Browsing by Subject "Genetic Predisposition to Disease"
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Item Analysis of Coding Region SNPs and Its Propensity to Cause Disease(2007-12-17) Kulkarni, Vinayak Vaman; Garner, Harold R.Single Nucleotide Polymorphisms or (SNPs) are the most abundant form of variation present in the human genome. These variations in individuals are considered to be the cause of diseases, difference in response to treatment, susceptibility to diseases or may have no impact. Association studies aim at correlating an observed disease or a phenotype with these sequence variations. However very few of these SNPs are actually characterized according to the disease or phenotype they are implicated in. Currently, it is not possible to test and validate each and every SNP in the coding region of the human genome. Hence, the real challenge in association studies lies in carefully selecting reliable marker alleles which are most likely responsible for the observed phenotype or disease. This thesis addresses this problem by providing for each and every nucleotide in the human genome with a probabilistic value of it being involved in a disease or an important phenotype. Our hypothesis hinges on the fact that evolutionary conserved nucleotides are most important for gene function and hence would cause a disease if altered than non conserved nucleotides. By calculating the conservation of each base in all human Refseq exons and correlating the results with all SNPs in the Human Gene Mutation Database, a database of known disease causing SNPs and Database of Single Nucleotide Polymorphisms, we have exhaustively confirmed that the most conserved bases are indeed most sensitive to variation. Other factors known to be responsible for causing disease like alleles were also investigated. All the factors that were found to be responsible for disease alleles were chosen for the design of a classifier, which subsequently assigned a disease probability score to each coding base, based on these factors. This probability score represented the potential sensitivity to variation of each base. This will aid researchers rank SNPs and select candidate SNPs from a cohort for SNP-disease association studies. Identification of SNPs with disease-like signatures in SNP databases could provide researchers and clinicians with valuable information to aid them in the design and interpretation of epidemiological and genetic studies especially for those databases devoid of such annotation.Item Does a Positive Family History of Glaucoma Foretell Severity?(2014-02-04) Vu, Khiem; Markel, Nathan; Parikh, Kisan; Adams-Huet, Beverley; Li, Xilong; Kooner, KaranjitPURPOSE/RELEVANCE: There is a threefold increase in the risk of primary open-angle glaucoma (POAG) in individuals with positive family history. We wished to see if the family history also led to a more severe form of the disease. METHODS: In an IRB-approved retrospective chart study at a university-affiliated medical center, data was collected from 224 patients diagnosed with glaucoma. Positive family history was defined by first, second, or third degree relatives affected (FHx-pos). Patients with negative family history were referred to as controls. Patients with unknown family history were excluded. Age, gender, race, BMI, cup/disk ratio (C/D), visual field defects, intraocular pressure (IOP), central corneal thickness (CCT), and current glaucoma medications were recorded. FHx-pos and control groups were compared using Fisher's Exact and Wilcoxon Rank sum tests for categorical and continuous variables, respectively. RESULTS: Among patients with glaucoma, there were 82, 120, and 22 patients with positive, negative, and unknown family history, respectively. The FHx-pos group was 47.6% white, 39% black, and 13.4% Hispanic, while the control group was 40.8% white, 40.8% black, and 18.4% Hispanic; no clinically significant differences were noted. Both groups were similar in age (63.3±14.8 vs. 64.9±11.8 years, p=0.5) and CCT (539 vs. 540 μm, p=0.8). The FHx-pos group was predominantly female (70.7% vs. 45%, p<0.001), had elevated IOPs (16.9±4.0 vs. 15.7±4.2 mm Hg, p=0.040), and were prescribed more glaucoma medications (98.9 vs. 92.5%, p=0.05). The mean C/D for both groups was approximately 0.73 (p=0.86) with the FHx-pos group having slightly more optic cupping (29.6 vs. 26.1% of patients, defined as C/D > 0.9; p=0.6). DISCUSSION: The results suggest that glaucoma patients with affected relatives tend to be female. Sex-specific genetic factors or expression may contribute to disease progression, but a full mechanism has yet to be completely delineated. The FHx-pos group also had higher IOP, required more medications, and experienced slightly more optic nerve cupping, all of which indicate a more severe form of the disease. CONCLUSION: The results of this study corroborate the importance of taking a family history of glaucoma. This is especially important for females, for whom aggressive treatment may be necessary. The gender finding merits further study into the possible heritability of predisposing factors in the pathogenesis of POAG