Zhiyun Wei

HLA-B*58:01 allele is associated with augmented risk for both mild and severe cutaneous adverse reactions induced by allopurinol in Han Chinese

AIM Allopurinol is widely used as an effective urate-lowering drug and is one of the most frequent causes of cutaneous adverse drug reactions (cADRs). Recently, a strong association of HLA-B*58:01 with allopurinol-induced severe cADRs was identified. This study investigated the predisposition to different types of allopurinol-cADRs conferred by HLA-B*5801 in a Han population from mainland China. PATIENTS & METHODS HLA-B genotyping was performed on 38 Chinese patients with different types of allopurinol-cADRs from 2008 to 2011. RESULTS All the allopurinol-cADR patients carried HLA-B*58:01, in contrast with only 11.11% (7/63) in the allopurinol-tolerant patients (odds ratio [OR] = 580.07; p < 0.0001) and 13.99% (80/572) in a Han Chinese population from the human MHC database (dbMHC; OR: 471.09; p < 0.0001) carried the genotype. Each type of allopurinol cADRs revealed a statistically significant association with HLA-B*58:01. In particular, the risk of allopurinol-induced maculopapular eruption was significantly higher in patients with HLA-B*58:01 (OR: 339.00; p < 0.0001). CONCLUSION The strong association of both the mild and severe types of allopurinol cADRs with the HLA-B*58:01 allele were observed. The results indicated that the prospective use of a genetic test of HLA-B*58:01 might reduce the prevalence of allopurinol-induced cADRs. Original submitted 7 March 2012; Revision submitted 21 May 2012.

The Effect of microRNAs in the Regulation of Human CYP3A4: a Systematic Study using a Mathematical Model

CYP3A4 metabolizes more than 50% of the drugs on the market. The large inter-individual differences of CYP3A4 expression may contribute to the variability of human drug responses. Post-transcriptional regulation of CYP3A4 is poorly understood, whereas transcriptional regulation has been studied much more thoroughly. In this study, we used multiple software programs to predict miRNAs that might bind to CYP3A4 and identified 112 potentially functional miRNAs. Then a luciferase reporter system was used to assess the effect of the overexpression of each potentially functional miRNA in HEK 293T cells. Fourteen miRNAs that significantly decreased reporter activity were measured in human liver samples (N = 27) as candidate miRNAs. To establish a more effective way to analyze in vivo data for miRNA candidates, the relationship between functional miRNA and target mRNA was modeled mathematically. Taking advantage of this model, we found that hsa-miR-577, hsa-miR-1, hsa-miR-532-3p and hsa-miR-627 could significantly downregulate the translation efficiency of CYP3A4 mRNA in liver. This study used in silico, in vitro and in vivo methods to progressively screen functional miRNAs for CYP3A4 and to enhance our understanding of molecular events underlying the large inter-individual differences of CYP3A4 expression in human populations.

Quantitative assessment of the effect of LRRK2 exonic variants on the risk of Parkinson’s disease: A meta-analysis

Leucine-rich repeat kinase 2 (LRRK2, PARK8) gene has attracted considerable attention since the variants in this gene are recognized as the most common cause of Parkinsons disease (PD) so far. A number of association studies concerning variants of LRRK2 gene and PD susceptibility have been conducted in various populations. However, some results were inconclusive. To derive a more precise estimation of the relationship between LRRK2 and genetic risk of PD, we performed a comprehensive meta-analysis which included 27,363 cases and 29,741 controls from 61 published case-control studies. Totally, the effect of five LRRK2 variants all within the coding regions, i.e. G2019S, G2385R, R1628P, P755L and A419V, were evaluated in the meta-analysis using fixed effect model or random effects model if heterogeneity existed. There were genetic associations between four variants (G2019S, G2385R, R1628P and A419V) and increased PD risk, while there was no evidence of statistically significant association between P755L and PD. Publication bias and heterogeneity were absent in most analyses. Within its limitations, this meta-analysis demonstrated that the G2019S, G2385R, R1628P and A419V variations are risk factors associated with increased PD susceptibility. However, these associations vary in different ethnicities.

