Association Between Dopamine D2 Receptor Gene Polymorphism、DNA Methylation And Persistent Postural-perceptual Dizziness

IntroductionPersistent postural-perceptual dizziness (PPPD) is a common kind of chronic dizziness in clinic, which accounts for about 10% of the outpatient dizziness. Due to being lack of understanding about the concept, clinical features and diagnostic criteria of PPPD by the clinicians, the patients were dubbed "spirituality dizzy" or " chronic cerebral circulation insufficiency (CCCI) " for a long time, which bring to delay for treatment of these patients. Here it is particularly important for understanding this disease correctly, including clinical features, pathogenesis, diagnostic criteria and treatment, etc. Current clinical research about PPPD was still limited to a few research centers of Europe and the United States, they thought that PPPD was more represented in middle-aged female, and was more easy merge with anxiety and depression, neuroticism and introverted personality are risk factors of the PPPD; But there has no related research about PPPD in China, therefore, it is particularly important to further explore the clinical features and treatment of PPPD in China.In terms of pathogenesis of PPPD, it is only limited at the aspect of Social-Psychology by present study. At the beginning of this century, professor Staab thought that PPPD tended to occur after acute vestibular disorder, panic attacks or other intense stress reactions, which seemed to manifest the adverse effects of acute anxiety on the readaptation disorder in the early phases of the illness. And there is no relevant research about the molecular pathological mechanism by now.Gene polymorphism is a hotspot of research in recent years. PPPD patients had the neurotic personality, where as neurotic personality was influenced by genetic and environmental interaction. According to the research of the neurobiology model theory, the dopamine system was the most close to the personality characteristics of neurobiology system. It was reported that dopamine D2 receptor (DRD2) gene especially Taq IA gene polymorphism was associated with neurotic personality, but whether the DRD2 TaqIA gene polymorphism was involved in the onset of PPPD, there is no relevant research report until now.In addition, DNA methylation, one of the epigenetic modification methods, managed gene expression through DNA and histone modifications, which did not change the premise of genome sequences. DNA methylation is becoming the pathogenesis research hotspot in recent years, especially in cancer, degenerative diseases and mental illness. PPPD is greatly influenced by genetic and environmental factors, the locus of DNA methylation including CpG islands which is located in DRD2 gene promoter may be related to its pathogenesis, there is also lack of related researches at present.In accordance with the above study, we had several speculations:(1) PPPD in China may also contain clinical features as followed:PPPD is more represented in women in clinic, anxiety is the main mood disorder to be identified, and neurotic personality is the main risk factors of the disease. However, whether it merged higher depression and introverted personality, there is no relevant study, and whether it has the other unknown clinical characteristics needs to further research. (2) If DRD2 TaqlA gene polymorphism was associated with PPPD, it indicated that DRD2 Taq1A gene polymorphism may be involved in the pathogenesis of PPPD. (3) Comparing with control group, if CpG methylation level in DRD2 gene promoter was significantly increased in PPPD, it hint that genetic or environmental factors may be involved in the PPPD. Such research helps to further explore the pathogenesis of genetic and environmental aspects in PPPD. It is helpful to further explore the genetic and environmental influence on PPPD patients about dopamine D2 receptor gene polymorphism and DNA methylation, which can provide the theoretical foundation in the pathogenesis of molecular biology, and then provide theoretical basis for the clinical treatment of the disease.Part 1 Analysis on the characteristics of the Persistent Postural-Perceptual Dizziness-a clinical study in ChinaBackground:Persistent postural-perceptual dizziness (PPPD) was a chronic dizziness, although it’s clinical characteristics and risk factors had been reported in recent years, no related research had been performed in China. Therefore, the purpose of this study was to analyze and evaluate the clinical characteristics of PPPD in China.Methods:The disease group consisted of 26 patients diagnosed with PPPD chosen from the outpatient and inpatient clinics in the Department of Neurology of Yantaishan Hospital between January and October 2015. The control group included 25 cases of hospitalized patients who had experienced acute vestibular peripheral vertigo from the same period and had fully recovered within 3 months without selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) medication. Clinical data was collected from all patients. All subjects were examined with Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), and the Eysenck Personality Questionnaire (EPQ). Data was analyzed using the chi-square test, Fisher’s exact test, measurement data using the non-matching t test, with P< 0.05 defined as statistical significance.Results:In the disease group, women were significantly more represented in the PPPD group than in controls, and in the majority of cases the age of onset was in middle-age, and sleep quality was clearly decreased compared with controls, with more significantly higher levels of anxiety (P< 0.05). Personality analysis identified that neuroticism was significantly higher than in controls (P< 0.01).Conclusions:In China, PPPD was more represented in female patients, the age of onset was 40 to 60 years old, the majority of patients had sleep disorders, anxiety is the main mood disorder to be identified, and neurotic personality is the main risk factor in PPPD.Part 2 Association between Dopamine D2 receptor gene Polymorphism and persistent postural-perceptual dizzinessBackground:Persistent postural-perceptual dizziness (PPPD) was a chronic dizziness, neurotic personality was considered a major risk factor for the onset, studies had found that DRD2 TaqIA genes associated with neurotic personality, but whether the gene was involved in the PPPD, there was no relevant research at home and abroad. Therefore, this study aimed at analyzing the relationship between DRD2 TaqIA gene polymorphism and PPPD, and then to explore the molecular mechanism of this disease.Methods:The disease group consisted of 22 patients diagnosed with PPPD chosen from the outpatient and inpatient clinics in the Department of Neurology of Yantaishan Hospital between January and October 2015. The control group included 23 cases of hospitalized patients who had experienced acute vestibular peripheral vertigo from the same period and had fully recovered within 3 months without selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) medication. Clinical data was collected from all patients, DRD2TaqIA gene polymorphism frequency was detected with polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) method on all cases of this group. Data was analyzed using the chi-square test, Fisher’s exact test, measurement data using the non-matching t test, with P< 0.05 defined as statistically significant.Results:In the disease group, A1、A2 allele frequency in the DRD2 were 68.2% and 31.8% respectively, which had significantly difference with the control group (43.5% and 43.5%, P< 0.05). On the genotype frequency, the disease group was A1/A1 (36.4%), A1/A2 (63.6%), A2/A2(0), which was significantly higher than control group (21.7%,43.5% and 34.8% respectively, P< 0.01)Conclusions:DRD2 Taq A1 allele is the susceptibility gene for PPPD, and A2/A2 gene type is the protective genotypes for PPPD, but it remains to be confirmed by independent research of a larger sample size.Part 3 CpG methylation of Dopamine D2 receptor gene promoter in persistent postural-perceptual dizzinessBackground:Persistent postural-perceptual dizziness (PPPD) was a chronic dizziness, neurotic personality was considered a major risk factor for the onset, Personality characteristics is influenced by genetic and environmental factors, DNA methylation whichwas one of the epigenetic modification method can reflect the molecular mechanism of PPPD, there had no relevant research at home and abroad. Therefore, this study aimed at analyzing the relationship between CpG methylation of Dopamine D2 receptor gene promoter and PPPD, and then to explore the molecular mechanism of the disease.Methods:The disease group consisted of 22 patients diagnosed with PPPD chosen from the outpatient and inpatient clinics in the Department of Neurology of Yantaishan Hospital between January and October 2015. The control group included 23 cases of hospitalized patients who had experienced acute vestibular peripheral vertigo from the same period and had fully recovered within 3 months without selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) medication. Clinical data was collected from all patients, CpG methylation was detected with Bisulfite Sequencing PCR (BSP) method on all cases of the group. Data was analyzed using the chi-square test, Fisher’s exact test, measurement data using the non-matching t test, with P< 0.05 defined as statistically significant.Results:In the disease group, the positive rate of CpG methylation in DRD2 gene promoter was 54.5%, which was significantly higher than control group (13.0%), and the CpG methylation loci of DRD2 gene promoter in the disease group (0.15±0.18) was also significantly higher than the control group (0.04±0.10)(P< 0.05).Conclusions:CpG methylation of DRD2 gene promoter is associated with the onset of PPPD. It remains to be confirmed by independent research of a larger sample size.