in female populations. REFERENCES: Fingert JH. Primary open-angle glaucoma genes. Eye. 2011; 25, 587-595Item Familial hypercholesterolemia: improving detection and management(2017-11-03) Khera, AmitItem The family ties of hereditary myeloid malignancy syndromes(2018-06-08) Patel, PraptiItem Genomic medicine in internal medicine practice(2023-03-24) Gharavi, Ali G.Item A Mutation in Alk6b Causes Impaired Germ Cell Differentation and Testicular Germ Cell Tumors in Zebrafish(2010-11-02) Neumann, Joanie; Amatruda, James F.Germ cell tumors (GCTs) affect infants, children and young adults and are increasing in incidence worldwide. GCTs arise from pluripotent germ cells and can exhibit differentiated and undifferentiated histologies, which vary in their malignant potential and response to treatment. The pathways that determine tumor cell differentiation are not known, impeding the development of new therapies. Thus, the treatment of GCTs has remained static since the introduction 30 years ago of cisplatin which, while effective, causes severe side effects including hearing loss, infertility and kidney damage. We identified a zebrafish mutant line with a high incidence of GCT during a forward genetic screen to identify cancer susceptibility loci. Homozygous adult males develop tumors consisting of undifferentiated spermatogonia by 4 months of age while heterozygous males develop tumors around 7 to 9 months of age. We used interval haplotype analysis and high-resolution recombinational mapping to localize the mutation to a 0.82 cM interval on zebrafish chromosome 10. We identified a premature termination codon in Alk6b (Activin Receptor-like Kinase 6b) in the mutant animals. Alk6b is a member of the TGF-beta/BMP superfamily of receptors. BMP signaling has diverse roles including regulation of cell proliferation, differentiation, embryonic development, germ cell specification and gonadogenesis. Misregulation of the BMP signaling pathway has been implicated in various human cancers. In agreement with a critical role for Alk6b in controlling germ cell differentiation, we find evidence of impaired BMP signal transduction in the zebrafish GCTs, as well as evidence of alterations in the expression level of BMP target genes. We have also examined BMP signaling in a series of 40 clinically-annotated human GCTs of diverse histologic subtypes. In agreement with the predictions made from our zebrafish model, we find that undifferentiated GCTs such as dysgerminomas lack BMP signaling activity, whereas signaling is maintained in the differentiated subtype of Yolk Sac Tumors. These results confirm the relevance of the zebrafish model for understanding germ cell tumorigenesis, and will foster the development of improved, targeted therapy of human GCTs.Item Nature, nurture, and nonalcoholic fatty liver disease(2014-05-16) Cohen, Jonathan C.Item Neural Mechanisms and Behaviors in Models of Conditional Nprl2 Loss(2020-08-01T05:00:00.000Z) Dentel, Brianne Marie; Johnson, Jane E.; Tu, Benjamin; Pascual, Juan M.; Tsai, PeterThe amino acid sensitive arm of mTORC1 regulation signals through the GATOR1 complex. Loss of function of GATOR1 contributes to several neurodevelopmental disorders and medically refractive epilepsy. Mutations to one of the essential subunits of GATOR1, NPRL2, are sufficient to cause focal epilepsy and schizophrenia; yet, little is known about its role in the nervous system. Here we demonstrate the loss of Nprl2 in excitatory cells in the neocortex and hippocampus is sufficient to cause mTOR-related pathology, decreased survival and spontaneous seizures. By inhibiting mTOR activity with rapamycin we were able to rescue brain size, seizures and survival. We also show that loss of Nprl2 results in a down-regulation of synaptic proteins, and several metabolic disruptions. Furthermore, we demonstrated that the significantly increased glycine was a primary mechanism which increased synaptic excitability. This suggests that targeting the glycine binding site on the NMDA receptor may be a targeted therapy for future study. We also demonstrated, in three different cell-specific conditional knockout models, distinct behavioral profiles which points to the importance of Nprl2 in various neurodevelopmental disorders. These findings demonstrate the multifaceted effects of Nprl2 loss in excitatory cells- which demonstrate seizures and early mortality; excitatory and inhibitory neurons- which had seizures, hyperactivity, social and learning deficits; inhibitory cells- which demonstrated severe hyperactivity, social and learning deficits; and Purkinje cell-specific loss- which had seizure susceptibility, reversal learning deficits and delayed-onset social deficits and altered PPI. These findings highlight the significant role NPRL2 has in the nervous system and future studies in these models will aid in understanding and potentially developing targeted therapies to address the molecular and cellular mechanisms underlying NDDs and seizures in NPRL2 loss.Item Pancreatitis and pancreatic cancer: genetics and clinical applications(2021-11-12) Rustgi, Anil K.Item [UT News](1986-04-15) Bosler, Tommy Joy