Medical Genetics Commons^™

Investigation Of Heterocyclic Amines And N-Acetyltransferase 2 Genetic Polymorphism In The Dysregulation Of Hepatic Energy Homeostasis: A Gene-Environment Approach., Kennedy M Walls

Electronic Theses and Dissertations

Heterocyclic amines (HCAs) are mutagens generated when cooking meat for prolonged periods of time or until well-done. Recent epidemiological studies reported significant associations between dietary HCA exposure and insulin resistance and type II diabetes. However, no previous studies have examined if HCAs, independent of meat consumption, contributes to pathogenesis of insulin resistance or metabolic disease. It is well known that HCAs require hepatic bioactivation by cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 2 (NAT2). NAT2 expresses a well-defined genetic polymorphism in humans that, depending on the combination of NAT2 alleles, correlate to rapid, intermediate, or slow acetylator phenotypes that exhibit differential …

Caregiver Perspectives On The Daily Function Of People Living With Hnrnph2-Related Neurodevelopmental Disorder: Developing A Conceptual Model, Rachel Salazar

Seton Hall University Dissertations and Theses (ETDs)

Introduction: Neurodevelopmental disorders are a group of conditions that start in childhood and lead to impairments in functioning. HNRNPH2-related neurodevelopmental disorder is an ultra-rare disorder in which individuals present with cognitive, behavioral, language and motor function impairments that often leads to reliance on their caregivers. Existing conceptual models of neurodevelopment are not specific to this ultra rare disorder and do not highlight the caregiver impact of living with HNRNPH2-related neurodevelopmental disorder.

Purpose: The purpose of this study is to understand the caregiver perspective on the everyday functioning of people living with HNRNPH2-related neurodevelopmental disorder to generate a …

Tolfenamic Acid Derivatives: A New Class Of Transcriptional Modulators With Potential Therapeutic Applications For Alzheimer’S Disease And Related Disorders, Juanetta Hill, Karim E. Shalaby, Syed W. Bihaqi, Bothaina H. Alansi, Benjamin Barlock, Keykavous Parang, Richard Thompson, Khalid Ourarhni, Nasser H. Zawia

Pharmacy Faculty Articles and Research

The field of Alzheimer’s disease (AD) has witnessed recent breakthroughs in the development of disease-modifying biologics and diagnostic markers. While immunotherapeutic interventions have provided much-awaited solutions, nucleic acid-based tools represent other avenues of intervention; however, these approaches are costly and invasive, and they have serious side effects. Previously, we have shown in AD animal models that tolfenamic acid (TA) can lower the expression of AD-related genes and their products and subsequently reduce pathological burden and improve cognition. Using TA as a scaffold and the zinc finger domain of SP1 as a pharmacophore, we developed safer and more potent brain-penetrating analogs …

Functional Characterization Of The Ipsc Generated Hepatocytes Using Genome-Wide Transcriptomic Analysis, Ashley Ikwuezunma, Erica De Leon, Ana C. Leandro, Joanne E. Curran, John Blangero, Satish Kumar

Research Colloquium

Advances in iPSC technologies now allow us to consider non-invasive large-scale in-vitro disease modeling experiments on disease appropriate cell types in human subjects to better understand human disease pathophysiology, disease genetics and to develop better diagnostic and therapeutic technologies. We performed differential gene expression and functional annotation analysis using genome wide mRNA sequencing data to evaluate the functional and disease modeling potential of iPSC generated hepatocytes. Following the criteria moderated t statistics FDR corrected p-value ≤ 0.05 and fold change-absolute ≥ 2.0, 7,246 genes/transcripts were significantly differentially expressed iPSCs and hepatocytes. The 3,791 of these DE genes/transcripts were significantly …

Gene By Environment Interaction And Metabolic-Associated Fatty Liver Disease In Mexican American Patients With Depression, Khalid Sheikh, Vincent P. Diego, Sandra L. Laston, Eron G. Manusov, Sarah Williams-Blangero, John Blangero

