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Search Results: 1 - 10 of 483441 matches for " Robert A Vierkant "
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Extended LTA, TNF, LST1 and HLA Gene Haplotypes and Their Association with Rubella Vaccine-Induced Immunity
Inna G. Ovsyannikova,Robert A. Vierkant,V. Shane Pankratz,Robert M. Jacobson,Gregory A. Poland
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011806
Abstract: Recent studies have suggested the importance of HLA genes in determining immune responses following rubella vaccine. The telomeric class III region of the HLA complex harbors several genes, including lymphotoxin alpha (LTA), tumor necrosis factor (TNF) and leukocyte specific transcript -1 (LST1) genes, located between the class I B and class II DRB1 loci. Apart from HLA, little is known about the effect of this extended genetic region on HLA haplotypic backgrounds as applied to immune responses.
Associations between SNPs in candidate immune-relevant genes and rubella antibody levels: a multigenic assessment
V Shane Pankratz, Robert A Vierkant, Megan M O'Byrne, Inna G Ovsyannikova, Gregory A Poland
BMC Immunology , 2010, DOI: 10.1186/1471-2172-11-48
Abstract: Single-SNP assessments identified 4 SNPs that appeared to be univariately associated with rubella antibody levels: rs2844482 (p = 0.0002) and rs2857708 (p = 0.001) in the 5'UTR of the LTA gene, rs7801617 in the 5'UTR of the IL6 gene (p = 0.0005), and rs4787947 in the 5'UTR of the IL4R gene (p = 0.002). While there was not significant evidence in favor of epistatic genetic associations among the candidate SNPs, multigenic analyses identified 29 SNPs significantly associated with rubella antibody levels when selected as a group (p = 0.017). This collection of SNPs included not only those that were significant univariately, but others that would not have been identified if only considered in isolation from the other SNPs.For the first time, multigenic assessment of associations between candidate SNPs and rubella antibody levels identified a broad number of genetic associations that would not have been deemed important univariately. It is important to consider approaches like those applied here in order to better understand the full genetic complexity of response to vaccination.The importance of developing protective humoral immunity following vaccination is widely recognized, as those who fail to respond are at increased risk of contracting the disease if exposed. Rubella is well controlled via vaccination programs in industrialized countries, but epidemics of the disease occasionally occur in developing countries and both rubella virus infection and congenital rubella syndrome remain a major health concern around the world [1,2]. Understanding how host genetic influences modify response to rubella immunization may shed light into the biology of immunity to rubella infection, as well as into the potential development of even more highly effective vaccines. While the heritability of antibody responses to rubella vaccination has been estimated to be as high as 46% [3], knowledge of the genetic control of rubella vaccine-induced immunity remains incomplete.Our group and o
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.
European American Stratification in Ovarian Cancer Case Control Data: The Utility of Genome-Wide Data for Inferring Ancestry
Paola Raska, Edwin Iversen, Ann Chen, Zhihua Chen, Brooke L. Fridley, Jennifer Permuth-Wey, Ya-Yu Tsai, Robert A. Vierkant, Ellen L. Goode, Harvey Risch, Joellen M. Schildkraut, Thomas A. Sellers, Jill Barnholtz-Sloan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0035235
Abstract: We investigated the ability of several principal components analysis (PCA)-based strategies to detect and control for population stratification using data from a multi-center study of epithelial ovarian cancer among women of European-American ethnicity. These include a correction based on an ancestry informative markers (AIMs) panel designed to capture European ancestral variation and corrections utilizing un-thinned genome-wide SNP data; case-control samples were drawn from four geographically distinct North-American sites. The AIMs-only and genome-wide first principal components (PC1) both corresponded to the previously described North or Northwest-Southeast axis of European variation. We found that the genome-wide PCA captured this primary dimension of variation more precisely and identified additional axes of genome-wide variation of relevance to epithelial ovarian cancer. Associations evident between the genome-wide PCs and study site corroborate North American immigration history and suggest that undiscovered dimensions of variation lie within Northern Europe. The structure captured by the genome-wide PCA was also found within control individuals and did not reflect the case-control variation present in the data. The genome-wide PCA highlighted three regions of local LD, corresponding to the lactase (LCT) gene on chromosome 2, the human leukocyte antigen system (HLA) on chromosome 6 and to a common inversion polymorphism on chromosome 8. These features did not compromise the efficacy of PCs from this analysis for ancestry control. This study concludes that although AIMs panels are a cost-effective way of capturing population structure, genome-wide data should preferably be used when available.
