Yanchen XieWashington Institute of Clinical Research · Neurology
· M.D., Ph.D.
Washington Institute of Clinical Research
Skills and Expertise
Research Items (37)
An array of cytokines influences the pathogenesis of early onset myasthenia gravis (MG) and its animal model, experimental autoimmune myasthenia gravis (EAMG). Patients with MG, in particular those with more severe weakness, have elevations of the pro-inflammatory cytokine IL-17 in the blood. We assessed the role of IL-17A in autoimmunity by inducing EAMG in mice with knockout of IL-17 and found a reduction of EAMG severity, but not a complete ablation of disease. The IL-17ko mice had no evidence of weakness, low levels of acetylcholine receptor antibodies, and retention of acetylcholine receptor at the neuromuscular junction. Splenic germinal center size was reduced in EAMG IL-17ko mice along with elevations of Foxp3 and BCL-6 gene expression, suggesting a shift away from pro-inflammatory signals. The results emphasize the importance of IL-17 in EAMG development and that IL-17 independent pathways drive the autoimmune reaction.
Biomarkers that assess treatment response for patients with the autoimmune disorder, myasthenia gravis (MG), have not been evaluated to a significant extent. We hypothesized the pro-inflammatory cytokine, osteopontin (OPN), may be associated with variability of response to glucocorticoids (GCs) in patients with MG. A cohort of 250 MG patients treated with standardized protocol of GCs was recruited, and plasma OPN and polymorphisms of its gene, secreted phosphoprotein 1 (SPP1), were evaluated. Mean OPN levels were higher in patients compared to healthy controls. Carriers of rs11728697*T allele (allele definition: one of two or more alternative forms of a gene) were more frequent in the poorly GC responsive group compared to the GC responsive group indicating an association of rs11728697*T allele with GC non-responsiveness. One risk haplotype (AGTACT) was identified associated with GC non-responsiveness compared with GC responsive MG group. Genetic variations of SPP1 were found associated with the response to GC among MG patients.
In this study, we intended to genotype 2 single nucleotide polymorphisms (SNPs) of tumor necrosis factor α-induced protein 3 (TNFAIP3) genes and explore an association of TNFAIP3 genetic polymorphism with the patients of myasthenia gravis (MG) at clinical level. In brief, 215 of adult MG patients were divided into subgroups according to their clinical features, age of onset, thymic pathology, and autoantibodies. Two hundred thirty-five of healthy controls were also divided into subgroups with gender- and age-matched. The allele and genotype frequencies of subgrouped patients were found to be higher than those of healthy controls. The distribution of TNFAIP3 gene rs7749323∗A allele of late onset MG (LOMG, with positive acetylcholine receptor antibody and without thymoma) subgrouped patients was also significantly higher than that of gender- and age-matched healthy controls (7.4% vs 2.4%, odds ratio [OR] = 3.27, 95% confidence interval [CI] 1.01–10.6, P = .04). Furthermore, analysis to the genotype frequencies indicates that the carriers of rs7749323∗A allele of LOMG group became more frequent than that of age-matched healthy controls (14.9% vs 4.8%, OR = 3.47, 95% CI 1.04–11.6, dominant model: P = .03). It is interesting to notice that there is no significant association between the rs7749323 and susceptibility of other MG subgroups. Therefore, it is suggested that the SNPs in the 3′ flanking region (rs7749323) of TNFAIP3 gene and the genetic variations of TNFAIP3 gene may take an important role in the susceptibility of LOMG.
