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Association of Polymorphisms of COMT and DAT Gene in Dopamine Metabolism System with Post-stroke Depression

Author: CaiWeiWei
Tutor: LiuZhenHua
School: Southern Medical University,
Course: Neurology
Keywords: Dopamine Post-stroke depression COMT DAT Polymorphism
CLC: R743.3
Type: Master's thesis
Year: 2011
Downloads: 99
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Abstract

Background: stroke caused by a variety of neurological dysfunction often leads to a series of emotional behavior changes, depression and neuropsychiatric complications after stroke is the most common and most important, the patient's cognitive, neurological recovery and The quality of life are adversely affected. Post-stroke depression (Post-stroke depression, PSD) is a common complication after the onset of obvious clinical symptoms of stroke to depression, decreased interest features after stroke. The incidence of clinical reports vary, the domestic literature PSD incidence from 31.2% to 63.1%, foreign reports of 25% to 79% PSD incidence is concentrated in about 40% to 50% can be seen from the large number of clinical reports. With the biomedical model to biological - psychological - social medical model conversion, post-stroke depression and antidepressant treatment concern. PSD pathogenesis is not yet clear, generally considered to be mediated by social psychology, neuroanatomy and neurobiology, and many other factors, including the Neurobiology factors has been in recent years, a hot research. PSD primary endogenous theory that it is a specific area of ??the brain injury, and is accompanied by the results of neurotransmitter changes, specifically, the frontal lobe of the brain, the limbic system, hypothalamus and brainstem locus coeruleus nuclear damage can make humans depression, and the communication between these neural structures is mainly done through various neurotransmission. Norepinephrine (Norepinephrine, NE) and 5 - hydroxytryptamine (5-Hydroxytryptamine ,5-HT) is an important neurotransmitter of the nervous system, neuronal cell bodies in the brainstem axons through the hypothalamus, basal ganglia area, surround corpus callosum and corona radiata, and then from front to back through the deep cortex, and gradually issuing branch termination on the surface, the formation of the frontal / temporal lobe - basal ganglia - brain stem ventral loop, the loop is responsible for the regulation of mood, sleep and cognition. Undermine the loop stroke can cause neuropsychological activities related to a variety of neurotransmitter synthesis, metabolism, and conduction disturbances, leading to reduced 5-HT, NE neurotransmitter synthesis, or cause the postsynaptic membrane receptor number and / or changes in sensitivity can lead to depression. Dopamine (Dopamine, DA) also participate in the mental and emotional activities, it contains the brain - the cerebral cortex in the brain - the limbic system is closely related to the human spirit and emotional activities. Tip: For the pathophysiological mechanisms of primary depression related to the low incidence of depression and brain monoamine neurotransmitter function activity, especially the 5-HT and NE, the relationship of both depression may have been The conclusion is widely recognized, but a lot of new antidepressant drugs DA metabolism, so researchers feel that DA plays an important role in the biochemical mechanisms of depression. Randrup first proposed as early as 1975, and dopamine may be involved in the pathogenesis of depression. Have the Schwaninger that patients with depression is not just the 5-HT, NE nerve conduction abnormalities, DA nerve conduction abnormalities involving the pathophysiology of depression. Recently Maj et al found that the use of agonists, rather than inhibitors apomorphine morphine after antidepressant therapy may increase the active state D2, and D3 receptor density, DA receptor responses decline in patients with paroxetine antidepressant treatment would be better. This prompted the perhaps SSRIS sensitivity function by increasing the DA receptors, suggesting that dopamine plays a very important role in primary depression. Otherwise Lui route research in recent years shows that the PSD plasma DA concentrations in the cerebrospinal fluid is less than the stroke depression group and even the normal control group; YB study cerebral ischemia reperfusion in mice hippocampus, striatum, cortex monoamine neurotransmitters and their metabolites variation that the occurrence of the PSD the hippocampal cerebral ischemia-reperfusion injury after NE, DA system abnormalities closely linked PSD patients with antidepressant drugs increase monoamine neurotransmitters in After treatment, the symptoms of depression can be alleviated, and further support the above theory. This suggests that the dopamine metabolism after stroke lead to system dysfunction may play an important role in the occurrence of the PSD. DA have antidepressant