Medical Genetics Commons^™

Cd33 Expression And Its Association With Gemtuzumab Ozogamicin Response: Results From The Randomized Phase Iii Children's Oncology Group Trial Aaml0531., Jessica A. Pollard, Michael Loken, Robert B. Gerbing, Susana C. Raimondi, Betsy A. Hirsch, Richard Aplenc, Irwin D. Bernstein, Alan S. Gamis, Todd A. Alonzo, Soheil Meshinchi

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: CD33 is variably expressed on acute myeloid leukemia (AML) blasts and is targeted by gemtuzumab ozogamicin (GO). GO has shown benefit in both adult and pediatric AML trials, yet limited data exist about whether GO response correlates with CD33 expression level.

PATIENTS AND METHODS: CD33 expression levels were prospectively quantified by multidimensional flow cytometry in 825 patients enrolled in Children's Oncology Group AAML0531 and correlated with response to GO.

RESULTS: Patients with low CD33 expression (lowest quartile of expression [Q1]) had no benefit with the addition of GO to conventional chemotherapy (relapse risk [RR]: GO 36% v No-GO 34%, …

Molecular Evolution And Intraclade Recombination Of Enterovirus D68 During The 2014 Outbreak In The United States., Yi Tan, Ferdaus Hassan, Jennifer E. Schuster, Ari Simenauer, Rangaraj Selvarangan, Rebecca A. Halpin, Xudong Lin, Nadia Fedorova, Timothy B. Stockwell, Tommy Tsan-Yuk Lam, James D. Chappell, Tina V. Hartert, Edward C. Holmes, Suman R. Das

Manuscripts, Articles, Book Chapters and Other Papers

In August 2014, an outbreak of enterovirus D68 (EV-D68) occurred in North America, causing severe respiratory disease in children. Due to a lack of complete genome sequence data, there is only a limited understanding of the molecular evolution and epidemiology of EV-D68 during this outbreak, and it is uncertain whether the differing clinical manifestations of EV-D68 infection are associated with specific viral lineages. We developed a high-throughput complete genome sequencing pipeline for EV-D68 that produced a total of 59 complete genomes from respiratory samples with a 95% success rate, including 57 genomes from Kansas City, MO, collected during the 2014 …

Prevalence And Spectrum Of Brca Germline Variants In Mainland Chinese Familial Breast And Ovarian Cancer Patients., Yeong C. Kim, Linli Zhao, Hanwen Zhang, Ye Huang, Jian Cui, Fengxia Xiao, Bradley Downs, San Ming Wang

Journal Articles: Genetics, Cell Biology & Anatomy

Germline mutations in BRCA1 and BRCA2 are the most penetrating genetic predispositions for breast and ovarian cancer, and their presence is largely ethnic-specific. Comprehensive information about the prevalence and spectrum of BRCA mutations has been collected in European and North American populations. However, similar information is lacking in other populations, including the mainland Chinese population despite its large size of 1.4 billion accounting for one fifth of the world's population. Herein, we performed an extensive literature analysis to collect BRCA variants identified from mainland Chinese familial breast and ovarian cancer patients. We observed 137 distinct BRCA1 variants in 409 of …

Genetic Loci Associated With Renal Function Measures And Chronic Kidney Disease In Children: The Pediatric Investigation For Genetic Factors Linked With Renal Progression Consortium., Matthias Wuttke, Craig S. Wong, Elke Wühl, Daniel Epting, Li Luo, Anselm Hoppmann, Anke Doyon, Yong Li, Gkdgen Consortium, Betül Sözeri, Daniela Thurn, Martin Helmstädter, Tobias B. Huber, Tom D. Blydt-Hansen, Albrecht Kramer-Zucker, Otto Mehls, Anette Melk, Uwe Querfeld, Susan L. Furth, Bradley A. Warady, Franz Schaefer, Anna Köttgen

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Chronic kidney disease (CKD) in children is characterized by rapid progression and a high incidence of end-stage renal disease and therefore constitutes an important health problem. While unbiased genetic screens have identified common risk variants influencing renal function and CKD in adults, the presence and identity of such variants in pediatric CKD are unknown.

