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Search Results: 1 - 10 of 403815 matches for " Julie M. Cunningham "
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Evaluation of Clustering and Genotype Distribution for Replication in Genome Wide Association Studies: The Age-Related Eye Disease Study
Albert O. Edwards, Brooke L. Fridley, Katherine M. James, Anil S. Sharma, Julie M. Cunningham, Nirubol Tosakulwong
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003813
Abstract: Genome-wide association studies (GWASs) assess correlation between traits and DNA sequence variation using large numbers of genetic variants such as single nucleotide polymorphisms (SNPs) distributed across the genome. A GWAS produces many trait-SNP associations with low p-values, but few are replicated in subsequent studies. We sought to determine if characteristics of the genomic loci associated with a trait could be used to identify initial associations with a higher chance of replication in a second cohort. Data from the age-related eye disease study (AREDS) of 100,000 SNPs on 395 subjects with and 198 without age-related macular degeneration (AMD) were employed. Loci highly associated with AMD were characterized based on the distribution of genotypes, level of significance, and clustering of adjacent SNPs also associated with AMD suggesting linkage disequilibrium or multiple effects. Forty nine loci were highly associated with AMD, including 3 loci (CFH, C2/BF, LOC387715/HTRA1) already known to contain important genetic risks for AMD. One additional locus (C3) reported during the course of this study was identified and replicated in an additional study group. Tag-SNPs and haplotypes for each locus were evaluated for association with AMD in additional cohorts to account for population differences between discovery and replication subjects, but no additional clearly significant associations were identified. Relying on a significant genotype tests using a log-additive model would have excluded 57% of the non-replicated and none of the replicated loci, while use of other SNP features and clustering might have missed true associations.
Regular Multivitamin Supplement Use, Single Nucleotide Polymorphisms in ATIC, SHMT2, and SLC46A1, and Risk of Ovarian Carcinoma
Linda E. Kelemen,Qinggang Wang,Robert A. Vierkant,Julie M. Cunningham,Ernest K. Amankwah,Thomas A. Sellers
Frontiers in Genetics , 2012, DOI: 10.3389/fgene.2012.00033
Abstract: ATIC, SHMT2, and SLC46A1 have essential roles in one-carbon (1-C) transfer. The authors examined whether associations between ovarian carcinoma and 15 variants in these genes are modified by regular multivitamin use, a source of 1-C donors, among Caucasian participants from two US case–control studies. Using a phased study design, variant-by-multivitamin interactions were tested, and associations between variants and ovarian carcinoma were reported stratified by multivitamin supplement use. Per-allele risk associations were modified by multivitamin use at six variants among 655 cases and 920 controls (Phase 1). In a larger sample of 968 cases and 1,265 controls (Phases 1 and 2), interactions were significant (P ≤ 0.03) for two variants, particularly among regular multivitamin users: ATIC rs7586969 [odds ratio (OR) = 0.7, 95% confidence interval (CI) = 0.6–0.9] and ATIC rs16853834 (OR = 1.5, 95% CI = 1.1–2.0). The two ATIC single nucleotide polymorphisms (SNPs) did not share the same haplotype; however, the haplotypes they comprised mirrored their SNP risk associations among regular multivitamin supplement users. A multi-variant analysis was also performed by comparing the observed likelihood ratio test statistic from adjusted models with and without the two ATIC variant-by-multivitamin interaction terms with a null distribution of test statistics generated by permuting case status 10,000 times. The corresponding observed P value of 0.001 was more extreme than the permutation-derived P value of 0.009, suggesting rejection of the null hypothesis of no association. In summary, there is little statistical evidence that the 15 variants are independently associated with risk of ovarian carcinoma. However, the statistical interaction of ATIC variants with regular multivitamin intake, when evaluated at both the SNP and gene level, may support these findings as relevant to ovarian health and disease processes.
