Genetic Phenomena Commons^™

Association Tests For Genetic Effect And Its Interaction With Environmental Factors, Zhengyang Zhou

Statistical Science Theses and Dissertations

My research is in the area of statistical genetics, and it contains three projects: (1) Differentiating the Cochran-Armitage (CA) trend test and Pearson’s chi-square test: location and dispersion; (2) Decomposing Pearson’s chi-square test: a linear regression and its departure from linearity; (3) Testing nonlinear gene-environment (GxE) interaction through varying coefficient and linear mixed models.

(1) In genetic case-control association studies, a standard practice is to perform the CA trend test with 1 degree-of-freedom (df) under the assumption of an additive model. However, when the true genetic model is recessive or near recessive, it is outperformed by Pearson’s chi-square test with …

Genes Associated With Mandibular Prognathism In The Chinese Population, Jacqueline Payne, Marie Tolarova M.D., Ph.D., D.Sc.

Excellence Day

Mandibular prognathism (MP) is the relationship of the mandible anteriorly positioned in relation to the cranial base. The prevalence of MP in Asians is estimated to be 15%, whereas American and European descent exhibit a 5% prevalence. Orthodontic treatment is lengthy and challenging, and severe cases require surgical intervention. However, when a treatment is planned well, the outcomes are predominantly successful. It has been known that genetics are involved in the etiology of prognathism and that greater genetic contribution corresponds to greater challenges to treatment. Thus, there is a desire to determine genes involved in the etiology of prognathism.

Variant Intestinal-Cell Kinase In Juvenile Myoclonic Epilepsy, J. N. Bailey, L. De Nijs, D. Bai, T. Suzuki, H. Miyamoto, M. Tanaka, C. Patterson, Y.-C. Lin, M. T. Medina, M. E. Alonso, J. M. Serratosa, R. M. Durón, Viet-Hong Nguyen, J. E. Wight, I. E. Martínez‑Juárez, A. Ochoa, A. Jara-Prado, L. Guilhoto, Y. Molina, E. M. Yacubian, M. López‑Ruiz, Y. Inoue, S. Kaneko, S. Hirose, M. Osawa, H. Oguni, S. Fujimoto, T. M. Grisar, J. M. Stern, K. Yamakawa, B. Lakaye, A. V. Delgado-Escueta

Pharmacy Faculty Articles and Research

BACKGROUND

In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis.

METHODS

Using Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase (ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds …

Integrating Genetic Counseling And Testing In The Pediatric Oncology Setting: Parental Attitudes And Influencing Factors, Lauren Renee Desrosiers

Theses and Dissertations

Cancer predisposition syndromes (CPS), caused by germline pathogenic variants in tumor suppressor genes and oncogenes, are genetic conditions that put an individual at increased risk to develop cancer. It is estimated that 10-15% of children with cancer have an underlying CPS. Although genetic testing for these conditions has become routine in the adult setting, incorporation of germline genomic technologies into pediatric cancer care has not occurred as rapidly. The purpose of this study is to assess desire for genetic counseling and testing services among parents of children with cancer to provide parental insight in the incorporation of genomic technologies in …

Clinical Relevance Of Μ-Opioid Receptor A118g Polymorphism In Demographically Variant Populations, Iryna Pokotylyuk, Srishti Kulshrestha, Zvi G. Loewy, Priyank Kumar

Touro College of Pharmacy (New York) Publications and Research

Use of opioids is essential in providing a broad and effective analgesic effect. Opioid dosing has to be monitored and controlled in order to manage pain and the corresponding side effects due to opioid treatment. A very common single nucleotide polymorphism (SNP) associated with the µ opioid receptor is A118G. A118G, located on exon 1 of the µ-opioid receptor gene (OPRM1), may alter how patients respond to opioid treatment. This polymorphism results in an exchange of adenine for guanine, which in turn leads to substitution of asparagine for the aspartic acid. In order to understand how individuals with the G …

Family Planning Decisions After A Child’S Diagnosis Of Rett Syndrome: A Pilot Study, Erin E. Huggins