This study was performed with the aim to investigate the correlations of tumor necrosis factor-alpha (TNF-α) gene promoter polymorphisms with the risk of thymoma-associated myasthenia gravis (T-MG) in a northern Chinese Han population. Between June 2005 and June 2015, 305 MG patients (150 males and 155 females, MG group) and 293 healthy volunteers (negative control (NC) group) were enrolled in this study. Among the MG patients, there were 121 patients with thymoma-associated MG (T-MG group) and 184 without T-MG (NT-MG group). Enzyme-linked immunosorbent assay (ELISA) was used for the serum TNF-α level. Polymerase chain reaction–restriction fragment length polymorphism was conducted to determine genotype and allele frequencies of TNF-α gene promoter -1031T/C, -857C/T and -863C/A. The haplotype was analyzed with the SHEsis software. Logistic regression analysis was performed for correlations between TNF-α gene promoter polymorphisms and the risk of T-MG. The T-MG group had higher frequencies of the CT/TT genotype and T allele of -857C/T than the NT-MG and NC groups. The frequencies of the CC genotype and C allele of -1031T/C were higher in the T-MG group than in the NT-MG and NC groups, and higher in male patients in the T-MG group than in male patients in the NC group. TTA and TTC haplotypes exhibited lower frequencies in the T-MG group than in the NT-MG group. The ocular MG patients exhibited lower frequencies of the TT genotype and T allele of -857C/T than the generalized MG patients did. The TNF-α level was elevated in the T-MG group compared with that in the NC and NT-MG groups, indicating that the TC+CC and CT+TT genotypes were increased compared with the TT and CC genotypes in the -1031T/C and -857C/T, respectively. Logistic regression analysis suggested that expressions of anti-acetylcholine receptor antibodies, Osserman’s classification, -1031T/C and -857C/T polymorphisms and the TTA haplotype were the independent risk factors for T-MG. These findings reveal that TNF-α -1031T/C and -857C/T polymorphisms and the TTA haplotype may be correlated with the occurrence of T-MG in a Northern Chinese Han population.
Polymorphism in autoimmune regulator (AIRE) gene is associated with various autoimmune disorders. Abnormal AIRE expression is associated with the development of myasthenia gravis (MG). We investigated the association of polymorphism in AIRE gene and the clinical features and severity of MG. The frequencies of alleles and genotypes were compared between 480 MG patients and 487 healthy controls, as well as among subgroups of MG patients. The frequencies of rs3761389 G allele in MG group (OR = 1.213, CI 95% 1.014–1.451, p = 0.035) and in mild (Oosterhuis score 0–2) subgroup (OR = 1.393, CI 95% 1.110–1.751, p = 0.004) were significantly higher than those in the control group. There were significant differences in the frequencies of rs3761389 genotypes (OR = 1.20, CI 95% 1.00–1.43, p = 0.046, log-additive model) and mild subgroup (OR = 1.32, CI 95% 1.03–1.69, p = 0.0058, log-additive model) compared with the control group. A Logistic regression analysis did not identify rs3761389 genotype as an independent risk factor to predict the severity of MG. This study provides the necessary preliminary data on the association with rs3761389 in AIRE gene with the susceptibility of MG, but not with the severity of MG.
In the international consensus for managing myasthenia gravis (MG), minimal manifestation status (MMS) or better was recommended as the treatment goal.¹ MMS refers to no symptoms of functional limitations from MG, but some weakness on examination of some muscles.² However, there are no criteria to detect the minimal weakness that is clinically important and biologically plausible. Only one study tried to link MMS and MG-specific quality of life scores.³ Moreover, the dose of pyridostigmine is an important factor that should be considered in attributing symptoms or functional limitations to MG. What is the optimal cutoff on measurements of weakness and pyridostigmine dose in the definition of MMS?
Myasthenia gravis (MG) is an antibody-mediated autoimmune disease against antigens at the neuromuscular junction. Both genetic and environmental factors contribute to the susceptibility of MG. We undertook a case–control study to explore the contribution of genes of the auto-antigen and immune-modulating proteins in the pathogenesis of MG. We enrolled 389 adult MG patients and 487 healthy controls. Eighteen SNPs were selected from genes of cholinergic receptor nicotinic alpha 1 (CHRNA1), autoimmune regulator (AIRE), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), protein tyrosine phosphatase nonreceptor type 22 (PTPN22), and interleukin-10 (IL-10). Rs16862847 and rs2229957 in CHRNA1, rs3761389 in AIRE, and rs733618 in CTLA-4 were significantly associated with MG, with the highest association in SNPs of CHRNA1. Carrier of rs16862847 G allele was found to be an independent risk factor in predicting high-level acetylcholine receptor (AChR) antibodies (P = 0.003, OR = 10.296). Genetic interaction analysis revealed a synergistic effect of CHRNA1 (rs16862847), AIRE (rs3761389), and CTLA-4 (rs733618) in the susceptibility of MG (P < 0.0001, OR = 1.95). These findings highlight the role of auto-antigen gene (CHRNA1) in the autoimmune reactions against AChR and reveal synergistic contribution of genes of both auto-antigen and immune-regulating proteins (AIRE and CTLA-4) in the pathogenesis of MG.