effects in the brain as a neurotransmitter affects movement, behavior, emotional and pituitary hormone release, some drugs affect DA metabolism, such as bupropion, it is a relatively selective DA reuptake inhibitor of DA receptor agonism, double-blind controlled studies have shown that this second-generation antidepressants better than placebo, and equivalent to amitriptyline. Recently been proposed DA metabolic system function abnormalities may be associated with the incidence of depression are two theories: One is that depression may be present in patients with DAD1 receptor dysfunction; another that DA dysfunction of the limbic system in the presence of depressed patients, Central Ventral tegmental area and the nucleus accumbens constitutes mesolimbic DA pathways in the reward process plays a key role recently come to realize that the reward pathway in regulating motivation, sleep, appetite, circadian rhythm and pleasure or aversive reaction plays an important role in the the Rewarded reaction of almost all of the long-term antidepressant therapy will increase DA induced. Catechol-O-methyltransferase (COMT) (Catechol-O-methyhl transferase, COMT) is a metabolic enzyme widely present in the human body, mainly through methylation directly and selectively degrade more than 60% of the prefrontal cortex synapses the DA, is biologically active or toxic catecholamine metabolizing enzymes, most key enzyme. The COMT gene is located on 22q11.2, is a variation of many genes. Stage the most studied is on its 4th exon of a G → A point mutation, so that the 108 or 158 amino acid residues by Val mutation Met, resulting in 3 to 4 times the change in enzyme activity, and thus of its encoded cause significantly different in different genotypes of neurotransmitters in the body content. Val / Val genotype of COMT having a high activity, Val / Met genotype of the enzyme having a moderate activity, Met / Met genotype of the enzyme has a low activity, which is a high active allele G and low activity allele A The two alleles decision genetic codominant way. Massat study found that high activity COMT Val allele, especially Val / Val genotype with early-onset depression, and pointed out that the COMT gene may play a complex and multi-effect in of neuropsychiatric disease susceptibility and symptomatology role. PSD neurotransmitter doctrine that the depression occurred with serum monoamine neurotransmitter function decreased activity, and studies have shown that the PSD patients after acute stroke DA dysfunction speculated that low DA function may be due to reduced DA generated or increased degradation, i.e. the effective precursor tyrosine reduction system is changed or the enzyme relating to the synthesis, metabolism, or amine pass due to the reduced functionality. The high activity of the enzyme allows the neurotransmitter dopamine as substrate degradation and eliminate speed up, thus shortening its duration of action, reducing the efficiency of DA role, can increase the risk of depression in patients with cognitive dysfunction, and thus the mutation point lead to changes in COMT activity in the population will result in the biology of related traits change, whether associated with the onset of the PSD, are very worthy of the subject of in-depth study of the genetics. Dopamine transporters (Dopamine transporter gene, DAT) is located in the DA neurons presynaptic membrane transmembrane protein that specifically reuptake the synaptic cleft DA, terminate the DA can signal pass and maintain DA neurons stable the most important factor, especially for normal brain function in maintaining very important. It limits the dopaminergic receptor activation time, the extent, scope, regulating DA concentration, while dopamine is the number associated with many neurological diseases. If abnormal uptake transporter protein, will result in the synaptic space is the neurotransmitter concentration increased or decreased, thereby causing a corresponding change in functional activity of the neurotransmitter system, a lot of drugs to treat neurological diseases transporter proteins as the target for its direct role adjust neurotransmitter transporter protein function by adjusting the time between the synapse, thereby changing the signaling pathways of the nervous system, to achieve therapeutic effect. Human DAT gene is located on 5p15.3, its 3'UTR 40bp VNTR. The VNTR polymorphism in the non-coding region, which itself can not directly change the structure and function of the DAT, but the study found that with the brain DAT expression and utilization. DAT to the polymorphic loci is not silent, but also affect the gene that produces high levels of mRNA expression, studies show that the 10 repeat allele have a stronger enhancing effect compared to the other allele for the expression of the DAT gene, the 10/10 gene type individual than the 9/10 genotype striatal DAT protein content increased by about 20%. Two additional studies that the 9-repeat allele encoding DAT has higher