miRNA Expression in Colon Polyps Provides Evidence for a Multihit Model of Colon Cancer
Ann L. Oberg,Amy J. French,Aaron L. Sarver,Subbaya Subramanian,Bruce W. Morlan,Shaun M. Riska,Pedro M. Borralho,Julie M. Cunningham,Lisa A. Boardman,Liang Wang,Thomas C. Smyrk,Yan Asmann,Clifford J. Steer,Stephen N. Thibodeau
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020465
Abstract: Changes in miRNA expression are a common feature in colon cancer. Those changes occurring in the transition from normal to adenoma and from adenoma to carcinoma, however, have not been well defined. Additionally, miRNA changes among tumor subgroups of colon cancer have also not been adequately evaluated. In this study, we examined the global miRNA expression in 315 samples that included 52 normal colonic mucosa, 41 tubulovillous adenomas, 158 adenocarcinomas with proficient DNA mismatch repair (pMMR) selected for stage and age of onset, and 64 adenocarcinomas with defective DNA mismatch repair (dMMR) selected for sporadic (n = 53) and inherited colon cancer (n = 11). Sporadic dMMR tumors all had MLH1 inactivation due to promoter hypermethylation. Unsupervised PCA and cluster analysis demonstrated that normal colon tissue, adenomas, pMMR carcinomas and dMMR carcinomas were all clearly discernable. The majority of miRNAs that were differentially expressed between normal and polyp were also differentially expressed with a similar magnitude in the comparison of normal to both the pMMR and dMMR tumor groups, suggesting a stepwise progression for transformation from normal colon to carcinoma. Among the miRNAs demonstrating the largest fold up- or down-regulated changes (≥4), four novel (miR-31, miR-1, miR-9 and miR-99a) and two previously reported (miR-137 and miR-135b) miRNAs were identified in the normal/adenoma comparison. All but one of these (miR-99a) demonstrated similar expression differences in the two normal/carcinoma comparisons, suggesting that these early tumor changes are important in both the pMMR- and dMMR-derived cancers. The comparison between pMMR and dMMR tumors identified four miRNAs (miR-31, miR-552, miR-592 and miR-224) with statistically significant expression differences (≥2-fold change).
Genome-Wide Transcriptional Profiling Reveals MicroRNA-Correlated Genes and Biological Processes in Human Lymphoblastoid Cell Lines
Liang Wang, Ann L. Oberg, Yan W. Asmann, Hugues Sicotte, Shannon K. McDonnell, Shaun M. Riska, Wanguo Liu, Clifford J. Steer, Subbaya Subramanian, Julie M. Cunningham, James R. Cerhan, Stephen N. Thibodeau
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005878
Abstract: Background Expression level of many genes shows abundant natural variation in human populations. The variations in gene expression are believed to contribute to phenotypic differences. Emerging evidence has shown that microRNAs (miRNAs) are one of the key regulators of gene expression. However, past studies have focused on the miRNA target genes and used loss- or gain-of-function approach that may not reflect natural association between miRNA and mRNAs. Methodology/Principal Findings To examine miRNA regulatory effect on global gene expression under endogenous condition, we performed pair-wise correlation coefficient analysis on expression levels of 366 miRNAs and 14,174 messenger RNAs (mRNAs) in 90 immortalized lymphoblastoid cell lines, and observed significant correlations between the two species of RNA transcripts. We identified a total of 7,207 significantly correlated miRNA-mRNA pairs (false discovery rate q<0.01). Of those, 4,085 pairs showed positive correlations while 3,122 pairs showed negative correlations. Gene ontology analyses on the miRNA-correlated genes revealed significant enrichments in several biological processes related to cell cycle, cell communication and signal transduction. Individually, each of three miRNAs (miR-331, -98 and -33b) demonstrated significant correlation with the genes in cell cycle-related biological processes, which is consistent with important role of miRNAs in cell cycle regulation. Conclusions/Significance This study demonstrates feasibility of using naturally expressed transcript profiles to identify endogenous correlation between miRNA and miRNA. By applying this genome-wide approach, we have identified thousands of miRNA-correlated genes and revealed potential role of miRNAs in several important cellular functions. The study results along with accompanying data sets will provide a wealth of high-throughput data to further evaluate the miRNA-regulated genes and eventually in phenotypic variations of human populations.