Background and purpose: Glucocorticoids (GCs) are the mainstay treatment of myasthenia gravis (MG). However, wide inter-individual variability exists in the response to GCs. Methods: A Chinese cohort of 257 MG patients treated with GCs was evaluated for the association between 19 single nucleotide polymorphisms in the GR gene and clinical response to the initial 3 month GC therapy. A quantitative MG score decreasing by ≥3 units or becoming zero was defined as sensitivity to GCs. Results: The rs17209237* G allele was less frequent in the GC insensitive group compared with the GC sensitive group [P = 0.013, odds ratio (OR) 0.119]. The rs9324921* A allele was more frequent in the GC insensitive group than in the GC sensitive group (P = 0.046, OR 1.94). Carriers of the rs17209237 G allele were less frequent in the GC insensitive group than in the GC sensitive group (dominant model, P = 0.009). Carriers of the rs9324921 A allele were more frequent in the GC insensitive group than in the GC sensitive group (dominant model, P = 0.037). Multivariate logistic regression revealed that the rs17209237 G allele carrier (P = 0.037, OR 0.12) and disease duration before GC treatment (P = 0.011, OR 3.45) were independent factors that contributed to GC efficacy. Conclusion: rs17209237 in the GR gene was identified as an independent factor that contributes to GC efficacy in MG patients. The genetic variations of the GR gene may play a role in predicting response to GC treatment.
Myasthenia gravis (MG) is a prototypic autoimmune disease with overt clinical and immunological heterogeneity. The data of MG is far from individually precise now, partially due to the rarity and heterogeneity of this disease. In this review, we provide the basic insights of MG data precision, including onset age, presenting symptoms, generalization, thymus status, pathogenic autoantibodies, muscle involvement, severity and response to treatment based on references and our previous studies. Subgroups and quantitative traits of MG are discussed in the sense of data precision. The role of disease registries and scientific bases of precise analysis are also discussed to ensure better collection and analysis of MG data.
To better define the role of IL-17A in myasthenia gravis (MG), we assessed plasma concentrations in 69 adult patients with MG prior to initiation of immunosuppression and monitored their clinical course for the subsequent 2years with quantitative MG scores (QMGS) and Osserman classification. IL-17A was higher among patients than healthy control subjects. Early-onset women without thymoma had greater elevations of IL-17A. Logistic regression analysis indicated that the absence of thymoma rather than women gender or early-onset was the significant determinant associated with IL-17A elevation. Elevated IL-17A levels were associated with more severe MG. In summary, IL-17A has role in the pathogenesis of a subgroup of patients with early-onset women with MG with greater disease severity who are most likely to have thymic hyperplasia. This subgroup may be a target for IL-17 treatments, which are under development.
Alleles of IL-17A and IL-17F genes were reported to be associated with many inflammatory and autoimmune disorders in Asian patients. Serum level and mRNA of IL-17A in peripheral blood mononuclear cells were reported to be significantly higher in MG patients than in healthy controls. In experimental autoimmune myasthenia gravis (EAMG) animals, IL-17 may have effects on the severity of MG. This study investigated the association between four SNPs of IL-17A and IL-17F gene (rs8193036, rs2275913 and rs3748067 in IL-17A; rs763780 in IL-17F) and MG in Chinese patients. The allele frequencies were compared between 480 MG patients and 487 healthy controls, between each MG subgroup and the control group, and between each pairs of MG subgroups. Subgroups were specified by clinical features (onset age, gender, thymoma, AChRAb and muscle involvement at onset) and maximal severity during the follow-up. No associations were found between the four SNPs of IL-17A and IL-17F gene and MG in Chinese patients.
