Altered Gene Expression Profiles in the Frontal Cortex of Cirrhotic Alcoholics

Liu, Jianwen; Lewohl, Joanne Marie; Harris, R. Adron; Dodd, Peter R.; Mayfield, R. Dayne

doi:10.1111/j.1530-0277.2007.00444.x

Cited by 60 publications

(71 citation statements)

References 42 publications

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“…Although a number of sophisticated in silico approaches have been used to predict the function of nsSNPs on protein structure and activity, the underpinnings for these algorithms are protein sequence alignment (Wang and Moult, 2001), physiochemical differences (Henikoff and Henikoff, 1992), mapping to known protein threedimensional structures (Sunyaev et al, 2001;Stitziel et al, 2003), and combinations thereof (Liu et al, 2007). Different in silico algorithms focus on different aspects of this information, among which the SIFT and PolyPhen algorithms are the main representatives in this field.…”

Section: Discussionmentioning

confidence: 99%

A Bioinformatics Approach for the Phenotype Prediction of Nonsynonymous Single Nucleotide Polymorphisms in Human Cytochromes P450

Wang

Li²,

Zhou

2009

Drug Metab Dispos

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ABSTRACT:Nonsynonymous single nucleotide polymorphisms (nsSNPs) in coding regions that can lead to amino acid changes may cause alteration of protein function and account for susceptivity to disease and altered drug response. Identification of deleterious nsSNPs from tolerant nsSNPs is important for characterizing the genetic basis of human disease, assessing individual susceptibility to disease, understanding the pathogenesis of disease, identifying molecular targets for drug treatment, and conducting individualized pharmacotherapy. Numerous nsSNPs have been found in genes coding for human cytochromes P450 (P450s), but there is poor knowledge on the relationship between the genotype and phenotype of nsSNPs in P450s. We have identified 791 validated nsSNPs in 57 validated human CYP genes from the National Center for Biotechnology Information Database of Single Nucleotide Polymorphism and Swiss-Prot database. Using the polymorphism phenotyping (PolyPhen; http://genetics.bwh.harvard.edu/pph) and sorting intolerant from tolerant (SIFT; http://blocks.fhcrc.org/sift/ SIFT.html) algorithms, 39 to 43% of nsSNPs in CYP genes were predicted to have functional impacts on protein function. There was a significant concordance between the predicted results using the SIFT and PolyPhen algorithms. A prediction accuracy analysis found that approximately 70% of nsSNPs were predicted correctly as damaging. Of nsSNPs predicted as deleterious, the prediction scores by the SIFT and PolyPhen algorithms were significantly associated with the numbers of nsSNPs with known phenotype confirmed by benchmarking studies, including site-directed mutagenesis analysis and clinical association studies. These amino acid substitutions are supposed to be the pathogenetic basis for the alteration of P450 enzyme activity and the association with disease susceptivity. This prediction analysis of nsSNPs in human CYP genes would be useful for further genotype-phenotype studies on individual differences in drug clearance and clinical response.

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Section: Discussionmentioning

confidence: 99%

A Bioinformatics Approach for the Phenotype Prediction of Nonsynonymous Single Nucleotide Polymorphisms in Human Cytochromes P450

Wang

Li²,

Zhou

2009

Drug Metab Dispos

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“…Immunoprecipitation experiments were performed to identify PPIs using synaptic proteins as baits. The following proteins encoded by alcohol-responsive genes were used as baits: syntaxin-1A (Worst et al, 2005), synaptosome-associated protein 25 (Liu et al, 2007), vesicle-associated membrane protein 2 (Worst et al, 2005), dynamin-1 (Saito et al, 2002), and the BK channel (Pietrzykowski et al, 2008). Subsequent immunoblots and mass spectrometric analyses confirmed known and identified novel, interacting protein partners in the co-immunoprecipitates.…”

Section: Interaction Proteomics Approachesmentioning

confidence: 94%

Proteomic Approaches and Identification of Novel Therapeutic Targets for Alcoholism