METHODS: The international Pediatric Investigation for Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) and Cardiovascular …

A Quality Improvement Collaborative To Improve Pediatric Primary Care Genetic Services., Michael L. Rinke, Amy Driscoll, Natalie Mikat-Stevens, Jill Healy, Elizabeth Colantuoni, Abdallah F. Elias, Beth A. Pletcher, Ruth S. Gubernick, Ingrid Larson, Wendy K. Chung, Beth A. Tarini

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVE: To investigate if a national pediatric primary care quality improvement collaborative (QIC) could improve and sustain adherence with process measures related to diagnosis and management of children with genetic disorders.

METHODS: Thirteen practices in 11 states from the American Academy of Pediatrics' Quality Improvement Innovation Networks participated in a 6-month QIC that included regular educational opportunities, access to genetic professionals, and performance feedback. The QIC identified 11 aims related to improving diagnosis and management of children with genetic disorders. The practices evaluated adherence by reviewing patient records at baseline, monthly for 6 months (active improvement period), and then once …

A Large Genome-Wide Association Study Of Age-Related Macular Degeneration Highlights Contributions Of Rare And Common Variants, Lars G. Fritsche, Wilmar Igl, Jessica N. Cooke Bailey, Felix Grassmann, Sebanti Sengupta, Jennifer L. Bragg-Gresham, Kathryn P. Burdon, Scott J. Hebbring, Matthew P. Johnson, John Blangero

School of Medicine Publications

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly with limited therapeutic options. Here, we report on a study of >12 million variants including 163,714 directly genotyped, most rare, protein-altering variant. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5×10–8) distributed across 34 loci. While wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first signal specific to wet AMD, near MMP9 (difference-P = 4.1×10–10). Very rare coding variants (frequency < 0.1%) in CFH, CFI, and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate …

Exome Screening To Identify Loss-Of-Function Mutations In The Rhesus Macaque For Development Of Preclinical Models Of Human Disease, Adam Cornish, Robert M. Gibbs, Robert B. Norgren

Journal Articles: Genetics, Cell Biology & Anatomy

BACKGROUND: Exome sequencing has been utilized to identify genetic variants associated with disease in humans. Identification of loss-of-function mutations with exome sequencing in rhesus macaques (Macaca mulatta) could lead to valuable animal models of genetic disease. Attempts have been made to identify variants in rhesus macaques by aligning exome data against the rheMac2 draft genome. However, such efforts have been impaired due to the incompleteness and annotation errors associated with rheMac2. We wished to determine whether aligning exome reads against our new, improved rhesus genome, MacaM, could be used to identify high impact, loss-of-function mutations in rhesus macaques that would …

Estimating Relationships Between Phenotypes And Subjects Drawn From Admixed Families., Elizabeth M. Blue, Lisa A. Brown, Matthew P. Conomos, Jennifer L. Kirk, Alejandro Q. Nato Jr., Alice B. Popejoy, Jesse Raffa, John Ranola, Ellen M. Wijsman, Timothy Thornton

Biochemistry and Microbiology

Background: Estimating relationships among subjects in a sample, within family structures or caused by population substructure, is complicated in admixed populations. Inaccurate allele frequencies can bias both kinship estimates and tests for association between subjects and a phenotype. We analyzed the simulated and real family data from Genetic Analysis Workshop 19, and were aware of the simulation model.

Results: We found that kinship estimation is more accurate when marker data include common variants whose frequencies are less variable across populations. Estimates of heritability and association vary with age for longitudinally measured traits. Accounting for local ancestry identified different true associations …

Southeastern Alumni Magazine- Winter 2016, Southeastern University - Lakeland

Southeastern Alumni Magazine

Dr. Aimee Franklin '07 returned to Southeastern in 2014 as an assistant professor of biology. Prior to returning, she earned her Ph.D. in Neuroscience at the University of Alabama Birmingham where she studied Fragile X Syndrome, the leading known genetic cause for autism. One of her articles published in Biological Psychology was one of the most cited articles in that journal in 2014.