Theses and Dissertations

Rett syndrome (RTT) is a rare neurodevelopmental disorder that primarily affects females. In 99% of cases, RTT is believed to occur sporadically, or de novo. However, in rare cases, RTT can be passed down from parent to child through gonadal mosaicism or asymptomatic carrier mothers. It is known that having a child with an inherited genetic condition can lead to changes in family planning; however, little research has investigated this phenomenon in sporadic genetic conditions, such as RTT. This present study used a questionnaire to assess family planning decisions of parents of children with RTT. Forty-three percent of respondents reported …

Optimisation Of Ion Exchange Chromatography Purification Protocols For A Staphylococcal Peptidoglycan Degrading Hydrolase Enzyme, Fiona Maher

Theses

Bacteriophage (phage) are the most abundant biological entities on earth and were first discovered by d’Herelle in 1917. They are found wherever their hosts live and, like all viruses they do not have the ability to make their own protein. Therefore, in order to reproduce, phage must invade and infect bacterial cells. This project focused on the optimisation of Ion Exchange Chromatography purification protocols for a staphylococcal peptidoglycan degrading hydrolase enzyme (CHAPk). The project objective was to obtain the greatest yield of enzyme from the growth of the E.coU XL 1-Blue expression system into which the vector pQE60 was previously …

Design And Evaluation Of Gemini Surfactant-Based Lipoplexes Modified With Cell-Binding Peptide For Targeted Gene Therapy, Waleed Mohammed-Saeid, Rania Soudy, Richa Tikoo, Kamaljit Kaur, Ronald E. Verrall, Ildiko Badea

Pharmacy Faculty Articles and Research

Purpose Achieving successful gene therapy requires delivery of a gene vector specifically to the targeted tissue with efficient expression and a good safety profile. The objective of this work was to develop, characterize and determine if a novel gemini surfactant-based lipoplex systems, modified with a cancer-targeting peptide p18-4, could serve this role. Methods The targeting peptide p18-4 was either chemically coupled to a gemini surfactant backbone or physically co-formulated with the lipoplexes. The influence of targeting ligand and formulation strategies on essential physicochemical properties of the lipoplexes was evaluated by dynamic light scattering and small angle X-ray scattering techniques. In …

Understanding Barriers To Genetic Testing For Sickle Cell Trait: The African-American Male Perspective, Shandrea Foster

Theses and Dissertations

Research has shown a reluctance in African-American males to pursue testing for sickle cell trait. Few studies have tried to discern what barriers are contributing to this issue within the African-American male community. Research suggests a lack of knowledge may be the biggest contributing factor. This study hypothesized there would be a significant difference in knowledge of sickle cell trait based on educational level, age, and health beliefs. African-America male participants (N=116), ages 18 and over, completed a questionnaire assessing knowledge, risk perception, health beliefs, barriers, and motivating factors within the context of sickle cell trait. One-way and two-way analysis …

A Polygenic Risk Score Derived From Episodic Memory Weighted Genetic Variants Is Associated With Cognitive Decline In Preclinical Alzheimer’S Disease, Tenielle Porter, Samantha C. Burnham, Greg Savage, Yen Ying Lim, Paul Maruff, Lidija Milicic, Madeline Peretti, David Ames, Colin L. Masters, Ralph N. Martins, Stephanie Rainey-Smith, Christopher C. Rowe, Olivier Salvado, Kevin Taddei, David Groth, Guiseppe Verdile, Victor L. Villemagne, Simon M. Laws

Research outputs 2014 to 2021

Studies of Alzheimer’s disease risk-weighted polygenic risk scores (PRSs) for cognitive performance have reported inconsistent associations. This inconsistency is particularly evident when PRSs are assessed independent of APOE genotype. As such, the development and assessment of phenotype-specific weightings to derive PRSs for cognitive decline in preclinical AD is warranted. To this end a episodic memory-weighted PRS (emPRS) was derived and assessed against decline in cognitive performance in 226 healthy cognitively normal older adults with high brain Aβ-amyloid burden participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The effect size for decline in a verbal episodic memory …

Revealing A Non-Canonical Role Of Anti-Apoptotic Mcl-1 In Early Embryonic Development, Xue Yang

Theses and Dissertations (ETD)

