UCLA Pharmacogenetics and Pharmacogenomics Research Grp*
Principal Investigator: Julio Licinio
Abstract: The UCLA Pharmacogenetics and Pharmacogenomics Research Group (PPRG) has been developed to test the hypothesis that pharmacogenetic approaches can be used to optimize treatment strategies for common and complex disorders of public health relevance to Mexican-Americans, who are the poorest minority group in the U.S. To test this general hypothesis, we will address three specific aims: (1) To study pharmacogenetics in Mexican-Americans, using obesity and depression treatments as a proof of the concept that pharmacogenetic approaches can be used to optimize treatment strategies for common and complex disorders in this population. (2) To discover novel single nucleotide polymorphisms (SNPs) and test their relevance to the underlying genetic differences governing their responses to the pharmacological treatments conducted in Aim 1. (3) To phenotypically characterize gene-drug efforts in this application on two common and complex disorders of general medical interest and public health relevance, namely depression and obesity. These disorders represent independent risk factors for cardiovascular morbidity and mortality. There is considerable clinical, neurobiological, genetic, and pharmacological overlap between these two disorders, making it appropriate for the same center to study them. Our projects are highly synergist and were designed to inform and enrich one another. Specifically, Aim I will be addressed by prospective, clinical trials in which clinical outcomes and DNA will be collected by a team of highly experienced bilingual personnel with an outstanding track record of work with the Los Angeles Mexican-American community. Aim 2 will be achieved by use of Bayesian analysis to identify functional SNPs by measuring the evidence for polymorphism vs. simple sequencing errors, followed by high-throughput methods to confirm those SNPs and test their role in pharmacogenetic responses. Those methods include fluorescent polarizing genotyping, multiplexing microsphere arrays (GAMMArrays), and oligonucleotide arrays for SNP detection. Phenotyping will be done by studies of drug-gene interaction in existing transgenic animals as well as by generating novel BAC transgenic mice that overexpress SNPs that we find to be of interest to Aims I and 2. We are currently funded by the NIGMS, Pharmacogenetic Research Network and Knowledge Base (UO1GM6 1394) to conduct a one-year pilot study on the pharmacogenetics of depression in Mexican-Americans. This renewal application was designed to expand that effort from a pilot study to a full proposal that brings together a crossdisciplinary group of highly accomplished experts in order to create a unique pharmacogenetics resource for the Mexican-American community. Our accomplishments in the first three months of pilot funding demonstrate the feasibility of our program of research. Our data will be deposited in PharmacoGKB, GenBank, and dbSNP. Additionally, our clinical responses data and DNA samples will be deposited in the UCLA DNA Bank that is accessible to other investigators.
Funding Period: 2001-08-01 - 2006-08-31
more information: NIH RePORT
- Modeling of the temporal patterns of fluoxetine prescriptions and suicide rates in the United StatesMichael S Milane
Center for Pharmacogenomics and Clinical Pharmacology, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA
PLoS Med 3:e190. 2006....
- Prediction of susceptibility to major depression by a model of interactions of multiple functional genetic variants and environmental factorsM L Wong
Department of Translational Medicine, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
Mol Psychiatry 17:624-33. 2012..These findings identify novel targets for therapeutics and for translation into preventive, clinical and personalized health care...
- Short-term plasticity of gray matter associated with leptin deficiency and replacementEdythe D London
Department of Psychiatry and Biobehavioral Sciences and Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90024, USA
J Clin Endocrinol Metab 96:E1212-20. 2011..We previously reported that leptin supplementation increased gray matter (GM) concentration in the anterior cingulate gyrus (ACG), cerebellum, and inferior parietal lobule, areas that are also involved in food intake...
- Promoter polymorphisms in the β-2 adrenergic receptor are associated with drug-induced gene expression changes and response in acute lymphoblastic leukemiaN Pottier
EA2679, Faculte de Medecine de Lille, Pole Recherche, Lille, France
Clin Pharmacol Ther 88:854-61. 2010..We conclude that germline polymorphisms in ADRB2 are linked to the antileukemic effects of ALL chemotherapy...
- Pathophysiological basis of cardiovascular disease and depression: a chicken-and-egg dilemmaGilberto Paz-Filho
The John Curtin School of Medical Research, Australian National University, Canberra, Australia
Rev Bras Psiquiatr 32:181-91. 2010..To describe the pathophysiological basis linking cardiovascular disease (CVD) and depression; to discuss the causal relationship between them, and to review the effects of antidepressant treatment on cardiovascular disease...