Linkage analysis of obesity phenotypes in pre- and post-menopausal women from a United States mid-western population
Linda E Kelemen, Elizabeth J Atkinson, Mariza de Andrade, V Shane Pankratz, Julie M Cunningham, Alice Wang, Christopher A Hilker, Fergus J Couch, Thomas A Sellers, Celine M Vachon
BMC Medical Genetics , 2010, DOI: 10.1186/1471-2350-11-156
Abstract: We performed univariate and bivariate linkage analysis for the phenotypes of body mass index (BMI), waist (W) and hip (H) circumferences (WC, HC), and WH ratio (WHR) separately among 172 pre-menopausal and 405 post-menopausal women from 90 multigenerational families using a genome scan with 403 microsatellite markers. Bivariate analysis used pair-wise combinations of obesity phenotypes to detect linkage at loci with pleiotropic effects for genetically correlated traits. BMI was adjusted in models of WC, HC and WHR.Pre-menopausal women, compared to post-menopausal women, had higher heritability for BMI (h2 = 94% versus h2 = 39%, respectively) and for HC (h2 = 99% versus h2 = 43%, respectively), and lower heritability for WC (h2 = 29% versus h2 = 61%, respectively) and for WHR (h2 = 39% versus h2 = 57%, respectively). Among pre-menopausal women, the strongest evidence for linkage was for the combination of BMI and HC traits at 3p26 (bivariate LOD = 3.65) and at 13q13-q14 (bivariate LOD = 3.59). Among post-menopausal women, the highest level of evidence for genetic linkage was for HC at 4p15.3 (univariate LOD = 2.70) and 14q13 (univariate LOD = 2.51). WC was not clearly linked to any locus.These results support a genetic basis for fat deposition that differs by menopausal status, and suggest that the same loci encode genes that influence general obesity (BMI) and HC, specifically, among pre-menopausal women. However, lower heritability among pre-menopausal women for WC and WHR suggests that pre-menopausal waist girth may be influenced to a greater extent by controllable environmental factors than post-menopausal waist girth. Possibly, targeted interventions for weight control among pre-menopausal women may prevent or attenuate post-menopausal abdominal weight deposition.Over the past 25 years, the prevalence of overweight adults increased by 40% and that of obese adults by almost 2-fold in the United States [1]. Together, overweight and obese adults account for 68% of
Dopamine Receptor Autoantibodies Correlate with Symptoms in Sydenham's Chorea
Hilla Ben-Pazi, Julie A. Stoner, Madeleine W. Cunningham
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0073516
Abstract: Background Sydenham chorea (SC), a neuropsychiatric sequela of group-A streptococcal infection, is associated with basal ganglia autoantibodies. Although autoantibodies have been proposed in neuropsychiatric disorders, little evidence has been shown to link autoimmunity and clinical symptoms. We hypothesized that dopamine receptor-autoantibody interactions may be the basis of neuropsychiatric symptoms in SC. Methods Sera from 22 children with SC (age 10.7±4.5 years) and 22 age-matched controls were studied. Clinical neuropsychiatric symptoms were measured in SC at sample collection using the UFMG-Sydenham's-Chorea-Rating-Scale (USCRS). Anti-dopamine D1 receptor (D1R) and anti-dopamine D2 receptor (D2R) autoantibodies were measured by the enzyme linked immunosorbent assay (ELISA) and were correlated with clinical symptoms. Results Anti-D1R and anti-D2R autoantibodies were significantly higher in SC compared to controls (n = 44; p = 0.010 and p = 0.017, respectively). We found that the ratio (anti-D2R/D1R) of the two anti-dopaminergic receptor antibodies correlated with neuropsychiatric symptoms as determined by USCRS measurements (n = 18; r = 0.53, p = 0.024). In addition, anti-D2R titers correlated with antistreptolysin-O titers (n = 43; r = 0.49, p = 0.0008). Interpretation Our report linked, for the first time, autoimmunity with neuropsychiatric symptoms. The significant correlation was found using ratios of autoantibodies against dopamine receptors (anti-D2R/D1R) rather than the absolute elevated individual anti-D1R or anti-D2R titers. We suggest that autoantibodies may lead to a receptor imbalance and induce greater sensitivity to dopamine signaling potentially leading to neuropsychiatric symptoms in SC. Our novel findings suggesting altered balance in the dopaminergic system may provide a new approach in understanding autoimmune neuropsychiatric disorders with possible implications for diagnosis and treatment.