MCL-1, a well-known pro-survival BCL-2 family member, is indispensable for the survival of various cellular lineages and is also among the most frequently amplified genes in a variety of human malignancies. Gene ablation studies previously revealed that Mcl-1 deficiency leads to embryonic lethality around E3.5 during peri-implantation stage. Strikingly, the study did not detect any increase in apoptotic cells of the blastocyst, indicating a function of MCL-1 beyond regulating apoptosis. Our previous studies revealed an unrecognized role of MCL-1 in promoting mitochondrial physiology, which is independent of its classical anti-apoptotic function and requires being imported into the mitochondrial matrix. In …

Caenorhabditis Elegans Dbl-1/Bmp Regulates Lipid Accumulation Via Interaction With Insulin Signaling, James F. Clark, Michael Meade, Gehan Ranepura, David H. Hall, Cathy Savage-Dunn

Publications and Research

Metabolic homeostasis is coordinately controlled by diverse inputs. Understanding these regulatory networks is vital to combating metabolic disorders. The nematode Caenorhabditis elegans has emerged as a powerful, genetically tractable model system for the discovery of lipid regulatory mechanisms. Here we introduce DBL-1, the C. elegans homolog of bone morphogenetic protein 2/4 (BMP2/4), as a significant regulator of lipid homeostasis. We used neutral lipid staining and a lipid droplet marker to demonstrate that both increases and decreases in DBL-1/BMP signaling result in reduced lipid stores and lipid droplet count. We find that lipid droplet size, however, correlates positively with the level …

Dnmt3a Haploinsufficiency Provokes Hematologic Malignancy Of B-Lymphoid, T-Lymphoid, And Myeloid Lineage In Mice, Garland Michael Upchurch

Theses & Dissertations

DNA methyltransferase 3A (DNMT3A) is a master epigenetic regulator of benign and malignant hematopoiesis. To dissect the biological consequences of homozygous and heterozygous Dnmt3a inactivation in malignant hematopoiesis, we generated Dnmt3a homozygous null (Dnmt3a^Δ/Δ) and Dnmt3a heterozygous (Dnmt3a^+/–) mice and compared the presentations of hematologic malignancies between cohorts. Bi-allelic inactivation of Dnmt3a results in the presentation of mature lymphoid neoplasms resembling chronic lymphocytic leukemia (CLL; B220⁺CD19⁺CD5⁺; 88% penetrance (37/42)) and CD8+ peripheral T-cell lymphoma (PTCL; TCRβ⁺CD3⁺CD8⁺CD4^—; 40% penetrance (17/42)). …

Aging With The Fmr1 Gene: A Life Course Perspective, Cornelia Lieb-Lundell

Physical Therapy Collection

Fragile X syndrome (FXS) is one of three syndromes identified as a health condition related to fragile X mental retardation (FMR1) gene dysfunction. The other two conditions are Fragile X-associated primary ovarian insufficiency syndrome (FXPOI) and Fragile X-associated tremor/ataxia syndrome (FXTAS) which together are referred to as Fragile X-associated disorders (FXD). Even though the three conditions share a common genetic defect each one is a separate health condition that results in a variety of body function impairments such as motor delay, musculoskeletal issues related to low muscle tone, coordination limitations, ataxia, tremor, undefined muscle aches and pains; and, …

Three Faces Of Fragile X Syndrome, Cornelia Lieb-Lundell

Physical Therapy Collection

Fragile X Syndrome (FXS) is well known and widely recognized in pediatrics. Less well known is that FXS, as an X-linked disorder of the FMR1 gene, is but one of three impairments that all have a common single-gene genetic basis. These three are labeled Fragile X-associated Disorders (FXD) and are, in turn, a part of a large group of impairments which have a collective name of trinucleotide repeat expansion disorders. Common to all three FXD disorders is that the x-gene carries a characteristic CGG expansion (of the DNA) that can range from 50-+200 (5-45 is normal) with premutation carriers having …

Anxiety Associated Increased Cpg Methylation In The Promoter Of Asb1: A Translational Approach Evidenced By Epidemiological And Clinical Studies And A Murine Model, Rebecca T. Emeny, Jens Baumert, Anthony S. Zannas, Sonja Kunze, Simone Wahl, Stella Iurato