Association analysis of serotonin receptor 7 gene (HTR7) and risperidone response in Chinese schizophrenia patients

Several lines of evidence suggest that the human 5-HT(7) receptor may be involved in the pharmacodynamics of risperidone and may influence clinical response of the drug. A pharmocogenetics study of this receptor may therefore be useful in developing individualized therapy. But few studies about it have been done. In this study, we genotyped ten single nucleotide polymorphisms (SNPs) distributed throughout the HTR7 gene and analyzed six of them for association with the reduction of Brief Psychiatric Rating Scale (BPRS) scores in drug-naive Chinese schizophrenia patients, following an eight-week period of risperidone monotherapy. The confounding effects of nongenetic factors were estimated and the baseline symptom score as well as the duration of illness were included as covariates for adjustment. No significant correlation of HTR7 with antipsychotic efficacy was detected in either genotype or haplotype analysis. These results demonstrate that variations in the HTR7 gene may not be good genetic markers for predicting the therapeutic efficacy of risperidone.

FoxP2 is significantly associated with schizophrenia and major depression in the Chinese Han Population

Abstract Objectives. The FoxP2 gene, located on 7q31, encodes a transcription factor. It was first discovered through investigations of a large multigenerational family (the KE family) with a rare severe speech and language disorder (Fisher et al., Nat. Genet. 1998;18:168; Lai et al., Nature 2001;413:519). Subsequent studies gave powerful and convincing functional evidence to the connection between FoxP2 and language disorder (; Groszer et al., Curr Biol 2008;18:354; Vernes et al., New Engl J Med 359(22):2337). Language disorder is commonly considered as a core symptom of schizophrenia and some other mental diseases; thus, we decided to investigate whether the FoxP2 gene played a significant role in schizophrenia, major depression or bipolar disorder in a sample set recruited from the Chinese Han population. Methods. In this study, we focused on 12 SNPs in the FoxP2 gene and carried out case–control studies in 1135 schizophrenia patients, 1135 unrelated major depression patients, 1135 unrelated bipolar disorder patients and 1135 unrelated normal controls recruited from the Chinese Han population. Results. We found rs10447760 was significantly associated with schizophrenia (allelic P = 0.00069) and major depression (allelic P = 0.0011). Conclusions. Our study indicated that the rare variant rs10447760 in FoxP2 may play an important role in schizophrenia and major depression in the Chinese Han population.

Metabolomic Analysis Reveals Metabolic Disturbance in the Cortex and Hippocampus of Subchronic MK-801 Treated Rats

Background Although a number of proteins and genes relevant to schizophrenia have been identified in recent years, few are known about the exact metabolic pathway involved in this disease. Our previous proteomic study has revealed the energy metabolism abnormality in subchronic MK-801 treated rat, a well-established animal model for schizophrenia. This prompted us to further investigate metabolite levels in the same rat model to better delineate the metabolism dysfunctions and provide insights into the pathology of schizophrenia. Methods Metabolomics, a high-throughput investigatory strategy developed in recent years, can offer comprehensive metabolite-level insights that complement protein and genetic findings. In this study, we employed a nondestructive metabolomic approach (1H-MAS-NMR) to investigate the metabolic traits in cortex and hippocampus of MK-801 treated rats. Multivariate statistics and ingenuity pathways analyses (IPA) were applied in data processing. The result was further integrated with our previous proteomic findings by IPA analysis to obtain a systematic view on our observations. Results Clear distinctions between the MK-801 treated group and the control group in both cortex and hippocampus were found by OPLS-DA models (with R2X = 0.441, Q2Y = 0.413 and R2X = 0.698, Q2Y = 0.677, respectively). The change of a series of metabolites accounted for the separation, such as glutamate, glutamine, citrate and succinate. Most of these metabolites fell in a pathway characterized by down-regulated glutamate synthesis and disturbed Krebs cycle. IPA analysis further confirmed the involvement of energy metabolism abnormality induced by MK-801 treatment. Conclusions Our metabolomics findings reveal systematic changes in pathways of glutamate metabolism and Krebs cycle in the MK-801 treated rats’ cortex and hippocampus, which confirmed and improved our previous proteomic observation and served as a valuable reference to the etiology research of schizophrenia.

