LncRNA LUCAT1 as a Plasma Biomarker for Assessing Disease Activity in Adult Patients with Crohn's Disease.

AIM: To explore the expression of long noncoding RNA (LncRNA) LUCAT1 in adult patients with Crohn's disease (CD) and evaluate the relationship between LncRNA LUCAT1 and the disease activity in Chinese patients with CD. METHODS: Patients with CD and healthy participants (≥18 years old) were enrolled in this study between January 2018 and December 2019. The expression of LncRNA LUCAT1 in plasma samples was evaluated by quantitative reverse transcription-polymerase chain reaction. Basic characteristics of patients with CD were collected, including gender, age, clinical stage, disease behavior, disease location, C-reactive protein (CRP), platelet (PLT), erythrocyte sedimentation rate (ESR), fecal calprotectin (FC), Crohn's disease activity index (CDAI) score, and simplified Crohn's disease endoscopic score (SES-CD). RESULTS: In total, 168 patients with CD and 65 healthy participants (≥18 years old) were enrolled in this study. Among them, ninety patients with clinically active CD, seventy-eight patients with CD in clinical remission, forty-eight patients with endoscopically active CD, thirty patients with endoscopically inactive CD, and sixty-five healthy participants. LncRNA LUCAT1 was increased in plasma of patients with CD compared with the control group. The plasma LncRNA LUCAT1 level of patients with CD both in the clinical and endoscopic active phase was higher than that of both the clinical and endoscopic remission phase. The plasma level of LncRNA LUCAT1 in patients with CD was positively correlated with ESR, CRP, FC, CDAI, and SES-CD. There was no significant correlation between the level of LUCAT1 and platelets. The plasma LncRNA LUCAT1 level in patients with CD had significant differences between severe active patients and mild/moderate active patients. CONCLUSION: The plasma LncRNA LUCAT1 is positively associated with the disease activity in patients with CD, and it may act as a noninvasive biomarker to identify the degree of disease activity.

Association Study of Polymorphisms in Neuronal Nicotinic Acetylcholine Receptor Subunit Genes With Schizophrenia in the Han Chinese Population.

OBJECTIVE: To investigate the relation between nicotinic acetylcholine receptor subunit (nAChR) genes and schizophrenia, and the relation between tag single nucleotide polymorphism (rs1317286, rs1044396, rs6494212, rs16969968, and rs684513) and schizophrenia in Han Chinese people. METHODS: The protein-protein interaction (PPI) network among nAChR protein and 350 proteins encoded by schizophrenia-related susceptibility genes was constructed through the String database to explore whether nAChR genes were associated with schizophrenia in these known databases. Then, five single nucleotide polymorphisms (SNPs) of CHRNA3 (rs1317286), CHRNA4 (rs1044396), CHRNA7 (rs6494212), and CHRNA5 (rs16969968, rs684513) were analyzed in a sample of 1,035 schizophrenic patients and 816 healthy controls. The interaction between the markers was analyzed using multifactor dimensionality reduction (MDR) software. Power analysis was performed using the Quanto program. RESULTS: There are no significant differences in genotype or allele distribution were identified between the patients and controls (p>0.05). The haplotypes constructed by four markers rs1317286, rs6494212, rs16969968, and rs684513 were not associated with schizophrenia either. However, a significant association between models made of rs1317286, rs1044396, rs6494212, and rs684513 and schizophrenia was revealed in interaction analysis (p<0.05). CONCLUSION: The nAChR protein may have effects on the development of schizophrenia through the interaction with proteins encoded by schizophrenia-related susceptibility genes, but no relation was found between selected polymorphisms and schizophrenia in the collected Han Chinese people. However, interaction analysis suggested four-SNP model has an important effect on schizophrenia.

Association of Corticotropin-Releasing Hormone Receptor-1 Gene Polymorphisms and Personality Traits with Violent Aggression in Male Adolescents.

