Browsing by Subject "Case-Control Studies"
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Item A nonparametric alternative to the Cochran-Armitage trend test in genetic case-control association studies: The Jonckheere-Terpstra trend test(PLOS, 2023-02-03) Manning, Sydney E.; Ku, Hung-Chih; Dluzen, Douglas F.; Xing, Chao; Zhou, ZhengyangIdentifications of novel genetic signals conferring susceptibility to human complex diseases is pivotal to the disease diagnosis, prevention, and treatment. Genetic association study is a powerful tool to discover candidate genetic signals that contribute to diseases, through statistical tests for correlation between the disease status and genetic variations in study samples. In such studies with a case-control design, a standard practice is to perform the Cochran-Armitage (CA) trend test under an additive genetic model, which suffers from power loss when the model assumption is wrong. The Jonckheere-Terpstra (JT) trend test is an alternative method to evaluate association in a nonparametric way. This study compares the power of the JT trend test and the CA trend test in various scenarios, including different sample sizes (200-2000), minor allele frequencies (0.05-0.4), and underlying modes of inheritance (dominant genetic model to recessive genetic model). By simulation and real data analysis, it is shown that in general the JT trend test has higher, similar, and lower power than the CA trend test when the underlying mode of inheritance is dominant, additive, and recessive, respectively; when the sample size is small and the minor allele frequency is low, the JT trend test outperforms the CA trend test across the spectrum of genetic models. In sum, the JT trend test is a valuable alternative to the CA trend test under certain circumstances with higher statistical power, which could lead to better detection of genetic signals to human diseases and finer dissection of their genetic architecture.Item Arginine Supplementation Promotes Extracellular Matrix and Metabolic Changes in Keratoconus(MDPI, 2021-08-13) McKay, Tina B.; Priyadarsini, Shrestha; Rowsey, Tyler; Karamichos, DimitriosKeratoconus (KC) is a common corneal ectatic disease that affects 1:500-1:2000 people worldwide and is associated with a progressive thinning of the corneal stroma that may lead to severe astigmatism and visual deficits. Riboflavin-mediated collagen crosslinking currently remains the only approved treatment to halt progressive corneal thinning associated with KC by improving the biomechanical properties of the stroma. Treatments designed to increase collagen deposition by resident corneal stromal keratocytes remain elusive. In this study, we evaluated the effects of arginine supplementation on steady-state levels of arginine and arginine-related metabolites (e.g., ornithine, proline, hydroxyproline, spermidine, and putrescine) and collagen protein expression by primary human corneal fibroblasts isolated from KC and non-KC (healthy) corneas and cultured in an established 3D in vitro model. We identified lower cytoplasmic arginine and spermidine levels in KC-derived constructs compared to healthy controls, which corresponded with overall higher gene expression of arginase. Arginine supplementation led to a robust increase in cytoplasmic arginine, ornithine, and spermidine levels in controls only and a significant increase in collagen type I secretion in KC-derived constructs. Further studies evaluating safety and efficacy of arginine supplementation are required to elucidate the potential therapeutic applications of modulating collagen deposition in the context of KC.Item Mirna Expression in Glaucomatous and TGFbeta2 Treated Lamina Cribrosa Cells(MDPI, 2021-06-08) Lopez, Navita N.; Rangan, Rajiv; Clark, Abbot F.; Tovar-Vidales, TaraGlaucoma is a group of optic neuropathies that leads to irreversible vision loss. The optic nerve head (ONH) is the site of initial optic nerve damage in glaucoma. ONH-derived lamina cribrosa (LC) cells synthesize extracellular matrix (ECM) proteins; however, these cells are adversely affected in glaucoma and cause detrimental changes to the ONH. LC cells respond to mechanical strain by increasing the profibrotic cytokine transforming growth factor-beta 2 (TGFbeta2) and ECM proteins. Moreover, microRNAs (miRNAs or miR) regulate ECM gene expression in different fibrotic diseases, including glaucoma. A delicate homeostatic balance between profibrotic and anti-fibrotic miRNAs may contribute to the remodeling of ONH. This study aimed to determine whether modulation of miRNAs alters the expression of ECM in human LC cells. Primary human normal and glaucoma LC cells were grown to confluency and treated with or without TGFbeta2 for 24 h. Differences in expression of miRNAs were analyzed using miRNA qPCR arrays. miRNA PCR arrays showed that the miR-29 family was significantly decreased in glaucomatous LC cell strains compared to age-matched controls. TGFbeta2 treatment downregulated the expression of multiple miRNAs, including miR-29c-3p, compared to controls in LC cells. LC cells transfected with miR-29c-3p mimics or inhibitors modulated collagen expression.Item Mitochondrial tRNA methylation in Alzheimer's disease and progressive supranuclear palsy(BioMed Central Ltd., 2020-05-19) Silzer, Talisa K.; Pathak, Gita A.; Phillips, Nicole R.BACKGROUND: Methylation of mitochondrial tRNAs (mt-tRNA) at the 9th position ("p9 site") is known to impact translational efficiency and downstream mitochondrial function; however, direct assessment of mt-RNA methylation is challenging. Recent RNA sequence-based methods have been developed to reliably identify post-transcriptional methylation. Though p9 methylation has been studied in healthy human populations and in the context of cancer, it has not yet been analyzed in neurodegenerative disease, where mitochondrial dysfunction is a prominent and early hallmark of disease progression. METHODS: Mitochondrial p9 methylation was inferred from multi-allelic calls in RNA-seq data. Gene-based association studies were performed in FUMA. Correlations between nuclear gene expression and p9 methylation were tested using Spearman's rho. Fisher's Exact test was used in PANTHER and IPA to test for overrepresentation and enrichment of biological processes and pathways in the top nuclear genes correlated with p9 methylation. RESULTS: Variable methylation was observed at 11 p9 sites in post-mortem cerebellar tissue of elderly subjects who were either healthy or diagnosed with Alzheimer's disease (AD), progressive supranuclear palsy (PSP) or pathological aging (PA). Similarities in degree of methylation were observed between AD and PSP. Certain nuclear encoded genes were identified as significantly associated with p9 methylation. Expression of 5300 nuclear encoded genes was significantly correlated with p9 methylation, with AD and PSP subjects exhibiting similar expression profiles. Overrepresentation and enrichment testing using the top transcripts revealed enrichment for a number of molecular processes, terms and pathways including many of which that were mitochondrial-related. CONCLUSION: With mitochondrial dysfunction being an established hallmark of neurodegenerative disease pathophysiology, this work sheds light on the potential molecular underpinnings of this dysfunction. Here we show overlap in cerebellar pathophysiology between common tauopathies such as Alzheimer's disease and progressive supranuclear palsy. Whether p9 hypermethylation is a cause or consequence of pathology remains an area of focus.