Gorini

Harris

Mayfield

2013

Neuropsychopharmacol

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Recent studies have shown that gene regulation is far more complex than previously believed and does not completely explain changes at the protein level. Therefore, the direct study of the proteome, considerably different in both complexity and dynamicity to the genome/transcriptome, has provided unique insights to an increasing number of researchers. During the past decade, extraordinary advances in proteomic techniques have changed the way we can analyze the composition, regulation, and function of protein complexes and pathways underlying altered neurobiological conditions. When combined with complementary approaches, these advances provide the contextual information for decoding large data sets into meaningful biologically adaptive processes. Neuroproteomics offers potential breakthroughs in the field of alcohol research by leading to a deeper understanding of how alcohol globally affects protein structure, function, interactions, and networks. The wealth of information gained from these advances can help pinpoint relevant biomarkers for early diagnosis and improved prognosis of alcoholism and identify future pharmacological targets for the treatment of this addiction.

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“…Damage to the liver due to long term alcohol misuse results in a higher effective dose reaching the brain, and greater neuropathological damage (Harper, 1998). In addition, the expression profile in the prefrontal cortex of alcohol misusers with cirrhosis of the liver is distinct from those without cirrhosis of the liver (Liu et al, 2007).…”

Section: Case Selectionmentioning

confidence: 99%

“…These include genes involved in protein trafficking, myelination, ubiquitination, apoptosis, cell adhesion, neurogenesis, and neural disease. Studies using whole-genome microarrays (Lewohl et al, 2000;Liu et al, 2004Liu et al, , 2007Liu et al, , 2006Mayfield et al, 2002) and 2-D gel proteomics (Etheridge et al, 2009;Lewohl et al, 2004) have suggested that α-synuclein is differentially regulated in the brain of alcohol misusers relative to controls. A recent study analysing data available from GWAS, animal and human genetic and gene expression studies found the α-synuclein gene (SNCA) to be the top candidate gene for alcoholism (Levey et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…The changes in brain function originate from alterations in gene expression that, in turn, underlie the cellular adaption to chronic alcohol misuse (Anni and Israel, 2002;Nestler, 2000). We and others have used whole-genome microarrays to delineate genes with altered expression in the brain following long-term alcohol consumption (Lewohl et al, 2000;Liu et al, 2004Liu et al, , 2006Mayfield et al, 2002), as well as the potentially confounding effects of concomitant diseases such as liver cirrhosis (Liu et al, 2007). The studies have identified genes that likely underlie the adaptive response of neurons in the prefrontal cortex, a brain region that is particularly susceptible to long-term alcohol misuse.…”

Section: Introductionmentioning

confidence: 99%

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Differential expression of α-synuclein splice variants in the brain of alcohol misusers: Influence of genotype

Janeczek

Brooker

Dodd

et al. 2015

Drug and Alcohol Dependence

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Please cite this article as: Janeczek, P., Brooker, C., Lewohl, P.D.,J.M., Differential Expression of rmalpha-Synuclein Splice Variants in the Brain of Alcohol Misusers: Influence of Genotype, Drug and Alcohol Dependence (2015), http://dx.doi.org/10. 1016/j.drugalcdep.2015.05.045 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Allele and genotype frequencies differed significantly between alcohol misusers and controls for three SNPs, rs356221, rs356219 and rs2736995. Two SNPs, rs356221 and rs356219, were in high linkage disequilibrium. There was no increased risk of alcoholism associated with specific genotypes or haplotypes. Our results suggest that the rs356219/356221 G-A haplotype may decrease the chance of having an alcohol misuse phenotype. Conclusion: These findings suggest that alcohol misuse may alter the expression of the individual α-synuclein splice variants differently in human brain. There was no evidence of an effect of sequence variation on the expression of α-synuclein splice variants in this population.

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Altered Gene Expression Profiles in the Frontal Cortex of Cirrhotic Alcoholics

Abstract: These changes in the transcriptome likely contribute to the more severe brain dysfunction in cirrhotic alcoholics.

Cited by 60 publications

References 42 publications

A Bioinformatics Approach for the Phenotype Prediction of Nonsynonymous Single Nucleotide Polymorphisms in Human Cytochromes P450

A Bioinformatics Approach for the Phenotype Prediction of Nonsynonymous Single Nucleotide Polymorphisms in Human Cytochromes P450

Proteomic Approaches and Identification of Novel Therapeutic Targets for Alcoholism

Differential expression of α-synuclein splice variants in the brain of alcohol misusers: Influence of genotype

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