How Do I Regret Thee? Let Me Count My Alternatives: Regret and Decision Making in Intimate Relationships  [PDF]
Richard E. Mattson, Ana M. Franco-Watkins, Karlene Cunningham
Psychology (PSYCH) , 2012, DOI: 10.4236/psych.2012.39100
Abstract: It is unsurprising when dissatisfied couples separate, but happy couples also dissolve their relationship. A hypothesized precursor to such outcomes is the availability of a better alternative partner. The current study examined regret over one’s current partner selection as the possible mechanism by which better alternatives leads to partner switching in otherwise happy unions. An undergraduate sample (N = 94) was administered several questionnaires; which included measures of partner regret, relationship satisfaction, the availability of more attractive alternative partners, and the probability of switching to an alternative in the future. For relatively satisfied individuals, the presence of a better alternative elicited regrets about their currently selected partner that, in turn, predicted greater hypothetical intentions to partner switch. Less satisfied individuals also endorsed partner regret, but irrespective of whether a current alternative was actually available. Only relatively satisfied individuals without more attractive alternatives endorsed low partner regret and, subsequently, greater intentions to remain in their current relationship.
Including Extra Virgin Olive Oil May More Improve Glycemic Control despite Similar Weight Loss Compared to the Diet Recommended by the Prostate Cancer Foundation: A Randomized, Pilot Study  [PDF]
Mary M. Flynn, Jennifer Cunningham, Joseph Renzulli, Anthony Mega
Journal of Cancer Therapy (JCT) , 2017, DOI: 10.4236/jct.2017.810077
Abstract: Recommendations for prostate cancer treatment include weight loss, but the most efficacious diet has not been determined. Men on active surveillance or with untreated biochemical relapse consumed both the diet recommended by the Prostate Cancer Foundation (PCF) and a plant-based that included three tablespoons of extra virgin olive oil per day for 8 weeks of weight loss and improvement in some laboratory biomarkers with random assignment to the diet order. They then selected one of the diets for six months of follow-up. Thirty men started the protocol and 18 completed the 44 week study. Mean age: 66.6 ± 5.9 years; baseline body mass index: 30.9 ± 2.7 kg/m2. Weight loss was comparable between the diets after 8 weeks (PCF: 2.5% ± 3.1% v olive oil: 2.8% ± 3.7%; p = 0.86), but the diet that included olive oil resulted in lower insulin (PCF: 13.7 ± 7.0 mU/L v olive oil: 11.5 ± 4.4 mU/L; p = 0.02), glucose (PCF: 104.9 ± 9.9 mg/dl v 99.1 ± 9.6 mg/dl; p = 0.01), and HOMA-IR (PCF: 3.6 ± 2.1 v olive oil: 2.9 ± 1.2; p = 0.02). Thirteen of the 18 men choose the olive oil diet for six months of follow-up and weight loss and lab improvements were maintained. This pilot study indicates that both the PCF diet and the plant-based diet that included extra virgin olive oil can produce similar weight loss short-term. However, a plant-based diet that includes extra virgin olive may be more acceptable for long-term use, and produce better glycemic control.