Molecular Genetics Of Ms4a6a And Alzheimer's Disease, Ryan Harpole

Lewis Honors College Capstone Collection

Increased Alzheimer’s disease (AD) risk has previously been associated with a SNP called rs610932 near the gene MS4A6A. The goal of this experiment was to quantify the expression of two MS4A6A isoforms in the brains of AD and non-AD subjects, particularly as a function of rs610932 genotype. According to an article titled “Alzheimer’s Disease Susceptibility Variants in the MS4A6A Gene are Associated with Altered Levels of MS4A6A Expression in Blood”, MS4A6A has four different isoforms that have been reported to be differentially expressed in the blood of AD subjects compared to non-AD subjects (Petroula et al., 2014). After statistically …

Capillary Endothelia From Two Adpkd Patients Are Polyploidy, Sarmed H. Kathem, Wissam A. Aboualaiwi, Xiaolin Zi, Surya M. Nauli

Pharmacy Faculty Articles and Research

Bilateral renal cyst formation is the main feature of autosomal dominant polycystic kidney disease (ADPKD). We and other laboratories have previously shown that cystlining epithelia of kidneys from ADPKD patients are characterized by polyploidy. In this report, we show that endothelia from the renal capillary beds of two ADPKD patients are also polyploidy. Spectral karyotyping study further confirms our flow cytometry analyses. We suggest that polyploidy may be used as a potential cellular marker in ADPKD.

Assembly And Regulation Of The Dream Complex, Jessica G. Felthousen

Theses and Dissertations

The DREAM complex assembles during G0/G1 when RB-like protein p130 recruits E2F4, DP1, and a core complex of five MuvB proteins to repress genes involved in cell cycle progression. In S-phase, the MuvB core dissociates from p130 and binds to BMYB transcription factor. Binding of the MuvB core to p130 requires phosphorylation of its subunit LIN52 at S28 residue by DYRK1A protein kinase. However, little is known about how the MuvB core interacts with p130 to form the DREAM complex, and how these interactions are manipulated throughout the cell cycle. In collaboration with Dr. Seth Rubin, we characterized the structural …

Efficacy In Screening Patients For Lynch Syndrome, Adria Ridl

Physician Assistant Scholarly Project Posters

Lynch syndrome is an autosomal dominant syndrome caused by an inherited germline mutation of the MMR proteins. A mutation of any of the MMR proteins, MLH1, MSH2, MSH6, PMS2 and EPCAM increases the risk of developing cancer, specifically colorectal and endometrial cancer. Approximately 3% of colorectal cancers are associated with Lynch Syndrome (LS). Early identification of a patient’s hereditary cancer risk offers the best outcome. To aid clinicians in the identification of a carrier of LS clinical guidelines and risk prediction models are used. In this analysis the Amsterdam II criteria and Revised Bethesda guidelines are compared to the more …

Investigating The Roles Of Zinc-Binding Protein (Zbp-89) And Rela (Nfkb-P65) In The Regulation Of Matrix Metalloproteinase 1 (Mmp1) Gene Expression, Nelly Khaselev

PCOM Biomedical Studies Student Scholarship

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases with the unique ability to breakdown virtually the entire extracellular matrix (ECM). Through ECM remodeling, MMPs play an important role in normal development, tissue repair, angiogenesis, and apoptosis. Studies have shown that unregulated MMP expression plays a role in many cancers and chronic inflammatory diseases. Previous research has used gene sequence analysis ofthe MMP-1 promoter to identify a putative ZBP-89 binding site at -1969 bp. Chromatin immuneprecipitation experiments showed that both ZBP-89 and Re!A (p65) could bind to this binding site. In this thesis research, transfection experiments were used to explore …

Genetic Factors Related To The Incidence Of Type Ii Diabetes In Adults, Andrew Bader

