Zhiyun Wei

Publications (34) View all

• Article: Heredity and cardiometabolic risk: naturally occurring polymorphisms in the human neuropeptide Y2 receptor promoter disrupt multiple transcriptional response motifs.

  Zhiyun Wei, Kuixing Zhang, Gen Wen, Karthika Balasubramanian, Pei-An B Shih, Fangwen Rao, Ryan S Friese, Jose P Miramontes-Gonzalez, Geert W Schmid-Schoenbein, Hyung-Suk Kim, Sushil K Mahata, Daniel T O'Connor
  [show abstract] [hide abstract]
  ABSTRACT: OBJECTIVES:: The neuropeptide Y2 G-protein-coupled receptor (NPY2R) relays signals from PYY or neuropeptide Y toward satiety and control of body mass. Targeted ablation of the NPY2R locus in mice yields obesity, and studies of NPY2R promoter genetic variation in more than 10 000 human participants indicate its involvement in control of obesity and BMI. Here we searched for genetic variation across the human NPY2R locus and probed its functional effects, especially in the proximal promoter. METHODS AND RESULTS:: Twin pair studies indicated substantial heritability for multiple cardiometabolic traits, including BMI, SBP, DBP, and PYY, an endogenous agonist at NPY2R. Systematic polymorphism discovery by resequencing across NPY2R uncovered 21 genetic variants, 10 of which were common [minor allele frequency (MAF) >5%], creating one to two linkage disequilibrium blocks in multiple biogeographic ancestries. In vivo, NPY2R haplotypes were associated with both BMI (P = 3.75E-04) and PYY (P = 4.01E-06). Computational approaches revealed that proximal promoter variants G-1606A, C-599T, and A-224G disrupt predicted IRF1 (A>G), FOXI1 (T>C), and SNAI1 (A>G) response elements. In neuroendocrine cells transfected with NPY2R promoter/luciferase reporter plasmids, all three variants and their resulting haplotypes influenced transcription (G-1606A, P < 2.97E-06; C-599T, P < 1.17E-06; A-224G, P < 2.04E-06), and transcription was differentially augmented or impaired by coexpression of either the cognate full-length transcription factors or their specific siRNAs at each site. Endogenous expression of transcripts for NPY2R, IRF1, and SNAI1 was documented in neuroendocrine cells, and the NPY2R mRNA was differentially expressed in two neuroendocrine tissues (adrenal gland, brainstem) of a rodent model of hypertension and the metabolic syndrome, the spontaneously hypertensive rat. CONCLUSION:: We conclude that common genetic variation in the proximal NPY2R promoter influences transcription factor binding so as to alter gene expression in neuroendocrine cells, and consequently cardiometabolic traits in humans. These results unveil a novel control point, whereby cis-acting genetic variation contributes to control of complex cardiometabolic traits, and point to new transcriptional strategies for intervention into neuropeptide actions and their cardiometabolic consequences.
  Journal of hypertension 11/2012; · 4.02 Impact Factor
• Article: HLA-B*58:01 allele is associated with augmented risk for both mild and severe cutaneous adverse reactions induced by allopurinol in Han Chinese.

  Zhi-hao Cao, Zhi-yun Wei, Qin-yuan Zhu, Jun-yu Zhang, Lun Yang, Sheng-ying Qin, Li-yan Shao, Yi-ting Zhang, Jie-kun Xuan, Qiao-li Li, Jin-Hua Xu, Feng Xu, Li Ma, Hui-yuan Huang, Qing-he Xing, Xiao-qun Luo
  [show abstract] [hide abstract]
  ABSTRACT: 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.
  Pharmacogenomics 07/2012; 13(10):1193-201. · 3.97 Impact Factor
• Article: Histamine h4 receptor polymorphism: a potential predictor of risperidone efficacy.

  Zhiyun Wei, Lei Wang, Tao Yu, Yang Wang, Liya Sun, Ti Wang, Ran Huo, Yang Li, Xi Wu, Shengying Qin, Yifeng Xu, Guoyin Feng, Lin He, Qinghe Xing
  [show abstract] [hide abstract]
  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 χ, 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.
  Journal of clinical psychopharmacology 04/2013; 33(2):221-5. · 5.09 Impact Factor
• Article: SASH1 regulates melanocyte transepithelial migration through a novel Gαs-SASH1- IQGAP1-E-Cadherin dependent pathway.

  Ding'an Zhou, Zhiyun Wei, Tang Wang, Meiqing Zai, Luo Guo, Lin He, Qinghe Xing
  [show abstract] [hide abstract]
  ABSTRACT: 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 dyschromatosis universalis hereditaria (DUH). In epidermal tissues from a DUH-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 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.
  Cellular signalling 01/2013; · 4.09 Impact Factor
• Article: A novel insertional mutation in the connexin 46 (gap junction alpha 3) gene associated with autosomal dominant congenital cataract in a Chinese family.

  Dingan Zhou, Hongyun Ji, Zhiyun Wei, Luo Guo, Yanpeng Li, Teng Wang, Yu Zhu, Xingran Dong, Yang Wang, Lin He, Qinghe Xing, Lirong Zhang
  [show abstract] [hide abstract]
  ABSTRACT: To identify the genetic defect associated with autosomal dominant congenital cataract (ADCC) in a Chinese family, in which 11 individuals across four generations are affected with coralliform cataract. Exome sequencing was performed in two of the ADCC-affected family members to scan for potential genetic defects. Sanger sequencing was used to verify these defects in the whole family. By combining whole exome sequencing and Sanger sequencing, the genetic defect was revealed to be a insertion of a cytosine after coding nucleotide 1,361 (1361insC) in the gap junction alpha 3 (GJA3) gene, causing a frameshift at codon 397 (p.Ala397Glyfs×71). This frameshift mutation cosegregates with the ADCC-affected pedigree members, but is absent in unaffected relatives and 100 normal individuals. A 1361 insC mutation in the C-terminus of GJA3 is found to be associated with autosomal dominant congenital coralliform cataract. This finding is similar to that of a previous publication, thus providing further evidence that the GJA3 C-terminal domain is also its mutation area, and further expanding the mutation spectrum of GJA3 in association with congenital cataract.
  Molecular vision 01/2013; 19:789-795. · 2.20 Impact Factor