Research Colloquium

Knowledge of genetic and environmental (G x E) interaction effects on metabolic-associated fatty liver disease (MAFLD) is limited. The purpose of this study was to examine the impact of G x E interaction effects on MAFLD in Mexican Americans in the Rio Grande Valley (RGV). The environment examined was depression as measured by the Beck Depression Inventory-II (BDI-II). We examined potential G x E interaction in the phenotypic expression of MAFLD, including hepatic steatosis and hepatic fibrosis, using variance component models and likelihood-based statistical inference. Significant G x E interactions were identified for hepatic fibrosis x BDI-II. These findings provide …

Variant Of Fii Gene Plays A Critical Role In Coagulation Potential In Mexican-Americans, Hoang Anh T. Nguyen, Shuchita Vijay Jhaveri, Marcio A. Almeida, Vincent P. Diego, Satish Kumar, Juan M. Peralta, Joanne E. Curran, Bernadette W. Luu, Donna M. Lehman, Ralph A. Defronzo, Laura Almasy, Sarah Williams-Blangero, Ravi Duggirala, John Blangero, Tom Howard

Research Symposium

Background: Disruption in the balance between coagulation and bleeding can result in varying phenotypes such as hypercoagulability and can lead to the development of cardiovascular disease. In our study utilizing extended families of Mexican-Americans from South Texas, we performed a search for protein-altering variants influencing coagulation potential.

Methods: Mexican-Americans in the study were genotyped using Illumina-(human)-exome-24 chip to screen for protein-altering variants. Variants were analyzed for their association with FII activity, aPTT, and PT. Linear-mixed-model analysis was performed to estimate trait heritabilities and to interrogate single nucleotide variations (SNV) for evidence of genetic association. To control for multiple testing, associations …

Cocaine Use Disorder Effects On Blood Oxytocin Levels And Oxtr Dna Methylation, Manassés Soares Souza, Breno Sanvicente-Vieira, Aline Zaparte, Talita Baptista, Maria Aparecida Nagai, Flávia Rotea Mangone, Ana Carolina Pavanelli, Thiago Wendt Viola, Rodrigo Grassi-Oliveira

School of Medicine Faculty Publications

Substance use disorders have been associated with alterations in the oxytocinergic system, but few studies have investigated both the peptide and epigenetic mechanisms potentially implicated in the regulation of oxytocin receptor. In this study, we compared plasma oxytocin and blood DNA methylation in the OXTR gene between people with and without cocaine use disorder (CUD). We measured the oxytocin levels of 51 people with CUD during acute abstinence and of 30 healthy controls using an enzyme immunoassay. The levels of DNA methylation in four CpG sites at exon III of the OXTR gene were evaluated in a subsample using pyrosequencing. …

Dpyd Pathogenic Variants Associated With Fluoropyrimidines Toxicity, Diana Cristina Pérez-Ibave, Noé Israel Oliva-García, Irasema Ramos-Martínez, Francisco Javier Villarreal Alvarado, Valeria Jimena Gómez Ordaz, Jonatán Isaí Cortes Alfaro, Carlos Horacio Burciaga-Flores, Juan Francisco González-Guerrero, Oscar Vidal-Gutiérrez, Maria De Lourdes Garza-Rodriguez

Research Symposium

Background: Genetic variants in dihydropyrimidine dehydrogenase gene (DPYD) coding for the key enzyme (DPD) of fluoropyrimidines (FPs) catabolism. DPYD contributes to the development of severe FPs-related toxicity, and pathogenic DPYD variants detection reduces side effects and complications associated with FP-toxicity. The allelic frequency of these variants in the Mexican population is currently unknown.

