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Search Results: 1 - 10 of 401138 matches for " Joellen M. Schildkraut "
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Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort
Soubry Adelheid,Schildkraut Joellen M,Murtha Amy,Wang Frances
BMC Medicine , 2013, DOI: 10.1186/1741-7015-11-29
Abstract: Background Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene. Methods We examined DNA from umbilical cord blood leukocytes from 79 newborns, born between July 2005 and November 2006 at Duke University Hospital, Durham, NC. Their mothers participated in the Newborn Epigenetics Study (NEST) during pregnancy. Parental characteristics were obtained via standardized questionnaires and medical records. DNA methylation patterns at two DMRs were analyzed by bisulfite pyrosequencing; one DMR upstream of IGF2 (IGF2 DMR), and one DMR upstream of the neighboring H19 gene (H19 DMR). Multiple regression models were used to determine potential associations between the offspring's DNA methylation patterns and parental obesity before conception. Obesity was defined as body mass index (BMI) ≥30 kg/m2. Results Hypomethylation at the IGF2 DMR was associated with paternal obesity. Even after adjusting for several maternal and newborn characteristics, we observed a persistent inverse association between DNA methylation in the offspring and paternal obesity (β-coefficient was -5.28, P = 0.003). At the H19 DMR, no significant associations were detected between methylation patterns and paternal obesity. Our data suggest an increase in DNA methylation at the IGF2 and H19 DMRs among newborns from obese mothers, but a larger study is warranted to further explore the potential effects of maternal obesity or lifestyle on the offspring's epigenome. Conclusions While our small sample size is limited, our data indicate a preconceptional impact of paternal obesity on the reprogramming of imprint marks during spermatogenesis. Given the biological importance of imprinting fidelity, our study provides evidence for transgenerational effects of paternal obesity that may influence the offspring's future health status.
Bayesian model search and multilevel inference for SNP association studies
Melanie A. Wilson,Edwin S. Iversen,Merlise A. Clyde,Scott C. Schmidler,Joellen M. Schildkraut
Statistics , 2009, DOI: 10.1214/09-AOAS322
Abstract: Technological advances in genotyping have given rise to hypothesis-based association studies of increasing scope. As a result, the scientific hypotheses addressed by these studies have become more complex and more difficult to address using existing analytic methodologies. Obstacles to analysis include inference in the face of multiple comparisons, complications arising from correlations among the SNPs (single nucleotide polymorphisms), choice of their genetic parametrization and missing data. In this paper we present an efficient Bayesian model search strategy that searches over the space of genetic markers and their genetic parametrization. The resulting method for Multilevel Inference of SNP Associations, MISA, allows computation of multilevel posterior probabilities and Bayes factors at the global, gene and SNP level, with the prior distribution on SNP inclusion in the model providing an intrinsic multiplicity correction. We use simulated data sets to characterize MISA's statistical power, and show that MISA has higher power to detect association than standard procedures. Using data from the North Carolina Ovarian Cancer Study (NCOCS), MISA identifies variants that were not identified by standard methods and have been externally ``validated'' in independent studies. We examine sensitivity of the NCOCS results to prior choice and method for imputing missing data. MISA is available in an R package on CRAN.
Association between DNA Damage Response and Repair Genes and Risk of Invasive Serous Ovarian Cancer
Joellen M. Schildkraut,Edwin S. Iversen,Melanie A. Wilson,Merlise A. Clyde,Patricia G. Moorman,Rachel T. Palmieri,Regina Whitaker,Rex C. Bentley,Jeffrey R. Marks,Andrew Berchuck
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010061
Abstract: We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study.
