Connie Zhao

PDE11A associations with asthma: Results of a genome-wide association scan

Andrew T. DeWan, PhDa, Elizabeth W. Triche, PhDc, Xuming Xu, PhDa, Ling-I Hsu, MPHa, Connie Zhao, PhDd, Kathleen Belanger, PhDb, Karen Hellenbrand, MPHb, Saffron A. G. Willis-Owen, PhDe, Miriam Moffatt, PhDe, William O. C. Cookson, MD, PhDe, Blanca E. Himes, PhDf, Scott T. Weiss, MDf, W. James Gauderman, PhDg, James W. Baurley, MSg, Frank Gilliland, MD, PhDg, Jemma B. Wilk, DSch, George T. O’Connor, MDh, David P. Strachan, PhDi, Josephine Hoh, PhDa, and Michael B. Bracken, PhDb

Nerve growth factor β polypeptide ( NGFB ) genetic variability: association with the methadone dose required for effective maintenance treatment

Opioid addiction is a chronic disease with high genetic contribution and a large inter-individual variability in therapeutic response. The goal of this study was to identify pharmacodynamic factors that modulate methadone dose requirement. The neurotrophin family is involved in neural plasticity, learning, memory and behavior and deregulated neural plasticity may underlie the pathophysiology of drug addiction. Brain-derived neurotrophic factor (BDNF) was shown to affect the response to methadone maintenance treatment. This study explores the effects of polymorphisms in the nerve growth factor (β polypeptide) gene, NGFB, on the methadone doses required for successful maintenance treatment for heroin addiction. Genotypes of 14 NGFB polymorphisms were analyzed for association with the stabilizing methadone dose in 72 former severe heroin addicts with no major co-medications. There was significant difference in methadone doses required by subjects with different genotypes of the NGFB intronic single-nucleotide polymorphism rs2239622 (P=0.0002). These results may have clinical importance.

Gene expression profiling in fetal rat lung during gestational perfluorooctane sulfonate exposure

Perfluorooctane sulfonate (PFOS) is a persistent environmental contaminant found in the tissues of humans and wildlife. It has been reported that gestational exposure to PFOS causes neonatal death of rats. However, the mechanism is still unclear. In this study, we investigated the effects of gestational PFOS exposure on the gene expression profiling of fetal rat lung at pseudoglandular stage. Adult Sprague Dawley dams were dosed orally from gestational day 12-18 with 0 (control), 5 mg/kg/day or 20 mg/kg/day PFOS. Animals were euthanized on day 18.5, fetal lung samples were collected for histochemical staining and RNA profiling analysis. PFOS did not cause apparent microscopic changes of fetal lungs. Gene expression profiling revealed that PFOS dose-dependently up-regulated the expression of 21 (5 mg/kg) and 43 (20 mg/kg) genes. These genes include five PPARα target genes (Acot1, Hmgcs2, Fabp4, Fabp1 and Myh7), and 4 of them are involved in lipid metabolism. The other genes were primarily included in the categories of cytoskeletal structure (Tpm1, Tnnt2, Actn3, Myoz2, Tmod1, and Mfap5), extracellular matrix (Ckm, Lum, Tnnc1, Art3, Dcn, Col17a1, Aspn, Ctsk, Itm2a, Spock2 and Orm1), transporting (Cox8h, Cox6a2 and Scnn1a) and secreted proteins (Scgb3a1, Nppb and Spp1). Our study demonstrates that in utero PFOS exposure resulted in the alteration of a set of genes which are involved in significant cytoskeletal, extracellular matrix remodeling, lipid metabolism and secreted proteins in the fetal rat lung.

Chronic Oxycodone Self-administration Altered Reward-related Genes in the Ventral and Dorsal Striatum of C57BL/6J Mice: An RNA-seq Analysis