Physician Assistant Scholarly Project Posters

As the seventh leading cause of death in the United States, diabetes affects 29.1 million people. In May, 2015 the U.S. CDC reported, the estimated total financial burden for diabetes in the United States at greater than $245 billion ($69 billion attributed to disability, lost days at work and premature death). The purpose of this study was to investigate genetic variances in parallel with type II diabetes. Through a five year prior search of Cochrane, Medline and Pubmed this review of the literature examined studies regarding type II diabetes related genetic variances specific to non-ethnic and ethnic populations of otherwise …

Investigating The Molecular Etiologies Of Sporadic Als (Sals) Using Rna-Sequencing, David G. Brohawn

Theses and Dissertations

ALS is an often lethal disease involving degeneration of motor neurons in the brain and spinal cord. Current treatments only extend life by several months, and novel therapies are needed. We combined RNA-Sequencing, systems biology analyses, and molecular biology assays to elucidate sporadic ALS group-specific differences in postmortem cervical spinal sections (7 sALS and 8 control samples) that may be relevant to disease pathology. >55 million 2X150 RNA-sequencing reads per sample were generated and processed.

In Chapter 2, we used bioinformatics tools to identify nuclear differentially expressed genes (DEGs) between our two groups. Further, we used Weighted Gene Co-Expression Network …

Lipidomic Risk Score Independently And Cost-Effectively Predicts Risk Of Future Type 2 Diabetes: Results From Diverse Cohorts, Manju Mamtani, Hemant Kulkarni, Gerard Wong, Jacquelyn M. Weir, Christopher K. Barlow, Thomas D. Dyer, Laura Almasy, Michael C. Mahaney, Anthony G. Comuzzie, David C. Glahn, Sarah Williams-Blangero, Ravindranath Duggirala, John Blangero, Joanne E. Curran

School of Medicine Publications

Background: Detection of type 2 diabetes (T2D) is routinely based on the presence of dysglycemia. Although disturbed lipid metabolism is a hallmark of T2D, the potential of plasma lipidomics as a biomarker of future T2D is unknown. Our objective was to develop and validate a plasma lipidomic risk score (LRS) as a biomarker of future type 2 diabetes and to evaluate its cost-effectiveness for T2D screening.

Methods: Plasma LRS, based on significantly associated lipid species from an array of 319 lipid species, was developed in a cohort of initially T2D-free individuals from the San Antonio Family Heart Study (SAFHS). The …

Il-15 Mediates Mitochondrial Activity Through A Ppar𝛿-Dependent-Ppar𝛼-Independent Mechanism In Skeletal Muscle Cells, Shantaé M. Thornton, James E. Krolopp, Marcia J. Abbott

Health Sciences and Kinesiology Faculty Articles

Molecular mediators of metabolic processes, to increase energy expenditure, have become a focus for therapies of obesity. The discovery of cytokines secreted from the skeletal muscle (SKM), termed “myokines,” has garnered attention due to their positive effects on metabolic processes. Interleukin-15 (IL-15) is a myokine that has numerous positive metabolic effects and is linked to the PPAR family of mitochondrial regulators. Here, we aimed to determine the importance of PPAR𝛼 and/or PPAR𝛿 as targets of IL-15 signaling. C2C12 SKM cells were differentiated for 6 days and treated every other day with IL-15 (100 ng/mL), a PPAR𝛼 inhibitor (GW-6471), a PPAR𝛿 …

Constellation: A Tool For Rapid, Automated Phenotype Assignment Of A Highly Polymorphic Pharmacogene,, Greyson P. Twist, Andrea Gaedigk, Neil A. Miller, Emily G. Farrow, Laurel K. Willig, Darrell L. Dinwiddie, Josh E. Petrikin, Sarah E. Soden, Suzanne Herd, Margaret Gibson, Julie A. Cakici, Amanda K. Riffel, J Steven Leeder, Deendayal Dinakarpandian, Stephen F. Kingsmore