- Sequence variations of ABCB1, SLC6A2, SLC6A3, SLC6A4, CREB1, CRHR1 and NTRK2: association with major depression and antidepressant response in Mexican-AmericansC Dong
Department of Psychiatry and Behavioral Sciences, Center for Pharmacogenomics, University of Miami Miller School of Medicine, Miami, FL, USA
Mol Psychiatry 14:1105-18. 2009..Moreover, these results highlight the importance of direct re-sequencing of key candidate genes in ethnic minority groups in order to discover novel genetic variants that cannot be simply inferred from existing databases...
- Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment responseJulio Licinio
Center on Pharmacogenomics, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida 33136, USA
Arch Gen Psychiatry 66:488-97. 2009..Variations in the brain-derived neurotrophic factor gene (BDNF) have been associated with psychiatric disorders. Deep sequencing of the BDNF gene may identify new variations and bring further insight into psychiatric genetics...
- Elevated stress-hemoconcentration in major depression is normalized by antidepressant treatment: secondary analysis from a randomized, double-blind clinical trial and relevance to cardiovascular disease riskMa Li Wong
Department of Psychiatry and Behavioral Sciences, Leonard M Miller School of Medicine, University of Miami, Miami, Florida, USA
PLoS ONE 3:e2350. 2008..Stress-hemoconcentration, a result of psychological stress that might be a risk factor for the pathogenesis of CVD, has been studied in stress-challenge paradigms but has not been systematically studied in MDD...
- Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant responseM L Wong
Department of Psychiatry and Behavioral Sciences, Center on Pharmacogenomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Mol Psychiatry 13:800-12. 2008..8% of the attributable risk in Mexican Americans with moderate MDD. Immune function genes are highly variable; therefore, different genes might be implicated in distinct population groups...
- Leptin replacement alters brain response to food cues in genetically leptin-deficient adultsKate Baicy
Department of Psychiatry and Biobehavioral Sciences and Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90024, USA
Proc Natl Acad Sci U S A 104:18276-9. 2007..Leptin appears to modulate feeding behavior through these circuits, suggesting therapeutic targets for human obesity...
- The brain-derived neurotrophic factor rs6265 (Val66Met) polymorphism and depression in Mexican-AmericansLuciana Ribeiro
Department of Psychiatry and Behavioral Sciences, Center on Pharmacogenomics, University of Miami Miller School of Medicine, Miami, Florida 33136 1013, USA
Neuroreport 18:1291-3. 2007..7 95% CI 1.17-2.47). Our findings support the association of BDNF single nucleotide polymorphism rs6265 and depression, suggesting that this polymorphism may increase susceptibility to major depression in Mexican-Americans...
- Expression of SMARCB1 modulates steroid sensitivity in human lymphoblastoid cells: identification of a promoter SNP that alters PARP1 binding and SMARCB1 expressionNicolas Pottier
Department of Pharmaceutical Sciences, St Jude Children s Research Hospital, Memphis, TN 38105, USA
Hum Mol Genet 16:2261-71. 2007..In summary, we provide functional evidence that SMARCB1 is involved in prednisolone resistance and identified a promoter SNP that alters the level of SMARCB1 mRNA and protein expression and the binding of PARP1 to the SMARCB1 promoter...
- Caspase 1 deficiency reduces inflammation-induced brain transcriptionClaudio Mastronardi
Center on Pharmacogenomics, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Proc Natl Acad Sci U S A 104:7205-10. 2007..Our results indicate that those genes may also play a role in several neuropsychiatric conditions in which inflammation has been implicated and indicate that casp1 might be a potential therapeutic target for such disorders...
- Suicidality scores during double-blind fluoxetine and desipramine treatment in Mexican AmericansAnil Sharma
J Clin Psychopharmacol 27:99-101. 2007
- Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment responseMa Li Wong
Center on Pharmacogenomics, Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
Proc Natl Acad Sci U S A 103:15124-9. 2006..This study identifies a potential CNS role for the PDE11 family. The hypothesis that drugs affecting PDE function, particularly cGMP-related PDEs, represent a treatment strategy for major depression should therefore be tested...
- Approaching the shared biology of obesity and depression: the stress axis as the locus of gene-environment interactionsS R Bornstein
Department of Medicine, University of Dresden, Carl Gustav Carus, Dresden, Germany
Mol Psychiatry 11:892-902. 2006....
- Effects of leptin deficiency and replacement on cerebellar response to food-related cuesSteven M Berman
Department of Psychiatry and Biobehavioral Sciences and the Semel Institute, David Geffen School of Medicine, University of California Los Angeles, 760 Westwood Plaza, C8 831, Los Angeles, CA 90024, USA
Cerebellum 12:59-67. 2013..The results suggest an underexplored role for the posterior cerebellum in the regulation of leptin-mediated processes related to food intake...