Human colon cancer profiles show differential microRNA expression depending on mismatch repair status and are characteristic of undifferentiated proliferative states
Aaron L Sarver, Amy J French, Pedro M Borralho, Venugopal Thayanithy, Ann L Oberg, Kevin AT Silverstein, Bruce W Morlan, Shaun M Riska, Lisa A Boardman, Julie M Cunningham, Subbaya Subramanian, Liang Wang, Tom C Smyrk, Cecilia MP Rodrigues, Stephen N Thibodeau, Clifford J Steer
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-401
Abstract: To identify miRNAs that are differentially expressed in tumors and tumor subtypes, we carried out highly sensitive expression profiling of 735 miRNAs on samples obtained from a statistically powerful set of tumors (n = 80) and normal colon tissue (n = 28) and validated a subset of this data by qRT-PCR.Tumor specimens showed highly significant and large fold change differential expression of the levels of 39 miRNAs including miR-135b, miR-96, miR-182, miR-183, miR-1, and miR-133a, relative to normal colon tissue. Significant differences were also seen in 6 miRNAs including miR-31 and miR-592, in the direct comparison of tumors that were deficient or proficient for mismatch repair. Examination of the genomic regions containing differentially expressed miRNAs revealed that they were also differentially methylated in colon cancer at a far greater rate than would be expected by chance. A network of interactions between these miRNAs and genes associated with colon cancer provided evidence for the role of these miRNAs as oncogenes by attenuation of tumor suppressor genes.Colon tumors show differential expression of miRNAs depending on mismatch repair status. miRNA expression in colon tumors has an epigenetic component and altered expression that may reflect a reversion to regulatory programs characteristic of undifferentiated proliferative developmental states.Colon cancer (CC) is the second most frequent cause of cancer-related death in the United States and in Europe [1,2]. The development of CC is considered a stepwise process with the accumulation of different genetic and epigenetic alterations. Most tumors (~85%) are generated by chromosomal instability (CIN) and associated with high frequency aneuploidy and allelic imbalance. The remaining 15% have defective DNA mismatch repair (dMMR), which is frequently measured by either the presence of microsatellite instability (MSI) or by testing for loss of the protein products for genes involved in DNA mismatch repair, most c
Polymorphisms in NF-κB Inhibitors and Risk of Epithelial Ovarian Cancer
Kristin L White, Robert A Vierkant, Catherine M Phelan, Brooke L Fridley, Stephanie Anderson, Keith L Knutson, Joellen M Schildkraut, Julie M Cunningham, Linda E Kelemen, V Shane Pankratz, David N Rider, Mark Liebow, Lynn C Hartmann, Thomas A Sellers, Ellen L Goode
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-170
Abstract: We used a case-control study to evaluate the association between single nucleotide polymorphisms (SNPs) in NFKBIA and NFKBIB (the genes encoding IκBα and IκBβ, respectively) and risk of epithelial ovarian cancer. We queried 19 tagSNPs and putative-functional SNPs among 930 epithelial ovarian cancer cases and 1,037 controls from two studies.The minor allele for one synonymous SNP in NFKBIA, rs1957106, was associated with decreased risk (p = 0.03).Considering the number of single-SNP tests performed and null gene-level results, we conclude that NFKBIA and NFKBIB are not likely to harbor ovarian cancer risk alleles. Due to its biological significance in ovarian cancer, additional genes encoding NF-κB subunits, activating and inhibiting molecules, and signaling molecules warrant interrogation.Despite estimates of more than 21,000 newly diagnosed cases of ovarian cancer and 15,000 related deaths each year in the United States [1], the etiology of ovarian cancer remains poorly understood. Known risk factors include increased risk with family history and use of fertility drugs, and decreased risk with oral contraceptive use, parity, and long duration of breast feeding [2]. Rare, high-penetrant mutations in BRCA1 and BRCA2 account for approximately 40% of familial risk, leaving most inherited risk unexplained [3,4]. The search for additional loci includes thoughtful selection of candidate genes in key biological pathways, an approach which has been successful in identifying new risk alleles for a variety of cancers [5].Inflammation has been implicated in ovarian carcinogenesis because of its role in ovulation and post-ovulatory repair. During ovulation the ovarian epithelial surface is damaged, requiring a repair process involving the recruitment of leukocytes and inflammatory cytokines, release of nitrous oxide, DNA repair, and tissue restructuring [6-9]. Over time, this continuous repair of the ovarian epithelial tissue increases the likelihood of errors during replicatio
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