Project Title
Genetic modifiers of the cardiovascular phenotype of chromosome 22q11 micro deletion syndrome: Next-generation sequencing of candidate regions identified by genome-wide association analysis
Partner Organisations
Internal ID
1130392
Principal Investigator
Type
basic research
Status
TERMINADO
Start Date
2013

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    Neuroimaging and clinical features in adults with a 22q11.2 deletion at risk of Parkinson’s disease
    (2017)
    Nancy J. Butcher
    ;
    Connie Marras
    ;
    Margarita Pondal
    ;
    Pablo Rusjan
    ;
    Erik Boot
    Scopus© Citations 45  1
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    Genome-Wide Association Study to Find Modifiers for Tetralogy of Fallot in the 22q11.2 Deletion Syndrome Identifies Variants in the GPR98 Locus on 5q14.3
    (2017)
    Tingwei Guo
    ;
    REPETTO LISBOA, MARIA GABRIELA  
    ;
    Donna M. McDonald McGinn
    ;
    Jonathan H. Chung
    ;
    Hiroko Nomaru
    <jats:sec> <jats:title>Background—</jats:title> <jats:p>The 22q11.2 deletion syndrome (22q11.2DS; DiGeorge syndrome/velocardiofacial syndrome) occurs in 1 of 4000 live births, and 60% to 70% of affected individuals have congenital heart disease, ranging from mild to severe. In our cohort of 1472 subjects with 22q11.2DS, a total of 62% (n=906) have congenital heart disease and 36% (n=326) of these have tetralogy of Fallot (TOF), comprising the largest subset of severe congenital heart disease in the cohort.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p> To identify common genetic variants associated with TOF in individuals with 22q11.2DS, we performed a genome-wide association study using Affymetrix 6.0 array and imputed genotype data. In our cohort, TOF was significantly associated with a genotyped single-nucleotide polymorphism (rs12519770, <jats:italic>P</jats:italic> =2.98×10 <jats:sup>−</jats:sup> <jats:sup>8</jats:sup> ) in an intron of the adhesion <jats:italic>GPR98</jats:italic> (G-protein–coupled receptor V1) gene on chromosome 5q14.3. There was also suggestive evidence of association between TOF and several additional single-nucleotide polymorphisms in this region. Some genome-wide significant loci in introns or noncoding regions could affect regulation of genes nearby or at a distance. On the basis of this possibility, we examined existing Hi-C chromatin conformation data to identify genes that might be under shared transcriptional regulation within the region on 5q14.3. There are 6 genes in a topologically associated domain of chromatin with <jats:italic>GPR98</jats:italic> , including <jats:italic>MEF2C</jats:italic> (Myocyte-specific enhancer factor 2C). <jats:italic>MEF2C</jats:italic> is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development.</jats:p> </jats:sec>
    Scopus© Citations 21  4
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    Scopus© Citations 25  2
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    A Novel Gemcitabine-Resistant Gallbladder Cancer Model Provides Insights into Molecular Changes Occurring during Acquired Resistance
    (2023)
    Luis Vergara-Gómez
    ;
    Carolina Bizama
    ;
    Jun Zhong
    ;
    Kurt Buchegger
    ;
    Felipe Suárez
    <jats:p>Treatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but the effectiveness of any regimen is limited and recurrence rates are high. Here, we investigated the molecular mechanisms of acquired resistance in GBC through the development and characterization of two gemcitabine-resistant GBC cell sublines (NOZ GemR and TGBC1 GemR). Morphological changes, cross-resistance, and migratory/invasive capabilities were evaluated. Then, microarray-based transcriptome profiling and quantitative SILAC-based phosphotyrosine proteomic analyses were performed to identify biological processes and signaling pathways dysregulated in gemcitabine-resistant GBC cells. The transcriptome profiling of parental and gemcitabine-resistant cells revealed the dysregulation of protein-coding genes that promote the enrichment of biological processes such as epithelial-to-mesenchymal transition and drug metabolism. On the other hand, the phosphoproteomics analysis of NOZ GemR identified aberrantly dysregulated signaling pathways in resistant cells as well as active kinases, such as ABL1, PDGFRA, and LYN, which could be novel therapeutic targets in GBC. Accordingly, NOZ GemR showed increased sensitivity toward the multikinase inhibitor dasatinib compared to parental cells. Our study describes transcriptome changes and altered signaling pathways occurring in gemcitabine-resistant GBC cells, which greatly expands our understanding of the underlying mechanisms of acquired drug resistance in GBC.</jats:p>
      1Scopus© Citations 6
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    Variance of IQ is partially dependent on deletion type among 1,427 22q11.2 deletion syndrome subjects
    (2018)
    Yingjie Zhao
    ;
    Tingwei Guo
    ;
    Ania Fiksinski
    ;
    Elemi Breetvelt
    ;
    Donna M. McDonald-McGinn
      12Scopus© Citations 37