Prescription opioid abuse, for example of oxycodone, is a pressing public health issue. This study focuses on how chronic oxycodone self-administration (SA) affects the reward pathways in the mouse brain. In this study, we tested the hypothesis that the expression of reward-related genes in the ventral and dorsal striatum, areas involved in different aspects of opioid addiction models, was altered within 1 h after chronic oxycodone SA, using transcriptome-wide sequencing (RNA-seq). Based on results from earlier human genetic and rodent preclinical studies, we focused on a set of genes that may be associated with the development of addictive diseases and the rewarding effect of drugs of abuse, primarily in the opioid, stress response and classical neurotransmitter systems. We found that 32 transcripts in the ventral striatum, and 7 in the dorsal striatum, were altered significantly in adult mice that had self-administered oxycodone (n = 5) for 14 consecutive days (4 h/day) compared with yoked saline controls (n = 5). The following 5 genes in the ventral striatum showed experiment-wise significant changes: proopiomelanocortin (Pomc) and serotonin 5-HT-2A receptor (Htr2a) were upregulated; serotonin receptor 7 (Htr7), galanin receptor1 (Galr1) and glycine receptor 1 (Glra1) were downregulated. Some genes detected by RNA-seq were confirmed by quantitative polymerase chain reaction (qPCR). Conclusion: A RNA-seq study shows that chronic oxycodone SA alters the expression of several reward-related genes in the dorsal and ventral striatum. These results suggest potential mechanisms underlying neuronal adaptation to chronic oxycodone self-exposure, of relevance to our mechanistic understanding of prescription opioid abuse.

Oxycodone Self-Administration Induces Alterations in Expression of Integrin, Semaphorin and Ephrin Genes in the Mouse Striatum

Oxycodone is one a commonly used medication for pain, and is also a widely abused prescription opioid, like other short-acting MOPr agonists. Neurochemical and structural adaptations in brain following chronic MOPr-agonist administration are thought to underlie pathogenesis and persistence of opiate addiction. Many axon guidance molecules, such as integrins, semaphorins, and ephrins may contribute to oxycodone-induced neuroadaptations through alterations in axon-target connections and synaptogenesis, that may be implicated in the behaviors associated with opiate addiction. However, little is known about this important area. The aim of this study is to investigate alterations in expression of selected integrin, semaphorin, ephrins, netrin, and slit genes in the nucleus accumbens (NAc) and caudate putamen (CPu) of mice following extended 14-day oxycodone self-administration (SA), using RNAseq. Methods: Total RNA from the NAc and CPu were isolated from adult male C57BL/6J mice within 1 h after the last session of oxycodone in a 14-day self-administration paradigm (4h/day, 0.25 mg/kg/infusion, FR1) or from yoked saline controls. Gene expressions were examined using RNA sequencing (RNA-Seq) technology. RNA-Seq libraries were prepared using Illuminas TruSeq® Stranded Total RNA LT kit. The reads were aligned to the mouse reference genome (version mm10) using STAR. DESeq2 was applied to the counts of protein coding genes to estimate the fold change between the treatment groups. False Discovery Rate (FDR) q < 0.1 were used to select genes that have a significant expression change. For selection of a subset of genes related to axon guidance pathway, REACTOME was used. Results: Among 38 known genes of the integrin, semaphorin, and ephrin gene families, RNA-seq data revealed up-regulation of six genes in the NAc: heterodimer receptor, integrins Itgal, Itgb2, and Itgam, and its ligand semaphorin Sema7a, two semaphorin receptors, plexins Plxnd1 and Plxdc1. There was down-regulation of eight genes in this region: two integrin genes Itga3 and Itgb8, semaphorins Sema3c, Sema4g, Sema6a, Sema6d, semaphorin receptor neuropilin Nrp2, and ephrin receptor Epha3. In the CPu, there were five differentially expressed axon guidance genes: up-regulation of three integrin genes, Itgal, Itgb2, Itga1, and down-regulation of Itga9 and ephrin Efna3 were thus observed. No significant alterations in expression of Netrin-1 or Slit were observed. Conclusion: We provide evidence for alterations in the expression of selective axon guidance genes in adult mouse brain following chronic self-administration of oxycodone. Further examination of oxycodone-induced changes in the expression of these specific axon guidance molecules and integrin genes in relation to behavior may provide new insights into development of addiction to oxycodone.

HTRA1 promoter polymorphism in wet age-related macular degeneration

Age-related macular degeneration (AMD), the most common cause of irreversible vision loss in individuals aged older than 50 years, is classified as either wet (neovascular) or dry (nonneovascular). Inherited variation in the complement factor H gene is a major risk factor for drusen in dry AMD. Here we report that a single-nucleotide polymorphism in the promoter region of HTRA1, a serine protease gene on chromosome 10q26, is a major genetic risk factor for wet AMD. A whole-genome association mapping strategy was applied to a Chinese population, yielding a P value of <10(-11). Individuals with the risk-associated genotype were estimated to have a likelihood of developing wet AMD 10 times that of individuals with the wild-type genotype.