Background Transient white matter lesions have been rarely reported in X-linked Charcot-Marie-Tooth disease type 1.Case presentationWe describe a 15-year-old boy who presented transient and recurrent weakness of the limbs for 5 days. His mother, his mother¿s mother and his mother¿s sister presented pes cavus. MRI and electrophysiology were performed in the proband. Gap junction protein beta l gene was analyzed by PCR-sequencing in the proband and his parents. The electrophysiological studies showed a mixed demyelinating and axonal sensorimotor neuropathy. MRI showed white matter lesions in the internal capsule, corpus callosum and periventricular areas, which showed almost complete resolution after two months. T278G mutation in Gap junction protein beta l gene was detected in the proband and his mother.Conclusion This case report highlights that the novel T278G mutation of Gap junction protein beta l maybe could result in X-linked Charcot-Marie-Tooth disease type 1 with predominant leucoencephalopathy. The white matter changes in MRI of X-linked Charcot-Marie-Tooth disease type 1 patient are reversible.
Background Cytotoxic T lymphocyte-associated antigen-4 (CTLA4), a critical negative regulator of the T-cell response, has been considered a candidate for many autoimmune diseases. Evidence from Caucasians supported a genetic predisposition of CTLA4 to myasthenia gravis (MG), but the contribution in East Asians has not been established. Objectives To investigate the role of CTLA4 variants in the susceptibility to MG and the contribution to subtypes of MG. Methods Six autoimmune disease-related risk alleles of CTLA4 (rs1863800, rs733618, rs4553808, rs5742909, rs231775, and rs3087243) were investigated for MG in northern Chinese. 168 patients with MG (mean age 37.1±20.5 years, 64 men and 104 women) and 233 healthy controls (mean age 53.3±8.7 years, 96 men and 137 women) were screened, and the contribution of CTLA4 to the general risk of MG and each subgroup was explored. Results rs1863800*C, rs733618*C, and rs231775*G were significantly associated with the whole cohort of patients with MG after permutation correction for multiple-testing adjustment (P = 0.027, 0.001, and 0.032, respectively). A risk haplotype (CCACG) [odds ratio (OR) = 1.535, range = 1.150–2.059, P = 0.004)] was also identified. The stratified subtype analysis indicated that the positive contribution was possibly derived from early onset MG (EOMG), seropositive MG (SPMG), female patients, and MG without thymoma. No association was observed in juvenile MG/LOMG, and MG coupled with thymoma. Conclusion A predisposing effect of rs1863800*C, rs733618*C, and rs231775*G of CTLA4 gene to general risk of MG in Chinese was demonstrated for the first time, which was likely derived from EOMG, SPMG, MG without thymoma and the female patients.
Miller Fisher's syndrome (MFS) commonly presents in the fourth and fifth decades and are rare in people over 70 years. An 85-year-old female with no significant medical history presented with upper extremity anesthesia, ptosis, and unsteady gait. The patient had a history of hypertension and diabetes mellitus. Physical examination showed bilateral total external ophthalmoplegia, areflexia, and cerebellar ataxia. Radiological and laboratory studies were unremarkable. Lumbar puncture showed albuminocytological dissociation. The combined history, physical examination, and lumbar puncture results established a presumptive diagnosis of MFS. Intravenous immunoglobulin was given for 5 days. The patient gradually improved 10 days after the onset of symptoms. Ophthalmoplegia had fully recovered after 6 months. To the best of our knowledge, this case represented the oldest patient with MFS.
To explore the characteristics of acute exacerbations of myasthenia gravis after fluoroquinolone exposure. Gender, age, prior type, absolute score, concurrent disease, precipitated disease, use of antibiotic, onset/symptom/degree of exacerbation, therapeutic measures and prognosis at Month 1 were retrospectively analyzed for 9 patients after fluoroquinolone systemic exposure. Ciprofloxacin (n = 4), levofloxacin (n = 1) and moxifloxacin (n = 4) exposure resulted in myasthenia gravis exacerbation. Myasthenia gravis exacerbations developed at 15 minutes to 4 days post-exposure. And the clinical scores of quantitative myasthenia gravis (QMG) increased by an average of 10. The main syndromes included dyspnea, diplopia, ptosis and dysphagia. All patients improved upon the withdrawal of fluoroquinolone in conjunctions with other interventions. Fluoroquinolone exposure may result in myasthenia gravis exacerbations in patients with underlying diseases. Healthcare professionals should be aware of this serious drug-disease association.