Methods: The study was carried out at the Centro Universitario Contra el Cáncer (CUCC) of the Universidad Autónoma de Nuevo León (UANL) in Monterrey México. Genomic DNA was isolated from 154 subjects using the QIAamp DNA Blood Midi kit (QIAGEN) following the manufacturer's recommendations. We …

Genotype-By-Socioeconomic Status Interaction Influences Heart Disease Risk Scores And Carotid Artery Thickness In Mexican Americans: The Predominant Role Of Education In Comparison To Household Income And Socioeconomic Index, Vincent P. Diego, Eron G. Manusov, Xi Mao, Joanne E. Curran, Harald H. H. Goring, Marcio Almeida, Michael Mahaney, Juan M. Peralta, John Blangero, Sarah Williams-Blangero

School of Medicine Publications and Presentations

Background: Socioeconomic status (SES) is a potent environmental determinant of health. To our knowledge, no assessment of genotype-environment interaction has been conducted to consider the joint effects of socioeconomic status and genetics on risk for cardiovascular disease (CVD). We analyzed Mexican American Family Studies (MAFS) data to evaluate the hypothesis that genotype-by-environment interaction (GxE) is an important determinant of variation in CVD risk factors.

Methods: We employed a linear mixed model to investigate GxE in Mexican American extended families. We studied two proxies for CVD [Pooled Cohort Equation Risk Scores/Framingham Risk Scores (FRS/PCRS) and carotid artery intima-media thickness (CA-IMT)] in …

The Use Of Prognostic Markers To Predict Disease Progression And Clinical Outcome In Monoclonal Gammopathy Of Undetermined Significance, Smouldering Multiple Myeloma And Multiple Myeloma., Róisín C. Mcmonagle

International Undergraduate Journal of Health Sciences

Multiple Myeloma (MM) is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smouldering Multiple Myeloma (SMM) precede MM, with variable risks and rates of disease progression. The continuing high relapse and death rate in MM cases has prompted research into more accurate prognostic markers to predict progression from MGUS and SMM to MM, as well as identify MM cases with aggressive disease, in order to begin early, targeted and effective therapeutic intervention. Many studies have focused on utilising current markers more effectively, including M-protein, serum-free light chain ratio, …

Committing To Genomic Answers For All Kids: Evaluating Inequity In Genomic Research Enrollment., Natalie J. Kane, Ana S A Cohen, Courtney D. Berrios, Bridgette Jones, T Pastinen, Mark A. Hoffman

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: Persistent inequities in genomic medicine and research contribute to health disparities. This analysis uses a context-specific and equity-focused strategy to evaluate enrollment patterns for Genomic Answers for Kids (GA4K), a large, metropolitan-wide genomic study on children.

METHODS: Electronic health records for 2247 GA4K study participants were used to evaluate the distribution of individuals by demographics (race, ethnicity, and payor type) and location (residential address). Addresses were geocoded to produce point density and 3-digit zip code maps showing local and regional enrollment patterns. Health system reports and census data were used to compare participant characteristics with reference populations at different …

Association Between Rs2787094 Genetic Variants In Adam33 Gene And Asthma In Indonesian Population: Preliminary Study, Kencono Viyati, Kinasih Prayuni, Yenni Zulhamidah, Intan Razari, Rika Yuliwulandari

Makara Journal of Health Research

Background: Asthma is a multifactorial disease that encompasses a multitude of genetic and environmental factors. One such factor is the disintegrin and metalloprotein-33 (ADAM33) gene, which is correlated with asthma and bronchial hyperresponsiveness. Previous studies conducted on Asian populations have reported a significant association between rs2787094 polymorphism in the ADAM33 gene and asthma.

Methods: Our study involved 153 Indonesian participants. TaqMan genotyping assay was used to analyze rs2787094 polymorphism in the ADAM33 gene.