SASH1 regulates melanocyte transepithelial migration through a novel Gαs–SASH1–IQGAP1–E-Cadherin dependent pathway

One important function of melanocytes (MCs) is to produce and transfer melanin to neighbouring keratinocytes (KCs) to protect epithelial cells from UV radiation. The mechanisms regulating the specific migration and localisation of the MC lineage remain unknown. We have found three heterozygous mutations that cause amino acid substitutions in the SASH1 gene in individuals with a kind of dyschromatosis. In epidermal tissues from an affected individual, we observed the increased transepithelial migration of melanocytes. Functional analyses indicate that these SASH1 mutations not only cause the increased migration of A375 cells and but also induce intensive bindings with two novel cell adhesion partners IQGAP1 and Gαs. Further, SASH1 mutations induce uniform loss of E-Cadherin in human A375 cells. Our findings suggest a new scaffold protein SASH1 to regulate IQGAP1-E-Cadherin signalling and demonstrate a novel crosstalking between GPCR signalling, calmodulin signalling for the modulation of MCs invasion.

Histamine H4 receptor polymorphism: a potential predictor of risperidone efficacy.

Abstract Histamine interacts with histamine H4 receptor (HRH4) to impact antipsychotic response. Pharmacogenetic information about this receptor could therefore be useful in developing individualized therapy. The aim of this investigation was to clarify whether polymorphisms at human HRH4 gene alter risperidone efficacy. We genotyped 5 tag-single nucleotide polymorphisms of the HRH4 gene and analyzed their association with the reduction in Positive and Negative Syndrome Scale (PANSS) scores in a group of 113 Chinese Han patients with schizophrenia who were following an 8-week period of risperidone monotherapy. Using &khgr;2, analysis of variance, haplotype, and receiver operating characteristics analysis, we found that HRH4 common variant rs4483927 is significantly associated with risperidone efficacy and that its TT genotype predicts poor therapeutic response both on the positive, negative, and general subscales and on the total scale of PANSS scores (P = 0.017, 0.019, 0.021, and 0.002, respectively, in analysis of variance). Our results provide the first evidence that an HRH4 polymorphism may be a molecular marker for the prediction of risperidone efficacy and suggest novel pharmacologic links between HRH4 gene and treatment of schizophrenia.

No Correlation of hsa-miR-148a with Expression of PXR or CYP3A4 in Human Livers from Chinese Han Population

There is a huge variability of hepatic CYP3A4 level in human populations, which was believed to contribute to different responses to drugs among individuals. Transcription of CYP3A4 was regulated by transcription factors such as pregnane X receptor (PXR). MiRNA hsa-miR-148a was previously reported to influence PXR expression in HepG2 cells and in Japanese populations. In this study, we conducted a similar correlation study in Chinese Han population (N = 24). No significant correlation of hsa-miR-148a was found with PXR expression or CYP3A4 expression. Our results suggest that hsa-miR-148a does not play a major role in the regulation of PXR or CYP3A4 expression in human livers from Chinese Han population.

A pharmacogenetic study of risperidone on histamine H3 receptor gene (HRH3) in Chinese Han schizophrenia patients

Evidence suggests that the human histamine H3 receptor (HRH3) may be involved in the pharmacodynamics of risperidone and influence clinical efficacy. More information on the pharmacogenetics of this receptor may therefore be useful in developing individualized therapy. However, to our knowledge, no study has been reported in this area. The aim of this investigation was to clarify whether H3 receptor polymorphism could affect risperidone efficacy. We genotyped tag single nucleotide polymorphisms (SNPs) of the HRH3 gene (rs3787429 and rs3787430) and analyzed their association with the reduction of Brief Psychiatric Rating Scale (BPRS) score in Chinese Han schizophrenia patients (N = 129), following an eight-week period of risperidone monotherapy. The confounding effects of non-genetic factors were estimated, and then the significant one was included as the covariate for adjustment in statistical analysis. Baseline symptom score was the only significant confounding effect and thus the covariate. After adjustment, significant association of HRH3 with antipsychotic efficacy was detected (for rs3787429, p = 0.013, 0.087 after 4 weeks and 8 weeks of treatment, respectively; for rs3787430, p = 0.024, 0.010 after 4 weeks and 8 weeks of treatment, respectively) and stood up to conservative Bonferroni correction. Our results demonstrate that polymorphism of the HRH3 gene may be a potential genetic marker for predicting the therapeutic effect of risperidone, and suggest novel pharmacological links between HRH3 and risperidone. Further studies with larger samples and different ethnic populations are warranted to confirm our results.