To explore the associations between vitamin D receptor (VDR) gene Tru9I polymorphism and myasthenia gravis (MG). A total of 302 MG patients, diagnosed and treated at Affiliated Hospital of Medical College, Qingdao University and Beijing Friendship Hospital from December 2006 to July 2010, were recruited. And 283 normal subjects were selected as the controls. Tru9I polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The frequencies of genotypes and alleles were compared among different MG subgroups and control group. The relationship between the genotype and susceptibility or severity of MG and immediate efficacies of glucocorticoid were explored. The SPSS17.0 was applied to statistical analysis. In the MG patients whose age of onset was above 15 years, the frequency of TT and tt genotypes in females was lower than that of the control group. However the frequency of Tt genotype was higher than that of the control group. And there were significant differences (χ(2) = 8.847, P = 0.012). The frequency of Tt + tt genotype in females (58/139, 41.7%) was higher than that of the control group (56/189, 29.6%). And there were also significant differences (OR = 1.70, 95% CI 1.07 - 3.41, χ(2) = 5.169, P = 0.023). Although the frequency of t alleles in females (61/278, 21.9%) was higher than that of the control group (65/378, 17.2%), no significant differences existed (P > 0.05). There were no differences in frequencies of genotypes and alleles between the patients with varying severity and different immediate efficacies of glucocorticoid (P > 0.05). VDR gene Tru9I polymorphism may be related to the risk of MG in females aged above 15 years.
The cause of myasthenia gravis (MG) is unknown, but it is widely believed to be an autoimmune disease occurring in genetically susceptible individuals. The human leukocyte antigen (HLA) region is considered to be the most important genetic region for MG susceptibility genes. To investigate the association between HLA-DRB1 and myasthenia gravis (MG) in a northern Han Chinese population, a polymerase chain reaction with sequence-specific oligonucleotide probe hybridization method was used to determine the HLA-DRB1 genotypes of 91 patients with MG and 171 healthy individuals. We found that the HLA-DRB1(*)09 allele was significantly more prevalent among patients with MG than among healthy controls, especially those who experienced early onset of the disease (≤40 years), those who were seronegative for acetylcholine receptor antibody, and those with ocular MG. The prevalence of the HLA-DRB1(*)08 allele was significantly lower among patients with MG than among controls. These results indicate that HLA-DRB1(*)09 might be positively associated and DRB1(*)08 negatively associated with MG in the northern Han Chinese population.
Genetic analyses indicate that HLA complex genes can be involved in susceptibility to autoimmune myasthenia gravis (MG). Various HLA alleles serve as genetic elements that either predispose to or protect against MG. This study investigates the probable relationship between HLA-DQ allele polymorphisms and MG cases in northern China. The HLA-DQA1 and DQB1 alleles were determined by polymerase chain reaction/sequence-specific primers (PCR-SSP) in 84 MG patients, and the results were compared to 293 healthy controls. Our findings indicate that DQ A1*0401(P=0.008, OR: 2.5, 95%CI: 1.24-3.07) and B1*0301(P=0.000, OR: 2.29, 95%CI: 1.48-3.54) were the most frequent allele; the frequencies of DQA1*0103(P=0.000, OR:0.24, 95%CI 0.13-0.49) and DQB1*0601(P=0.001, OR:0.40, 95%CI 0.22-0.50) were significantly decreased in MG patients compared with healthy controls. Patients with thymomatous MG were positively associated with DQA1 *0401(P=0.011, OR:4.57, 95% CI 1.40-14.90) and DQB1 *0604 (P=0.001, OR:4.01, 95% CI 1.65-9.73) as compared to MG patients without thymoma. Different genetic mechanisms may exist between MG patients with thymoma and those without thymoma. The HLA-DQ associations in MG subgroups suggest that disease heterogeneity may be influenced by different genes or alleles.