There is evidence that corticotropin-releasing hormone receptor 1 (CRHR1) gene polymorphisms and indifferent impulsive personality traits play an important role in violent aggression in male adolescents. Genotyping for two tag single-nucleotide polymorphisms (SNP) (rs242924, rs17689966) was conducted using TaqMan SNP for 138 violent young male criminals, 98 nonviolent young male criminals, and 153 noncriminal adults. The general situation and personality traits (SSP) questionnaire was given to the young violent and nonviolent male criminal groups. The results showed that the frequency of the G allele in rs242924 of the CRHR1 gene in the violent aggression group was higher than that in the normal adult controls (P < 0.025, OR = 2.29, 95% CI = 1.13-4.62). The difference in genotype distribution was significant among the three groups (P < 0.05), and when the violent group was compared with the two control groups, no significant difference was found (P > 0.025). The impulsiveness, trait irritability, verbal trait aggression, and physical trait aggression scores in the violent group were significantly higher than those in the nonviolent group of adolescents. These findings suggest that the variance in CRHR1 gene polymorphisms and personality traits may play a role in violent aggression in male adolescents, and that the interaction of the CRHR1 gene and the impulsive personality trait may cause an increased susceptibility to violence towards others.

Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation.

BACKGROUND: Methyl-CpG-binding protein-2 (MeCP2) is a critical regulator for neural development. Either loss- or gain-of-function leads to severe neurodevelopmental disorders, such as Rett syndrome (RTT) and autism spectrum disorder (ASD). We set out to screen for MECP2 mutations in patients of ASD and determine whether these autism-related mutations may compromise the proper function of MeCP2. METHODS: Whole-exome sequencing was performed to screen MECP2 and other ASD candidate genes for 120 patients diagnosed with ASD. The parents of patients who were identified with MECP2 mutation were selected for further Sanger sequencing. Each patient accomplished the case report form including general information and clinical scales applied to assess their clinical features. Mouse cortical neurons and HEK-293 cells were cultured and transfected with MeCP2 wild-type (WT) or mutant to examine the function of autism-associated MeCP2 mutants. HEK-293 cells were used to examine the expression of MeCP2 mutant constructs with Western blot. Mouse cortical neurons were used to analyze neurites and axon outgrowth by immunofluorescence experiments. RESULTS: We identified three missense mutations of MECP2 from three autism patients by whole-exome sequencing: p.P152L (c.455C>T), p.P376S (c.1162C>T), and p.R294X (c.880C>T). Among these mutations, p.P152L and p.R294X were de novo mutations, whereas p.P376S was inherited maternally. The diagnosis of RTT was excluded in all three autism patients. Abnormalities of dendritic and axonal growth were found after autism-related MeCP2 mutants were expressed in mouse cortical neurons; suggesting that autism-related MECP2 mutations impair the proper development of neurons. CONCLUSIONS: Our study identified genetic mutations of the MECP2 gene in autism patients, which were previously considered to be associated primarily with RTT. This finding suggests that loss-of-function mutations of MECP2 may also lead to autism spectrum disorders.

[Association between MAOA-u VNTR polymorphism and its interaction with stressful life events and major depressive disorder in adolescents].

OBJECTIVE: To investigate whether the genetic polymorphism, upstream variable number of tandem repeats (uVNTR), in the monoamine oxidase A (MAOA) gene, is associated with major depressive disorder (MDD) in adolescents and to test whether there is gene-environment interaction between MAOA-uVNTR polymorphism and stressful life events (SLEs). METHODS: A total of 394 Chinese Han subjects, including 187 adolescent patients with MDD and 207 normal students as a control group, were included in the study. Genotyping was performed by SNaP-shot assay. SLEs in the previous 12 months were evaluated. The groups were compared in terms of the frequency distributions of MAOA-uVNTR genotypes and alleles using statistical software. The binary logistic regression model of gene-environment interaction was established to analyze the association of the gene-environment interaction between MAOA-u VNTR genotypes and SLEs with adolescent MDD. RESULTS: The distribution profiles of MAOA-u VNTR genotypes and alleles were not related to the onset of MDD, severity of depression, comorbid anxiety and suicidal ideation/behavior/attempt in adolescents. The gene-environment interaction between MAOA-u VNTR genotypes and SLEs was not associated with MDD in male or female adolescents. CONCLUSIONS: It is not proven that MAOA-u VNTR polymorphism is associated with adolescent MDD. There is also no gene-environment interaction between MAOA-u VNTR polymorphism and SLEs that is associated with adolescent MDD.

[Progress of research on 5-hydroxymethylcytosine].