No association between a candidate TCF7L2 variant and risk of breast or ovarian cancer
Ellen L Goode, Csilla Szabo, Ludmila Prokunina-Olsson, Robert A Vierkant, Zachary S Fredericksen, Francis S Collins, Kristin L White, Michele Schmidt, Brooke L Fridley, Fergus J Couch
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-312
Abstract: Two clinic-based case-control studies at the Mayo Clinic were assessed including 798 breast cancer cases, 843 breast cancer controls, 391 ovarian cancer cases, and 458 ovarian cancer controls. Genotyping at TCF7L2 rs12255372 used a 5' endonuclease assay, and statistical analysis used logistic regression among participants as a whole and among a priori-defined subsets.No associations with risk of breast or ovarian cancer were observed (ordinal model, p = 0.62 and p = 0.75, respectively). In addition, no associations were observed among sub-groups defined by age, BMI, family history, stage, grade, histology, or tumor behavior.Although the biology of the Wnt/β-catenin signaling pathway and prior association between rs12255372 and numerous phenotypes warranted examination of this TCF7L2 SNP, no compelling evidence for association with breast or ovarian cancer was observed.Transcription factor 7-like 2 (TCF7L2) encodes a transcription factor involved in Wnt/β-catenin signaling pathway which encompasses an intronic single-nucleotide polymorphism (SNP, rs12255372) that has been associated with risk of Type 2 diabetes in linkage studies and genome-wide association studies [1-4] with potential modification by obesity [5]. TCF7L2 forms an active nuclear complex with β-catenin that binds and induces the expression of target genes involved in cellular proliferation, evasion of apoptosis, and tissue invasion and metastasis. Because of the protein's relevance in this canonical cancer pathway, several cancer association studies have been conducted. Studies report associations with increased risk of familial breast cancer [6] and aggressiveness of prostate cancer [7]; there are conflicting reports in colon cancer showing decreased risk [8], increased risk [9], or differential risk by NSAIDs use [10]. We sought to assess the role of this polymorphism in risk of breast and ovarian cancer and, based on other reports, in subsets defined by body mass index (BMI), family history, and mea
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
Genetic variation in stromal proteins decorin and lumican with breast cancer: investigations in two case-control studies
Linda E Kelemen, Fergus J Couch, Shahana Ahmed, Alison M Dunning, Paul DP Pharoah, Douglas F Easton, Zachary S Fredericksen, Robert A Vierkant, V Shane Pankratz, Ellen L Goode, Christopher G Scott, David N Rider, Xianshu Wang, James R Cerhan, Celine M Vachon
Breast Cancer Research , 2008, DOI: 10.1186/bcr2201
Abstract: We investigated associations of 14 common polymorphisms in the DCN and LUM genes with 798 breast cancer cases and 843 controls from Mayo Clinic, MN, USA. One polymorphism per gene with the strongest risk association in the Mayo Clinic sample was genotyped in 4,470 breast cancer cases and 4,560 controls from East Anglia, England (Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH)).In the Mayo Clinic sample, six polymorphisms were associated with breast cancer risk (Ptrend ≤ 0.05). The association with LUM rs2268578, evaluated further in SEARCH, was positive, although the odds ratios (OR) were weaker and not statistically significant. ORs were 1.4 (95% confidence interval [CI], 1.1 to 1.8) for heterozygotes and 2.2 (95% CI, 1.1 to 4.3; P2 df = 0.002) for homozygotes in the Mayo Clinic sample, and were 1.1 (95% CI, 0.9 to 1.2) for heterozygotes and 1.4 (95% CI, 1.0 to 2.1; P2 df = 0.13) for homozygotes in the SEARCH sample. In combined analyses, the ORs were 1.1 (95% CI, 1.0 to 1.2) for heterozygotes and 1.6 (95% CI, 1.2 to 2.3; P2 df = 0.005) for homozygotes. Positive associations for this polymorphism were observed for estrogen receptor-positive tumors in