Results: No significant association was detected between the allele and genotype frequencies of rs2787094 and asthma in the case and control subjects (p …

Variant Characterization Of A Representative Large Pedigree Suggests “Variant Risk Clusters” Convey Varying Predisposition Of Risk To Lynch Syndrome, Mouadh Barbirou, Amanda A. Miller, Amel Mezlini, Balkiss Bouhaouala-Zahar, Peter J. Tonellato

Department of Medical Oncology Faculty Papers

Recently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with 12 LS-affected individuals to identify putative germline variants associated with varying risk of LS. Whole-genome sequencing analysis was performed to identify known and novel germline variants shared between affected and non-affected pedigree members. SNPs, indels, and structural variants (SVs) were computationally identified, and their oncological influence was predicted using the Genetic Association of Complex Diseases and Disorders, …

Advantage Of Precision Metagenomics For Urinary Tract Infection Diagnostics, Sadia Almas, Rob E. Carpenter, Chase Rowan, Vaibhav Tamrakar, Rahul Sharma

Human Resource Development Faculty Publications and Presentations

Background: Urinary tract infections (UTIs) remain a diagnostic challenge and often promote antibiotic overuse. Despite urine culture being the gold standard for UTI diagnosis, some uropathogens may lead to false-negative or inconclusive results. Although PCR testing is fast and highly sensitive, its diagnostic yield is limited to targeted microorganisms. Metagenomic next-generation sequencing (mNGS) is a hypothesis-free approach with potential of deciphering the urobiome. However, clinically relevant information is often buried in the enormous amount of sequencing data.

Methods: Precision metagenomics (PM) is a hybridization capture-based method with potential of enhanced discovery power and better diagnostic yield without diluting clinically relevant …

31-Gene Expression Profile Testing In Cutaneous Melanoma And Survival Outcomes In A Population-Based Analysis: A Seer Collaboration, Christine N. Bailey, Brian J. Martin, Valentina I. Petkov, Nicola C. Schussler, Jennifer L. Stevens, Suzanne Bentler, Rosemary D. Cress, Jennifer A. Doherty, Eric B. Durbin, Scarlett L. Gomez, Lou Gonsalves, Brenda Y. Hernandez, Lihua Liu, Bozena M. Morawski, Maria J. Schymura, Stephen M. Schwartz, Kevin C. Ward, Charles Wiggins, Xiao-Cheng Wu, Matthew S. Goldberg, Jennifer J. Siegel, Robert W. Cook, Kyle R. Covington, Sarah J. Kurley

School of Public Health Faculty Publications

PURPOSE: The DecisionDx-Melanoma 31-gene expression profile (31-GEP) test is validated to classify cutaneous malignant melanoma (CM) patient risk of recurrence, metastasis, or death as low (class 1A), intermediate (class 1B/2A), or high (class 2B). This study aimed to examine the effect of 31-GEP testing on survival outcomes and confirm the prognostic ability of the 31-GEP at the population level. METHODS: Patients with stage I-III CM with a clinical 31-GEP result between 2016 and 2018 were linked to data from 17 SEER registries (n = 4,687) following registries' operation procedures for linkages. Melanoma-specific survival (MSS) and overall survival (OS) differences by …

Investigating The Role Of Endothelial Breast Cancer Susceptibility Gene 2 In Doxorubicin-Induced Cardiotoxicity, Berk U. Rasheed

Electronic Thesis and Dissertation Repository

Doxorubicin (Dox) is a chemotherapeutic drug used to treat various malignancies including breast and ovarian cancers. Accumulating evidence implicates cardiac impairments associated with Dox treatment. The Breast Cancer Susceptibility Gene 2 (BRCA2) functions to maintain genome-wide stability by promoting DNA-damage repair. Accordingly, cardiomyocyte damage is specifically regulated by contributors of DNA damage repair such as BRCA2. The endothelium, the innermost cells of every blood vessel, act to protect our tissues from noxious elements, however, recent evidence suggests that BRCA2 knockdown compromises endothelial cell function. A putative role of endothelial BRCA2 during Dox-induced cardiotoxicity (DIC) remains unknown. We hypothesized that endothelial-specific …