expression and utilization. The high activity of the DAT can increase the presynaptic membrane of DA re-uptake, synaptic gap DA reduce efficiency drops. Brunswick found that depression in patients with basal ganglia dopamine transporter affinity may be higher than the normal control group, suggesting that patients with depression dopamine function can change, maybe this is antidepressant drugs may be valid reasons. Animal studies have confirmed that all types of antidepressant drugs can cause changes in dopamine transporter affinity. Joyce PR that DAT-9-fold repeat allele is a risk factor of depression in patients with borderline personality disorder in elderly patients with depression is particularly evident. The stroke damaged the DA signaling pathway but also feedback caused DAT functional activity and changes in the affinity, speculated that may play a role in the occurrence of the PSD. Purpose: To investigate the the DA neurotransmitter metabolism related proteins of COMT Val108/158Met, DAT40 the bp in VNTR two gene polymorphism and PSD relationships. Research methods and grouping: Zhujiang Hospital, Department of Neurology, inpatient study population, patients with cerebrovascular According to the Fourth National Conference to make a stroke diagnosis and Hamilton depression scale to make a depression diagnosis, inclusion criteria to select 159 cases enrolled patients divided into simple stroke group, 91 cases (59 male, 32 females) and post-stroke depression group, 68 patients (40 male, 28 female). Use of the polymerase chain reaction - restriction fragment length polymorphism analysis of technology acquisition subjects whole blood 2mL EDTA anticoagulant after phenol - chloroform extraction method peripheral leukocytes and genomic DNA. PCR primers (upstream 5'-ACT GTG GCT ACT CAG CTG TG-3 ', downstream: 5'-CCT TTT TCC AGG TCT the GAC AA-3') COMT gene was amplified endonuclease Nla Ⅲ detection COMT gene Val108/158Met polymorphism. While using the PCR primers (upstream 5'-TGT the GGT GTA in GGG AAC GGC CTG AG-3 'and downstream: 5'-CTT CCT GGA AGG. The GGT CAC GGC TCA-3') amplified the DAT gene, and comparing the amplified fragment size. Using SPSS13.0 statistical package, using the chi-square test is relatively simple stroke group with post-stroke depression group allele, genotype frequency distribution of the difference, when the theoretical frequency lt;, replaced by the Fisher exact test. The results: (1) COMT Val108/158Met polymorphism analysis: the poststroke depression allele A frequency (21.3%) lower than the stroke group (33.5%), allele the G frequency (78.7%) higher than the simple stroke group (66.5%), the difference between the two groups overall statistical significance (χ 2 = 5.703, P = 0.017, OR = 1.860, 95% CI = 1.114 ~~ 3.107). By sex allele frequencies of G and A in the difference between the two groups of men was not statistically significant (χ2 = 1.864, P = 0.172), and compare the differences between the two groups of women was statistically significant ( χ2 = 4.610, P = 0.032, OR = 2.455,95% CI = 1.069 ~ 5.635). Poststroke depression group of wild-type G / G in the majority (63.2%), mutant A / A only (5.9%), the simple stroke group heterozygous A / G accounted for the majority (47.3%), mutant A / A (9.9%), two sets of three genotypes A / A, A / G, G / G overall difference was statistically significant (χ2 = 6.489, P = 0.039), but compared by gender in the two groups of men Compare the difference was not statistically significant (χ2 = 1.701, P = 0.476) compared two groups of women, the difference was statistically significant (χ2 = 6.547, P = 0.024). (2) DAT 40 bp VNTR polymorphism analysis: The DAT gene 40 bp VNTR to 10 times (480bp) repeat fragment-based, post-stroke depression group and the stroke group alone accounted for 91.9% and 90.7%, respectively, followed by 9 times ( 440bp) repeat fragment, two groups accounted for 5.9% and 5.5%, respectively. Allele and genotype frequencies and heterozygosity between the two groups showed no significant difference (χ 2 = 1.966, P = 0.634; χ2 = 2.248, P = 1.000; χ2 = 0.125, P = 0.724). DAT genotype and allele divided into 10/10 times repeat genotype non 10/10 times repeat genotype, 10-fold repeat allele and non 10 times repeat allele comparing two sets of 10-fold repeat genotype with non-10-fold repeat genotype was no significant difference (χ 2 = 0.145, P = 0.703); two sets of 10-fold repeat allele with non-10-fold repeat allele was no significant difference (χ 2 = 0.152, P = 0.697). Conclusion: The study group, the occurrence of the the COMT Val108/158Met gene polymorphism with PSD may correlation, this correlation is mainly reflected in female patients, indicating that the gene polymorphism may be genetic disease of depression in women after stroke play a greater role in the mechanism. DAT 40bp VNTR gene polymorphism with PSD genetic susceptibility may be irrelevant, further research is needed to verify.

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