5-methylcytosine (5mC) in cytosine-guanine dinucleotide (CpG) is a usual epigenetic modification in mammals. It plays crucial roles in gene regulation, development, genomic imprinting and so on. In the last three years, it was discovered that in addition to 5mC, another modified cytosine base-5-hydroxymethylcytosine (5hmC) was abundant in many mammalian tissues, which may have different biological function from 5mC. This paper reviews the recent progresses in the studies of 5hmC.

The peripheral messenger RNA expression of glycogen synthase kinase-3ß genes in Alzheimer's disease patients: a preliminary study.

OBJECTIVE: To explore the peripheral leucocytic messenger RNA (mRNA) expression of glycogen synthase kinase-3ß (GSK-3ß) gene in Alzheimer's disease (AD) patients. METHODS: Using TaqMan relative quantitative real-time polymerase chain reaction, we analyzed leucocytic gene expression of GSK-3ß in 48 AD patients and 49 healthy controls. Clinical data of AD patients were also collected. RESULTS: The mRNA expression level of the GSK-3ß gene was significantly higher in the AD group (3.13±0.62) than in the normal group (2.77±0.77). Correlational analyses showed that the mRNA expression level of GSK-3ß gene in AD patients was associated with the age of onset (P=0.047), age (P=0.055), and Behavioral Pathology in Alzheimer's Disease Rating Scale total score (P=0.062) and subscores: aggressiveness score (P=0.073) and anxieties and phobias score (P=0.067). Through multivariate regression model, older age, higher anxieties and phobias score and aggressiveness score were associated with higher mRNA expression level of GSK-3ß gene. CONCLUSION: In AD patients, the mRNA expression level of the GSK-3ß gene is increased and may be related to age and behavioural pathology in AD.

[Association analysis between dopamine D1 receptor gene and symptom quantitative trait of schizophrenia].

OBJECTIVE: To explore the relationship between dopamine D1 receptor gene (DRD1) and symptom quantitative trait of schizophrenia. METHODS: Peripheral blood samples were collected from 211 schizophrenics and 247 healthy controls at our center. Five tag SNPs (single nucleotide polymorphisms) (rs4532, rs5326, rs2168631, rs6882300 & rs267418) within DRD1 gene were genotyped by TaqMan SNP genotyping assay. The positive and negative syndrome scale (PANSS) was used to quantify the phenotypes of schizophrenia. RESULTS: No significant differences existed in the frequencies of genotypes and alleles of DRD1 gene between the schizophrenics and normal controls (Ps > 0.05); strong linkage disequilibrium was observed between rs4532 and rs5326 (D' = 0.84); no significant difference of haplotypic distribution was identified between the patients and controls (Ps > 0.05); the patients with rs4532G allele had a higher negative subscale score than those without G allele (20.3 ± 3.3 vs 18.2 ± 3.9, P < 0.01). CONCLUSION: The rs4532 within DRD1 gene may be associated with negative symptom quantitative trait in schizophrenia.

[Association of DNA methyltransferase 3B gene polymorphism with early-onset schizophrenia].

OBJECTIVE: To investigate the association of DNA methyltransferase 3B (DNMT3B) gene polymorphism with the development of early-onset schizophrenia. METHODS: A single nucleotide polymorphism (rs6119954) of DNMT3B gene was genotyped in 279 early-onset schizophrenic patients and 395 healthy controls, using TaqMan SNP Genotyping Assays. To detect the interaction between the DNMT3B gene and environmental factors, the prenatal information of the patients was collected. RESULTS: Genotype distribution of the rs6119954 locus was significantly different between patients and controls (Chi-square = 12.27, P< 0.01). The frequency of the G allele of this locus was significantly higher in patients than in controls (Chi-square = 12.76, P< 0.01). The G allele was highly associated with an earlier age of onset (P= 0.026). No interaction between the DNMT3B gene and environmental factors was found. CONCLUSION: DNMT3B gene is associated with early-onset schizophrenia and rs6119954 may plays an important role in age of onset of schizophrenia.

[Association of cyclic adenosine monophosphate response element-binding protein gene and major depressive disorder].