To investigate the association of two glucocorticoid receptor (GR) polymorphisms (BclI, ER22/23EK) with Myasthenia Gravis (MG). The genotypes of GR in 61 MG patients (MGG) and 57 age and gender-matched healthy controls (HCG) were determined by polymerase chain reaction and nucleotide sequence determination. The frequencies of three genotypes (GG, CG, CC) in BclIwere 3.3%, 34.4%, 62.3% in MGG and 3.5%, 38.6%, 57.9%in HCG respectively. The difference in the distribution of genotypes between MGG and HCG was statistically insignificant (P = 0.887). The frequencies of G and C allele were 20.5% vs 79.5 %in MGG, and 22.8% vs 77.2% in HCG. The difference in the distribution of alleles between MGG and HCG was statistically insignificant (P = 0.968). The genotype frequencies in two groups were both in Hardy-Weinberg equilibrium (P > 0.05). The genotypes of ER22/23EK in MGG and HCG were all GG and no mutation was detected. BclI and ER22/23EK polymorphisms of GR have no definite relationship with the risk of MG.
To investigate the imaging and clinical feature of leukoencephalopathy with hearing loss first complaint. The head MRI and clinical feature of 7 cases leukoencephalopathy with hearing loss first complaint were retrospectively analysed, including their place, shape, range and blood plasma very-long-chain fatty acid (VLCFA). The head MRI of 2 cases shows symmetry distributed long T, and T2 signal like butterfly aliform in white matter beside both cornu posterior ventriculi lateralis. The head MRI of 5 cases shows abnormal long T1 and T2 signal in different part in Alba. The pathological changes often located in white matter of frontal lobe and secondly beside both cornu posterior ventriculi lateralis. The shape shows little patching in 7 cases. The range only shows beside cornu posterior ventriculi lateralis in 2 cases. The range only shows in frontal lobe in 1 cases. Two or more than two parts shows in the rest 5 cases. The result of VLCFA is normal in 3 cases. The rest 4 cases refused to have examination of VLCFA. The patient who firstly complained of hearing loss should be routinely done head MRI. The head MRI imaging could clearly show abnormal white matter in order to avoid omitting existent pathological changes.
Neuroinflammation and abnormal phosphorylation of TAU proteins have been implicated in the etiology of Alzheimer's disease (AD). Several studies have suggested the G-308A promoter polymorphism in one of the proinflammatory cytokine genes tumor necrosis factor-α (TNF-α) encoding TNF-α may be associated with AD pathogenesis. Association between the Q7R polymorphism in saitohin (STH), a gene nested within the intron of the Tau gene, has also been reported.To determine whether these two polymorphisms contribute to the risk for late-onset AD (LOAD) in Chinese, we have investigated 207 sporadic LOAD patients and 222 healthy controls.The associations of the AA genotype and A-allele with LOAD (χ2 = 8.74, df = 1, P = 0.0031, and χ2 = 4.47, df = 1, P = 0.035) were found. After stratifying by apolipoprotein E allele 4 (APOE ε4) status, increased LOAD risks associated with the AA genotype and A-allele only in the APOE ε4 non-carriers (χ2 = 9.21, df = 1, P = 0.002; χ2 = 10.02, df = 1, P = 0.0015) were seen. These results suggested that the TNF-α gene G-308A polymorphism might be a risk factor for LOAD and dependent on APOE ε4 status in Chinese.Homozygous Q/Q of STH Q7R polymorphism was the only one genotype found in either LOAD group or controls. No R allele was detected in LOAD and control groups. The extremely rare frequency of the ancestral R allele differs sharply from that observed in studies in the Caucasian population, suggesting obvious ethnic differences.
A functional polymorphism of mitochondrial aldehyde dehydrogenase gene (ALDH2 1/2 polymorphism) can influence the accumulation of acetaldehyde which may have a role in Alzheimer's disease (AD), and is widely prevalent among Mongoloids. Therefore ALDH2 1/2 polymorphism may represent a good candidate for genetic risk factors for AD, especially in East Asian. A case-control study from Japan found that ALDH2*2 was associated with late-onset AD (LOAD), interacting synergistically with the presence of the apolipoprotein E allele 4 (APOE epsilon4). But the subsequent studies in Koreans didn't find the similar result. To determine whether the ALDH2 gene 1/2 polymorphism contributes to the risk for LOAD in Chinese, we have investigated 188 sporadic LOAD patients and 223 healthy controls from Chinese. A significantly increased risk of AD in the carriers of ALDH2*2 allele (OR=3.11, 95% CI 2.06-4.69, P<0.001) was observed. After stratifying by APOE epsilon4 status, increased LOAD risks associated with the ALDH2 2 allele carriers only in the APOE epsilon4 non-carriers (chi2=31.79, df=1, P<0.001) and with the 2-allele in either groups (chi2=6.64 df=1, P=0.0099 and chi2=37.38, df=1, P<0.001) were seen. These results suggested that the ALDH2 gene 1/2 polymorphism might be a risk factor for LOAD and dependent on APOE epsilon4 status in Chinese.