Manuscripts, Articles, Book Chapters and Other Papers

An important component of precision medicine-the use of whole-genome sequencing (WGS) to guide lifelong healthcare-is electronic decision support to inform drug choice and dosing. To achieve this, automated identification of genetic variation in genes involved in drug absorption, distribution, metabolism, excretion and response (ADMER) is required. CYP2D6 is a major enzyme for drug bioactivation and elimination. CYP2D6 activity is predominantly governed by genetic variation; however, it is technically arduous to haplotype. Not only is the nucleotide sequence of CYP2D6 highly polymorphic, but the locus also features diverse structural variations, including gene deletion, duplication, multiplication events and rearrangements with the nonfunctional, …

Introduction To Bioethics Special Supplement V: Ethical Issues In Genomic Testing Of Children., John D. Lantos

Manuscripts, Articles, Book Chapters and Other Papers

Next-generation genome sequencing of children is one of the most promising and most challenging new technologies in pediatrics. On the one hand, it offers the hope that we will be able to diagnose rare conditions that were previously impossible to diagnose, which, in turn, might lead to new treatments. On the other hand, the technology for sequencing presents daunting problems of interpretation. It is problematic to conduct the research necessary to characterize the pathogenicity of those variants at the same time that we are using them to guide the clinical care of children who have complex medical problems. It is …

The Challenge Of Analyzing The Results Of Next-Generation Sequencing In Children., Isabelle Thiffault, John Lantos

Manuscripts, Articles, Book Chapters and Other Papers

In recent years, next-generation sequencing technologies have revolutionized approaches to genetic studies. Whole-exome or whole-genome sequencing allows diagnoses in many patients who have complex phenotypes and unusual clinical presentations. As genomic and exomic testing expands in both the research and clinical settings, pediatricians will need to understand the technology of next-generation sequencing and the complexity of interpreting genomic variants relevant to patient phenotypic features. This article briefly explains the technology by which genomes are sequenced and discusses some of the complexity related to interpreting genomic variants. We conclude with some thoughts on the clinical applications of such testing.

Whole-Genome Sequencing And Disability In The Nicu: Exploring Practical And Ethical Challenges., Michael J. Deem

Manuscripts, Articles, Book Chapters and Other Papers

Clinical whole-genome sequencing (WGS) promises to deliver faster diagnoses and lead to better management of care in the NICU. However,several disability rights advocates have expressed concern that clinical use of genetic technologies may reinforce and perpetuate stigmatization of and discrimination against disabled persons in medical and social contexts. There is growing need, then, for clinicians and bioethicists to consider how the clinical use of WGS in the newborn period might exacerbate such harms to persons with disabilities. This article explores ways to extend these concerns to clinical WGS in neonatal care. By considering these perspectives during the early phases of …

Genetic Variation In The Histamine Production, Response, And Degradation Pathway Is Associated With Histamine Pharmacodynamic Response In Children With Asthma., Bridgette Jones, Catherine M T Sherwin, Xiaoxi Liu, Hongying Dai, Carrie A. Vyhlidal

Manuscripts, Articles, Book Chapters and Other Papers

Introduction: There is growing knowledge of the wide ranging effects of histamine throughout the body therefore it is important to better understand the effects of this amine in patients with asthma. We aimed to explore the association between histamine pharmacodynamic (PD) response and genetic variation in the histamine pathway in children with asthma. Methods: Histamine Iontophoresis with Laser Doppler Monitoring (HILD) was performed in children with asthma and estimates for area under the effect curve (AUEC), maximal response over baseline (Emax), and time of Emax (Tmax) were calculated using non-compartmental analysis and non-linear mixed-effects model with a linked effect PK/PD …

Renal And Cardiovascular Morbidities Associated With Apol1 Status Among African-American And Non-African-American Children With Focal Segmental Glomerulosclerosis., Robert P. Woroniecki, Derek K. Ng, Sophie Limou, Cheryl A. Winkler, Kimberly J. Reidy, Mark Mitsnefes, Matthew G. Sampson, Craig S. Wong, Bradley A. Warady, Susan L. Furth, Jeffrey B. Kopp, Frederick J. Kaskel

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND AND OBJECTIVES: African-American (AA) children with focal segmental glomerulosclerosis (FSGS) have later onset disease that progresses more rapidly than in non-AA children. It is unclear how APOL1 genotypes contribute to kidney disease risk, progression, and cardiovascular morbidity in children.