OBJECTIVE: To investigate the association between single nucleotide polymorphisms (SNPs) in cyclic adenosine monophosphate response element-binding protein(CREB1) gene and major depressive disorder (MDD). METHODS: We recruited 105 parent-offspring trios of Chinese descent, extracted whole blood genomic DNA, and genotyped the SNPs in rs10932201 and rs6740584 loci. Single-marker transmission disequilibrium test (TDT), pairwise SNP linkage disequilibrium(LD) and haplotype-based TDT were performed. RESULTS: No significant association with MDD was observed for SNPs rs10932201 and rs6740584 (P=0.1004 and P=0.4986). However, there was strong positive association between the rs10932201-rs6740584 haplotype and MDD (P=0.00003241), and both haplotypes of A-C and A-T were significantly associated with MDD (P=0.020 and P=0.00022). CONCLUSION: The rs10932201-rs6740584 haplotype of the CREB1 gene may play an important role in the pathogenesis of MDD.

[Gene-gene interaction between DNMT3B and DRD1 in schizophrenia].

OBJECTIVE: to identify the impact of gene-gene interaction between DNMT3B and DRD1 on the risk of schizophrenia. METHODS: two SNPs (rs2424908 and rs6119954) within DNMT3B and five SNPs (rs4532, rs5326, rs2168631, rs6882300 and rs267418) within DRD1 were genotyped in 365 schizophrenic patients and 365 healthy controls. The gene-gene interaction between DNMT3B and DRD1 was analyzed by Multifactor Dimensionality Reduction (MDR) software. RESULTS: the frequency of genotypes of rs6119954 within DNMT3B was significantly higher in patients than that in controls (χ(2) = 8.06, P = 0.018). MDR revealed that the significance were shown in patterns with 2 SNPs (rs6119954-rs267418) (OR = 1.79, 95%CI: 1.29 - 2.47; χ(2) = 12.51, P = 0.0004), 3 SNPs (rs6119954-rs5326-rs267418) (OR = 2.36, 95%CI: 1.73 - 3.22; χ(2) = 29.33, P < 0.0001) and 4 SNPs (rs2424908-rs6119954-rs5326-rs267418) (OR = 3.08, 95%CI: 2.24 - 4.24;χ(2) = 48.88, P < 0.0001). CONCLUSION: the gene-gene interaction between DNMT3B and DRD1 may exist and increase the risk for schizophrenia.

[An association study of brain-derived neurotrophic factor gene polymorphism in bipolar disorders].

OBJECTIVE: To investigate the association between brain-derived neurotrophic factor (BDNF) gene polymorphism and bipolar disorder. METHODS: Single nucleotide polymorphisms rs6265 and rs11030101 in BDNF gene were detected and compared between 228 patients with bipolar disorder and 361 healthy controls. RESULTS: The genotypes, alleles and combinative genotype of BDNF gene single nucleotide polymorphism rs6265 and rs11030101 did not show significant differences between two groups. There were also no significant differences in genotypes and combinative genotypes between diagnostic subtypes, genders and on-set age of bipolar disorder and controls. CONCLUSION: This study did not found that BDNF gene single nucleotide polymorphism rs6265 and rs11030101 are associated with bipolar disorders.

[Expression levels of APP and PS1 genes in patients with Alzheimer's disease].

The gene expression levels of amyloid precursor protein (APP) and presenilin 1 (PS1) in the peripheral blood samples of patients with Alzheimer's disease(AD) and their association with the disease were studied. The absolute expression levels of APP and PS1 genes were quantified in 45 AD patients, 25 patients with vascular dementia (VD) and 60 healthy controls by real-time quantitative PCR using SYBR Green I. The APP expression levels in healthy controls, AD cases and VD cases are 0.026+/-0.005, 0.044+/-0.006 and 0.072+/-0.013 amol/microg cDNA, respectively; and the PS1 expression levels are 0.026+/-0.004, 0.051+/-0.011 and 0.039+/-0.005 amol/microg cDNA, respectively. Both APP and PS1 expression levels were significantly elevated in AD or in VD cases (APP, AD vs Control, t=2.639, P<0.01, VD vs Control, t=3.028P<0.01; PS1, AD vs Control, t=2.173P<0.05, VD vs Control, t=2.012P<0.05). It seems that elevated APP and PS1 gene expression is associated with dementia but not especially with AD.

Mutation screening and association study of the beta-adrenergic receptor kinase 2 gene in schizophrenia families.