Spinocerebellar ataxia type 7 is a rare autosomal dominant cerebellar ataxia (ADCA). Herein, we describe the molecular and clinical findings in patients within six generations of a large Chinese family with spinocerebellar ataxia. To identify the genetic cause(s), 4 affected patients and 26 asymptomatic relatives were recruited for the study. Molecular screening of the SCA1 and SCA7 genes was carried out by subcloning and direct PCR-sequencing methods. Both neurological and ophthalmic examinations were performed to investigate the clinical characteristics of the disease. The patients had typical cerebellar ataxia, achromatopsia and macular degeneration, and displayed a rare phenotype manifesting as a combination of cerebellar ataxia and craniocervical dystonia. Mutational analysis of the SCA7 genes demonstrated expanded CAG-repeats in the four patients. In conclusion, we identified expanded CAG-repeats in the SCA7 gene within members of a large Chinese family with spinocerebellar ataxia. The defined phenotypic characteristics of the patients may be helpful for clinical diagnosis and genetic typing of new patients.
The oxidative stress caused by nitric oxide (NO) in the brain has been proposed as a pathogenic mechanism in Alzheimer’s disease. Endothelial NO synthase (ecNOS) produces the majority of circulating NO. The biological functional and genetic association studies suggested that the Glu298Asp polymorphism of the ecNOS gene (NOS3) may be a genetic risk factor for late-onset Alzheimer’s disease (LOAD). To investigate an association between the NOS31 Glu298Asp polymorphism and sporadic LOAD in Chinese, we examined 338 LOAD patients and 378 healthy controls. The associations of the Glu/Glu genotype and Glu allele with LOAD (χ 2 = 9.12, df = 1, P = 0.003 by genotype; χ 2 = 8.37, df = 1, P = 0.038 by allele) were found. After stratifying by apolipoprotein E allele 4 (APOE ɛ4) status, increased LOAD risks associated with the Glu/Glu genotype and Glu allele only in the APOE ɛ4 noncarriers (χ 2 = 6.28, df = 1, P = 0.012 by genotype; χ 2 = 5.62, df = 1, P = 0.018 by allele) were seen. These results suggest that the NOS3 gene Glu298Asp polymorphism might be a risk factor for LOAD and dependent on APOE ɛ4 status in Chinese.
Alzheimer's disease (AD) is a complex multifactorial disorder involving a number of genetic and environmental factors. Cystatin C (CST3), which belongs to the type II cystatin gene family, is a potent inhibitor of lysosomal proteinases. Immunohistochemical studies have demonstrated the colocalization of the b-amyloid (A-beta) and cystatin C peptides within arteriolar walls in the AD brain. The G73A polymorphism of the CST3 genemay be associated with AD development. To investigate a possible association between the CST3 G73A polymorphism and late-onset AD (LOAD) in Mainland Chinese, we examined 281 LOAD patients and 376 healthy controls. All subjects were genotyped for CST3 and apolipoprotein E (APOE). There were no significant differences in the CST3 genotype or allele frequencies between the cases and the controls. Likewise, with the stratification of the APOE epsilon4 status, no statistical difference was observed between the cases and the controls. Our findings suggest that this polymorphism may not represent an additional genetic risk factor for LOAD in Mainland Chinese.