DESIGN SETTING PARTICIPANTS AND MEASUREMENTS: We examined the prevalence of APOL1 genotypes and associated cardiovascular phenotypes among children with FSGS in the Chronic Kidney Disease in Children (CKiD) study; an ongoing multicenter prospective cohort study of children aged 1-16 years with mild to moderate kidney disease.

RESULTS: A total of 140 AA children in the CKiD study were genotyped. High …

Diagnostics Of Primary Immunodeficiencies Through Next-Generation Sequencing., Vera Gallo, Laura Dotta, Giuliana Giardino, Emilia Cirillo, Vassilios Lougaris, Roberta D'Assante, Alberto Prandini, Rita Consolini, Emily G. Farrow, Isabelle Thiffault, Carol J. Saunders, Antonio Leonardi, Alessandro Plebani, Raffaele Badolato, Claudio Pignata

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Recently, a growing number of novel genetic defects underlying primary immunodeficiencies (PIDs) have been identified, increasing the number of PID up to more than 250 well-defined forms. Next-generation sequencing (NGS) technologies and proper filtering strategies greatly contributed to this rapid evolution, providing the possibility to rapidly and simultaneously analyze large numbers of genes or the whole exome.

OBJECTIVE: To evaluate the role of targeted NGS and whole exome sequencing (WES) in the diagnosis of a case series, characterized by complex or atypical clinical features suggesting a PID, difficult to diagnose using the current diagnostic procedures.

METHODS: We retrospectively analyzed …

China Suboptimal Health Cohort Study: Rationale, Design And Baseline Characteristics, Youxin Wang, Siqi Ge, Yuxiang Yan, Anxin Wang, Zhongyao Zhao, Xinwei Yu, Jing Qui, Mohamed Ali Alzain, Hao Wang, Honghong Fang, Qing Gao, Manshu Song, Jie Zhang, Yong Zhou, Wei Wang

Research outputs 2014 to 2021

Background:

Suboptimal health status (SHS) is a physical state between health and disease, characterized by the perception of health complaints, general weakness, chronic fatigue and low energy levels. SHS is proposed by the ancient concept of traditional Chinese medicine (TCM) from the perspective of preservative, predictive and personalized (precision) medicine. We previously created the suboptimal health status questionnaire 25 (SHSQ-25), a novel instrument to measure SHS, validated in various populations. SHSQ-25 thus affords a window of opportunity for early detection and intervention, contributing to the reduction of chronic disease burdens.

Methods/design:

To investigate the causative effect of SHS in non-communicable …

Expression Of Cell-Surface Marker Abcb5 Causes Characteristic Modifications Of Glucose, Amino Acid And Phospholipid Metabolism In The G3361 Melanoma-Initiating Cell Line, Norbert W. Lutz, Pallavi Banerjee, Brian J. Watson, Jie Ma, Patrick J. Cozzone, Markus H. Frank

Research outputs 2014 to 2021

We present a pilot study aimed at determining the effects of expression of ATP-binding cassette member B5 (ABCB5), a previously described marker for melanoma-initiating cells, on cellular metabolism. Metabolic profiles for two groups of human G3361 melanoma cells were compared, i.e. wildtype melanoma cells with intact ABCB5 expression (ABCB5-WT) and corresponding melanoma cell variants with inhibited ABCB5 expression, through shRNA-mediated gene knockdown (ABCB5-KD). A comprehensive metabolomic analysis was performed by using proton and phosphorus NMR spectroscopy of cell extracts to examine water-soluble metabolites and lipids. Parametric and non-parametric statistical analysis of absolute and relative metabolite levels yielded significant differences for …