Chromosome 22q12 is one of the most promising regions for harboring a risk gene for schizophrenia. We have reported significant linkage of intermediate phenotypes for schizophrenia with markers within or near the beta-adrenergic receptor kinase 2 (ADRBK2, or GRK3) gene, which is highly expressed in dopaminergic pathways in the central nervous system, and mediates homologous desensitization for a variety of neurotransmitters and hormones through phosphorylation of G protein-coupled receptors (GPCRs). A polymorphism in the promoter region of the ADRBK2 was reported to be associated with bipolar disorder. We screened the putative promoter region, and all 21 exonic and flanking intronic regions of the ADRBK2 gene for mutations in 48 schizophrenia probands (including 16 Japanese and 32 Chinese patients), and evaluated the detected polymorphisms and those reported in the JSNP database for associations with schizophrenia in 113 family trios of schizophrenia probands. Four single nucleotide variants in the 5'-UTR/promoter region, and 16 rare variants in exonic and flanking regions, were identified. Among them, the Cys208Ser variant was the only non-synonymous mutation. Cys208Ser was found in one family without cosegregation between the variant and schizophrenia. Moreover, allelic, genotypic and haplotypic analyses provided no evidence for association between alleles at these polymorphisms and schizophrenia. The present study indicates that the ADRBK2 gene is unlikely to contribute strongly to schizophrenia susceptibility in this set of families.

Significant linkage to chromosome 22q for exploratory eye movement dysfunction in schizophrenia.

A genome-wide scan for a locus responsible for exploratory eye movement (EEM), which is quantitative and can be disturbed in association with schizophrenia, was performed. A 10-cM resolution genome-wide linkage analysis of the EEM disturbance with 358 highly polymorphic microsatellite markers in 38 nuclear families with 122 members (38 probands, 47 sibs, and 37 parents) including 58 sib-pairs yielded the suggestive linkage to the GCT10C10 marker on chromosome 22q11.2 (LOD = 2.48). Dense mapping with additional markers around the GCT10C10 marker yielded evidence for significant linkage between EEM disturbance and markers D22S429 and D22S310 on chromosome 22q12.1 (LOD score of 4.63) with suggestive evidence for the chromosome region 22q11.2-q12.1. Our findings suggest that a relatively small number of loci may control the schizophrenia-related quantitative EEM trait. We believe that identifying gene(s) on chromosome 22q associated with the EEM phenotype may forward our understanding of the etiology of schizophrenia.

Family-based association study of the NOTCH4 gene in schizophrenia using Japanese and Chinese samples.

BACKGROUND: A family based association study in a British sample found the NOTCH4 gene to be associated with schizophrenia; however, all six replication studies failed to confirm the finding. METHODS: We performed a family based association study of NOTCH4 and schizophrenia in 123 trios (16 Japanese and 107 Chinese). In addition to the original study's polymorphisms, we examined four new single nucleotide polymorphisms (SNPs)--SNPs_A, B, C and D--around SNP1 of the original study. We genotyped all samples for SNPs_A-D and for SNP1 and (CTG)n of the original study. RESULTS: We found no significant associations between NOTCH4 and schizophrenia or its subtypes for all polymorphisms, regardless of gender. The finding remained negative when the Chinese sample was analyzed separately. Exploratory analyses suggested that SNP_A may be associated with early-onset schizophrenia and that SNP1 may be associated with schizophrenia characterized by numerous negative symptoms. CONCLUSIONS: NOTCH4 is not a significant susceptibility gene for schizophrenia when clinical heterogeneity is ignored; however, NOTCH4 may be associated with early-onset schizophrenia or schizophrenia with many negative symptoms, but these findings should be interpreted cautiously.

Family-based association study of markers on chromosome 22 in schizophrenia using African-American, European-American, and Chinese families.

Several studies suggest that loci at chromosome 22q11.2-q13 might be linked to susceptibility to schizophrenia. Here we performed family-based association studies on chromosome 22q using 12 DNA microsatellite markers in African-American, European-American, and Chinese pedigrees. The marker D22S683 showed significant linkage and association with schizophrenia in not only the European-American sample but also in a combined sample (European-American and Chinese samples). Notably, D22S683 is located nearby and between D22S278 and D22S283, which have shown linkage and association to schizophrenia in prior reports. However, we found no significant association for the African-American sample. In conclusion, our data provide further support for the idea that the region around D22S683 contains a susceptibility gene for schizophrenia.