF-alpha levels over 8.1 pg/mL, considered pathological; conversely, the GA/AA
genotype was significantly more frequent in those subjects with serum TNF-alpha
levels below 8.1 pg/mL (χ2 =5.034; p<0.019, df=1) (Figure 1).
Statistical analysis of the HRH2-1018G>A
genotype (Figure 2) presents a
significantly higher frequency of the GA genotype in subjects with serum hs-CRP
above normal values (≥ 3.0 mg/dL), while the GG genotype presents a higher
proportion of subjects with hs-CRP below 3.0 mg/dL (χ2 =13.9;
p=0.001, df=1). Subjects with GA genotype have significantly higher levels of
serum hs-CRP than subjects with GG genotype (3.8 ± 8.6 vs. 6.6 ± 11.2 mg/dL; p<0.02). The percentage of monocytes is
increased in the GG genotype in comparison with the GA genotype (7.5 ± 2.1 vs. 6.2 ± 1.8 %; p<0.05).
The
results concerning the HNMT Ile105Thr
gene polymorphism (Figure 3) showed
a significant association of the CT/TT genotype with higher blood histamine
levels (CT/TT=107.0 ± 53.9 vs.
CC=85.6 ± 45.7 ng/mL; p<0.03). Subjects bearing the CC genotype present
higher levels of serum IL-8 than subjects with the CT/TT genotype (2.1 ± 1.8 vs. 1.2 ± 0.7; p<0.02). A
significantly higher frequency of CT/TT genotype was observed in subjects with
histamine levels above the normal range (≥90 ng/mL), while the CC genotype is
more frequent in subjects with histamine levels within normal values (≤ 90
ng/mL) (χ2 =5.83; p=0.02, df=1).
DISCUSSION
In this study we show the association of genetic polymorphisms in the
histamine pathway with several biological markers related to the immune
response. We observed significant associations between genotypes and
biochemical and hematological markers. The polymorphism rs901865 in the HRH1 gene is associated with serum
TNF-alpha levels and blood monocytes; the polymorphism rs2067474 in the HRH2 gene is associated with serum
hs-CRP levels and blood monocytes; and the polymorphism rs11558538 in the HNMT gene is linked to blood histamine
and serum IL8 levels.
Monocytes are circulating white blood cells that are essential
components of the innate immune system, and they establish the first line of
defense against external or internal danger signals through the initiation of
an inflammatory response [34]. Monocytes have the biological property of
differentiating into tissue macrophages and dendritic cells, all of these
constituting the mononuclear phagocyte system (MPS). The MPS plays crucial
roles in development, wound healing, tissue homeostasis and even cancer
progression [35]. Blood monocytes express both H1 and H2 histamine receptors,
and they exert immunomodulatory effects by influencing the functions of a number
of immune cells that play a primary role in initiating and sustaining
inflammation [36,37]. In the present study, the polymorphisms rs901865 within
the HRH1 5’UTR and rs2067474, which
is located in an enhancer element of the HRH2
promoter, are both associated with increased blood monocyte count. The HRH1 -17GG homozygote is significantly
associated with elevated blood monocyte count in comparison with the -17GA/AA
genotype. Previous investigations of this polymorphism were focused principally
on hypersensitivity to drugs (aspirin, non-steroidal anti-inflammatory agents),
response to drugs (clozapine, olanzapine) in schizophrenia and bipolar
disorders, antipsychotic medication and obesity, but no conclusive results were
found [27-32]. The HRH2 -1018GG
homozygote is significantly associated with elevated blood monocyte count in
comparison with the -1018GA genotype. Different studies have linked this
polymorphism to different diseases or pathological situations such as
Parkinson, schizophrenia, gastric cancer, breast cancer, gastric mucosal
atrophy, chronic heart failure, and hypersensitivity to non-steroidal
anti-inflammatory agents [27-32].
We found that the HRH1-17GG
genotype is associated with elevated serum TNF-alpha levels and we observed an
increased frequency of subjects with the -17GG genotype and serum TNF-alpha
levels above normal values. TNF-alpha is a cytokine thought to be involved in
the pathogenesis of asthma and in several other inflammatory conditions.
TNF-alpha is mainly secreted by macrophages, a monocyte-derived cell. It has
been demonstrated that histamine regulates the production of TNF-alpha by
monocytes, and this effect is mediated through H1 and H2 histamine receptors
[38,39].
Subjects with the HRH2
-1018GA genotype present significantly higher levels of hs-CRP protein in
comparison with -1018GG subjects, and we observed a higher proportion of
subjects with the -1018GA genotype and serum hs-CPR above normal values. CRP is
the prototypical acute phase protein in humans; it is an important mediator of
host defense and is part of the innate immune response. It is predominantly
synthesized in the liver parenchymal cells by cytokines from stimulated
leucocytes and released into the circulation. Histamine is able to modulate
acute phase proteins through the release of pro-inflammatory cytokines as IL1
and IL6, the latter being the principal inducer of CRP gene expression during
the acute phase [40,41].
The third genetic polymorphism analyzed in this study is an amino acid
change in the HNMT gene. The sequence
variation consists of a thr105-to-Ile change in exon 4 (314C-T). This
polymorphism has been associated with a decrease in the activity of the HMT
enzyme, resulting in reduced histamine metabolism. The enzyme containing Ile at
position 105, T allele, was associated with decreased levels of HMT activity
and immunoreactivity. The Thr105Ile polymorphism has been linked to
predisposition of more than 30 diseases, such as asthma, Parkinson´s disease,
schizophrenia, Alzheimer’s disease, atopic dermatitis and cancer [20,22-27].
Our results showed a significant increase in the levels of blood histamine in
the HNMT 314CT/TT genotype, which is
in accordance with the decrease in histamine metabolism due to a lower enzyme
activity in 105Ile carriers. We also show that in those subjects with blood
histamine levels above normal range, the 314CT/TT genotype is more frequent. A
significant increase in IL-8 levels is found in subjects with the HNMT 314CC genotype. This effect might
indicate a possible relationship between the 314CC genotype and inflammation;
although the interrelation between histamine and IL-8 has not been sufficiently
studied, it is known that histamine increases the expression of IL-8 via H1
receptors in vitro, and enhances the
release of IL-8 in different cell types [42]. This cytokine is synthesized by
monocytes, macrophages, epithelial cells and smooth muscle cells, and is
involved in inflammatory processes. It is also involved in the pathophysiology
of several inflammatory-based diseases such as cystic fibrosis, rheumatoid
arthritis, inflammatory bowel disease and psoriasis, among others [43].
These
results presented here are important in understanding how histamine genetic
variation may affect markers of inflammation and allergy. The results provide
new data concerning histamine genomics and biochemical and cellular components
of inflammatory and immunological processes. Two important inflammatory
markers, TNF-alpha and hs-CRP, showed association with genomic markers of the
histamine pathway. We also show that the observed increase in blood monocyte
count is genotype-dependent. Monocytes are very interesting white blood cells,
having the capacity to differentiate into macrophages and dendritic cells, this
ability of monocytes being central for the functioning of the immune system.
Further investigations are needed in order to clarify some of the genomic
associations presented here.
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