To evaluate the expression of glucocorticoid receptor (GR) alpha and GRbeta in peripheral blood mononuclear cells (PBMC) from patients of myasthenia gravis (MG). To investigate the relationship between the expression level of GR and glucocorticoid (GC) therapeutic effects to MG patients. The clinical score was recorded and used to assessing the therapeutic effects. Then the expression level of GRalpha and GRbeta in PBMC by immunocytochemistry was measured. We analysed the relationship of the therapeutic effects with expression level of GR. The scores of GRalpha positive PBMC score were same in healthy-control group, GC sensitive group, and GC dependent group. But GRalpha positive PBMC score in GC resistance group was decreased compared with the others (P < 0.01). The scores of GRbeta positive PBMC score were same in healthy-control group, GC sensitive group, and GC resistant group. But GRbeta positive PBMC score in GC dependent group was increased compared with the others (P < 0.01). The expression of GRalpha in GC resistant group are decreased, and the expression of GRbeta in GC dependence group is increased. The expression level of GRalpha or GRbeta is associated with the effect of GC in treatment of MG.
Alterations of the NAD(P)H:quinone oxidoreductase (NQO1) activity are associated with Alzheimer's disease (AD). A polymorphism consisting of a single nucleotide (C-->T) change at position 609 of NQO1 influences the NQO1 activity. Therefore the NQO1 C609T polymorphism may confer susceptibility for AD developing. To test the hypothesis, we have performed an association study between the NQO1 gene polymorphism C609T and late-onset Alzheimer's disease (LOAD) in Chinese population. Totally 104 LOAD patients and 128 controls were enrolled in our data set. All subjects were genotyped for NQO1 and Apolipoprotein E (APOE). There were no significant differences in NQO1 genotype or allele frequencies between cases and controls. Likewise, with the stratification of APOE psilon4 status, no statistical difference was observed between cases and controls. Our findings suggested that this polymorphism might not represent additional genetic risk factor for LOAD. However, the present study cannot exclude NQO1 as a possible candidate for LOAD. Further study in a larger population and biological functional analysis of NQO1 gene is required to verify the role of NQO1 in LOAD.
To investigate the relationship between the HLA-DQB1 allele polymorphisms and the clinical features of 15 familial myasthenia gravis (MG) cases in north China. By polymerase chain reaction-sequence specific primers (PCR-SSP), the HLA-DQB1 gene polymorphisms were determined in 64 MG patients (15 familial and 49 sporadic) and 52 healthy individuals as control group. The clinical characteristics of 15 familial MG patients and 49 sporadic were analyzed. The measurement data was analyzed by t test and enumeration data by chi-square test. The frequency of DQB1*0501 was significantly increased in familial MG, especially in the ocular type, compared with sporadic MG (P<0.05, OR=3.08) and healthy controls (P<0.01, OR=4.439). Comparing with healthy controls, the frequency of DQB1*0301/4 was increased (P<0.05, OR=2.56), while the frequency of DQB1*0601 was significantly decreased (P<0.05, OR=0.33) in sporadic MG. The familial patients had an early age of disease onset, but less severity and good prognosis. The familial MG has distinctive clinical features. DQB1*0501 allele is positively related to the genetic susceptibility to familial MG patients in north China, especially to the ocular type. DQB1*0301/4 allele is positively related to the pathogenesis of sporadic MG. DQB1*0601 may be a protecting allele for sporadic MG. The phenotype of MG may be the result of interaction of hereditary defects and environmental factors. The familial MG may be different from sporadic patients in genetic immune mechanism.
Objective: To analyze the association between HLA-DQA1 gene polymorphism and familial myasthenia gravis and the features of these patients. Methods: The clinical features of 15 familial myasthenia gravis patients and 36 sporadic myasthenia gravis patients were analyzed. All the patients and 47 healthy controls were investigated for HLA-DQA1 genotyping by polymerase chain reaction-sequence specific primers (PCR-SSP). Results: Familial patients had an earlier onset age (18.7vs34.4, P = 0.006), less severity and good prognosis. Compared with sporadic myasthenia gravis patients and healthy controls, the frequency of DQA1 * 0301 allele was higher in familial myasthenia gravis patients (40% vs 19.4% vs 20.2%, P < 0.05). The difference had statistical significance. In the ocular form this difference existed, too. There was no association between sex of the familial patients and DQA1 polymorphism. Conclusions: Familial myasthenia gravis has different clinical features. HLA-DQA1 * 0301 allele should be positively related to the genetic susceptibility of familial myasthenia gravis patients especially to the ocular form, and familial myasthenia gravis is maybe different from sporadic patients in genetic immune mechanism.