Parents’ Perspectives On The Utility Of Genomic Sequencing In The Neonatal Intensive Care Unit, Amy A. Lemke, Michelle L. Thompson, Emily C. Gimpel, Katelyn C. Mcnamara, Carla A. Rich, Candice R. Finnila, Meagan E. Cochran, James M.J. Lawlor, Kelly M. East, Kevin M. Bowling, Donald R. Latner, Susan M. Hiatt, Michelle D. Amaral, Whitley V. Kelley, Veronica Greve, David E. Gray, Stephanie A. Felker, Hannah Meddaugh, Ashley Cannon, Amanda Luedecke, Kelly E. Jackson, Laura G. Hendon, Hillary M. Janani, Marla Johnston, Lee Ann Merin, Sarah L. Deans, Carly Tuura, Trent Hughes

School of Medicine Faculty Publications

Background: It is critical to understand the wide-ranging clinical and non-clinical effects of genome sequencing (GS) for parents in the NICU context. We assessed parents’ experiences with GS as a first-line diagnostic tool for infants with suspected genetic conditions in the NICU. Methods: Parents of newborns (N = 62) suspected of having a genetic condition were recruited across five hospitals in the southeast United States as part of the SouthSeq study. Semi-structured interviews (N = 78) were conducted after parents received their child’s sequencing result (positive, negative, or variants of unknown significance). Thematic analysis was performed on all interviews. Results: …

Sars-Cov-2 Next Generation Sequencing (Ngs) Data From Clinical Isolates From The East Texas Region Of The United States, Rob E. Carpenter, Vaibhav K. Tamrakar, Advanta Genetics

Human Resource Development Faculty Publications and Presentations

The SARS-CoV-2 virus has evolved throughout the pandemic and is likely to continue evolving into new variants. Some of these variants may affect functional properties, including infectivity, interactions with host immunity, and disease severity. And compromised vaccine efficacy is an emerging concern with every new viral variant. Next-generation sequencing (NGS) has emerged as the tool of choice for discovering new variants and understanding the transmission dynamics of SARS-CoV-2. Deciphering the SARS-CoV-2 genome has enabled epidemiological survivance and forecast of altered etiologically. Clinical presentations of the infection are influenced by comorbidities such as age, immune status, diabetes, and the infecting variant. …

Genome Editing For Cystic Fibrosis, Guoshun Wang

School of Medicine Faculty Publications

Cystic fibrosis (CF) is a monogenic recessive genetic disorder caused by mutations in the CF Transmembrane-conductance Regulator gene (CFTR). Remarkable progress in basic research has led to the discovery of highly effective CFTR modulators. Now ~90% of CF patients are treatable. However, these modulator therapies are not curative and do not cover the full spectrum of CFTR mutations. Thus, there is a continued need to develop a complete and durable therapy that can treat all CF patients once and for all. As CF is a genetic disease, the ultimate therapy would be in-situ repair of the genetic lesions in the …

Extrinsic Allergic Alveolitis: A Systematic Review Of Hla-Dr In Pigeon Breeder’S Disease, Dylan Thibaut, Ryan A. Witcher, Anitha Kunnath, James Toldi

Advances in Clinical Medical Research and Healthcare Delivery

Abstract

Introduction: Pigeon Breeder’s Pneumonitis (PBP) results due to a complex pathophysiology that includes exposure to avian antigens. Susceptibility has been linked to human leukocyte antigen (HLA) class II, though consensus has not been reached. The goal of this systematic review is to further elucidate the association between PBP and HLA-DR subtypes.

Methods: Databases utilized included PubMed, Google Scholar, ScienceDirect, and Cochrane Library. Inclusion required a minimum of three studies in English presenting HLA-DR alleles of PBP and control subgroups. Exclusion was due to insufficient data or non-feasible control groups. Forest plots were created for HLA-DR subtypes’ association …