Dartmouth Scholarship

Epigenetic regulation in anxiety is suggested, but evidence from large studies is needed. We conducted an epigenome-wide association study (EWAS) on anxiety in a population-based cohort and validated our finding in a clinical cohort as well as a murine model. In the KORA cohort, participants (n= 1522, age 32–72 years) were administered the Generalized Anxiety Disorder (GAD-7) instrument, whole blood DNA methylation was measured (Illumina 450K BeadChip), and circulating levels of hs-CRP and IL-18 were assessed in the association between anxiety and methylation. DNA methylation was measured using the same instrument in a study of patients with anxiety disorders recruited …

Activity Of Distinct Growth Factor Receptor Network Components In Breast Tumors Uncovers Two Biologically Relevant Subtypes, Moom Roosan, Shelley M. Macneil, David F. Jenkins, Gajendra Shrestha, Sydney R. Wyatt, Jasmine A. Mcquerry, Stephen R. Piccolo, Laura M. Heiser, Joe W. Gray, W. Evan Johnson, Andrea H. Bild

Pharmacy Faculty Articles and Research

Background
The growth factor receptor network (GFRN) plays a significant role in driving key oncogenic processes. However, assessment of global GFRN activity is challenging due to complex crosstalk among GFRN components, or pathways, and the inability to study complex signaling networks in patient tumors. Here, pathway-specific genomic signatures were used to interrogate GFRN activity in breast tumors and the consequent phenotypic impact of GRFN activity patterns.

Methods
Novel pathway signatures were generated in human primary mammary epithelial cells by overexpressing key genes from GFRN pathways (HER2, IGF1R, AKT1, EGFR, KRAS (G12V), RAF1, BAD). The pathway analysis toolkit Adaptive Signature Selection …

A Review Of Ankylosing Spondylitis, Hannah L. Owen

Senior Honors Theses

Ankylosing spondylitis (AS) is a systemic autoimmune disorder that induces ankylosis of the spine (fusion of the vertebrae at their various joints) and inflammatory arthritis of peripheral joints among other symptoms. Overexpression of cytokines, the presence of genetic mutations not exclusive to the human leucocyte antigen (HLA)-B27 region, and environmental factors all have large roles in the progressive development of AS. Although a definitive pathology continues to be sought after, researchers believe the adaptive immune system in AS patients attacks fibrocartilaginous entheses (supportive connective tissue between bone and attached structures like tendon, ligament, and fascia).

AS markedly reduces proper systemic …

P33. Design And Evaluation Of An Escherichia Coli Biomarker For Indication Of Ph, Kevin X. Zhou, Luana Langlois, Ashmita Singh, John Prince

Western Research Forum

Measuring pH is one of the most commonly used techniques in both the laboratory as well as the field due to its importance in a multitude of biochemical processes. Traditional methods of measuring pH may be highly developed in accuracy and precision but often involve disruption of the environment. Biological markers offer an alternative that allows for long-term pH monitoring. This innovative approach allows for vast applications such as in the manufacturing, food processing and research industries. Under moderate acidic conditions, the asr (acid shock RNA) gene is highly inducible and has been demonstrated to be crucial for growth at …

Age-Dependent Absolute Abundance Of Hepatic Carboxylesterases (Ces1 And Ces2) By Lc-Ms/Ms Proteomics: Application To Pbpk Modeling Of Oseltamivir In Vivo Pharmacokinetics In Infants., Mikael Boberg, Marc Vrana, Aanchal Mehrotra, Robin E. Pearce, Andrea Gaedigk, Deepak Kumar Bhatt, J Steven Leeder, Bhagwat Prasad

Manuscripts, Articles, Book Chapters and Other Papers

The age-dependent absolute protein abundance of carboxylesterase (CES) 1 and CES2 in human liver was investigated and applied to predict infant pharmacokinetics (PK) of oseltamivir. The CES absolute protein abundance was determined by liquid chromatography-tandem mass spectrometry proteomics in human liver microsomal and cytosolic fractions prepared from tissue samples obtained from 136 pediatric donors and 35 adult donors. Two surrogate peptides per protein were selected for the quantification of CES1 and CES2 protein abundance. Purified CES1 and CES2 protein standards were used as calibrators, and the heavy labeled peptides were used as the internal standards. In hepatic microsomes, CES1 and …