both the Mayo Clinic sample (OR for heterozygotes = 1.5, 1.1 to 1.9 and OR for homozygotes = 2.5, 1.2 to 5.3;P2 df = 0.001) and the SEARCH sample (OR for heterozygotes = 1.0, 0.9 to 1.1 and OR for homozygotes = 1.6, 1.0 to 2.5; P2 df = 0.10). In combined analyses, the ORs were 1.1 (95% CI, 0.9 to 1.2) for heterozygotes and 1.9 (95% CI, 1.3 to 2.8; P2 df = 0.001) for homozygotes.Although LUM rs2268578 was associated with breast cancer in the Mayo Clinic study, particularly estrogen receptor-positive breast cancer, weaker and modest associations were observed in the SEARCH sample. These modest associations will require larger samples to adequately assess the importance of this polymorphism in breast cancer.Stromal changes are well documented in breast tumors [1,2] and in preinvasive breast lesions [2
Visualizing Open Access
Paul Vierkant
Libreas : Library Ideas , 2012,
Abstract:
Risk of Ovarian Cancer and Inherited Variants in Relapse-Associated Genes
Abraham Peedicayil,Robert A. Vierkant,Lynn C. Hartmann,Brooke L. Fridley,Zachary S. Fredericksen,Kristin L. White,Elaine A. Elliott,Catherine M. Phelan,Ya-Yu Tsai,Andrew Berchuck,Edwin S. Iversen Jr,Fergus J. Couch,Prema Peethamabaran,Melissa C. Larson,Kimberly R. Kalli,Matthew L. Kosel,Vijayalakshmi Shridhar,David N. Rider,Mark Liebow,Julie M. Cunningham,Joellen M. Schildkraut,Thomas A. Sellers,Ellen L. Goode
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008884
Abstract: We previously identified a panel of genes associated with outcome of ovarian cancer. The purpose of the current study was to assess whether variants in these genes correlated with ovarian cancer risk.
Inherited Variants in Regulatory T Cell Genes and Outcome of Ovarian Cancer
Ellen L. Goode, Melissa DeRycke, Kimberly R. Kalli, Ann L. Oberg, Julie M. Cunningham, Matthew J. Maurer, Brooke L. Fridley, Sebastian M. Armasu, Daniel J. Serie, Priya Ramar, Krista Goergen, Robert A. Vierkant, David N. Rider, Hugues Sicotte, Chen Wang, Boris Winterhoff, Catherine M. Phelan, Joellen M. Schildkraut, Rachel P. Weber, Ed Iversen, Andrew Berchuck, Rebecca Sutphen, Michael J. Birrer, Shalaka Hampras, Leah Preus, Simon A. Gayther, Susan J. Ramus, Nicolas Wentzensen, Hannah P. Yang, Montserrat Garcia-Closas, Honglin Song, Jonathan Tyrer, Paul P. D. Pharoah, Gottfried Konecny, Thomas A. Sellers, Roberta B. Ness, Lara E. Sucheston, Kunle Odunsi, Lynn C. Hartmann, Kirsten B. Moysich, Keith L. Knutson
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053903
Abstract: Although ovarian cancer is the most lethal of gynecologic malignancies, wide variation in outcome following conventional therapy continues to exist. The presence of tumor-infiltrating regulatory T cells (Tregs) has a role in outcome of this disease, and a growing body of data supports the existence of inherited prognostic factors. However, the role of inherited variants in genes encoding Treg-related immune molecules has not been fully explored. We analyzed expression quantitative trait loci (eQTL) and sequence-based tagging single nucleotide polymorphisms (tagSNPs) for 54 genes associated with Tregs in 3,662 invasive ovarian cancer cases. With adjustment for known prognostic factors, suggestive results were observed among rarer histological subtypes; poorer survival was associated with minor alleles at SNPs in RGS1 (clear cell, rs10921202, p = 2.7×10?5), LRRC32 and TNFRSF18/TNFRSF4 (mucinous, rs3781699, p = 4.5×10?4, and rs3753348, p = 9.0×10?4, respectively), and CD80 (endometrioid, rs13071247, p = 8.0×10?4). Fo0r the latter, correlative data support a CD80 rs13071247 genotype association with CD80 tumor RNA expression (p = 0.006). An additional eQTL SNP in CD80 was associated with shorter survival (rs7804190, p = 8.1×10?4) among all cases combined. As the products of these genes are known to affect induction, trafficking, or immunosuppressive function of Tregs, these results suggest the need for follow-up phenotypic studies.
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