Folic acid supplementation before and during pregnancy in the Newborn Epigenetics STudy (NEST)
Cathrine Hoyo, Amy P Murtha, Joellen M Schildkraut, Michele R Forman, Brian Calingaert, Wendy Demark-Wahnefried, Joanne Kurtzberg, Randy L Jirtle, Susan K Murphy
BMC Public Health , 2011, DOI: 10.1186/1471-2458-11-46
Abstract: During 2005-2008, pre-pregnancy and pregnancy-related data on dietary supplementation were obtained by interviewing 539 pregnant women enrolled at two obstetrics-care facilities in Durham County, North Carolina.Before pregnancy, 51% of women reported FA supplementation and 66% reported this supplementation during pregnancy. Before pregnancy, 11.9% (95% CI = 9.2%-14.6%) of women reported supplementation with FA doses above the TUL of 1,000 μg/day, and a similar proportion reported this intake prenatally. Before pregnancy, Caucasian women were more likely to take FA doses above the TUL (OR = 2.99; 95% = 1.28-7.00), compared to African American women, while women with chronic conditions were less likely to take FA doses above the TUL (OR = 0.48; 95%CI = 0.21-0.97). Compared to African American women, Caucasian women were also more likely to report FA intake in doses exceeding the TUL during pregnancy (OR = 5.09; 95%CI = 2.07-12.49).Fifty-one percent of women reported some FA intake before and 66% during pregnancy, respectively, and more than one in ten women took FA supplements in doses that exceeded the TUL. Caucasian women were more likely to report high FA intake. A study is ongoing to identify possible genetic and non-genotoxic effects of these high doses.Previous studies have demonstrated that daily folic acid (FA) supplementation during preconception lowers the risk of neural tube defects [1-4] and other adverse pregnancy outcomes such as low birth weight [5]. Because of this beneficial effect with no apparent adverse health outcomes in pregnancy, FA supplementation of approximately 400 micrograms per day (μg/d) from fortified foods, supplements, or both, was recommended for all women at risk of pregnancy [3,6]. To meet this recommendation, women take over-the-counter multivitamin supplements containing approximately 400 μg/d of FA [7]. Since clinical trials data showed that the full benefit of FA was conferred prior to conception and the national unintended preg
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.
Activating mutation in MET oncogene in familial colorectal cancer
Deborah W Neklason, Michelle W Done, Nykole R Sargent, Ann G Schwartz, Hoda Anton-Culver, Constance A Griffin, Dennis J Ahnen, Joellen M Schildkraut, Gail E Tomlinson, Louise C Strong, Alexander R Miller, Jill E Stopfer, Randall W Burt
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-424
Abstract: MET exons were amplified by PCR from germline DNA of 148 affected sibling pairs with colorectal cancer. Amplicons with altered sequence were detected with high-resolution melt-curve analysis using a LightScanner (Idaho Technologies). Samples demonstrating alternative melt curves were sequenced. A TaqMan assay for the specific c.2975C > T change was used to confirm this mutation in a cohort of 299 colorectal cancer cases and to look for allelic amplification in tumors.Here we report a germline non-synonymous change in the MET proto-oncogene at amino acid position T992I (also reported as MET p.T1010I) in 5.2% of a cohort of sibling pairs affected with CRC. This genetic variant was then confirmed in a second cohort of individuals diagnosed with CRC and having a first degree relative with CRC at prevalence of 4.1%. This mutation has been reported in cancer cells of multiple origins, including 2.5% of colon cancers, and in <1% in the general population. The threonine at amino acid position 992 lies in the tyrosine kinase domain of MET and a change to isoleucine at this position has been shown to promote metastatic behavior in cell-based models. The average age of CRC diagnosis in patients in this study is 63 years in mutation carriers, which is 8 years earlier than the general population average for CRC.Although the MET p.T992I genetic mutation is commonly found in somatic colorectal cancer tissues, this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial colorectal cancer. Future studies on the cancer risks associated with this mutation and the prevalence in different at-risk populations will be an important extension of this work to define the clinical significance.Colorectal cancer (CRC) is one of the more familial of cancers, and the presence of a family history of this malignancy is a well established risk factor. Twin studies suggest inherited and/or familial factors contribute to 25-35% of CRC cases [1].
Maternal BMI, IGF-I Levels, and Birth Weight in African American and White Infants
Adriana C. Vidal,Amy P. Murtha,Susan K. Murphy,Kimberly Fortner,Francine Overcash,Nikki Henry,Joellen M. Schildkraut,Michele R. Forman,Wendy Demark-Wahnefried,Joanne Kurtzberg,Randy Jirtle,Cathrine Hoyo
International Journal of Pediatrics , 2013, DOI: 10.1155/2013/191472
Abstract: At birth, elevated IGF-I levels have been linked to birth weight extremes; high birth weight and low birth weight are risk factors for adult-onset chronic diseases including obesity, cardiovascular disease, and type 2 diabetes. We examined associations between plasma IGF-I levels and birth weight among infants born to African American and White obese and nonobese women. Prepregnancy weight and height were assessed among 251 pregnant women and anthropometric measurements of full term infants (≥37 weeks of gestation) were taken at birth. Circulating IGF-I was measured by ELISA in umbilical cord blood plasma. Linear regression models were utilized to examine associations between birth weight and high IGF-I, using the bottom two tertiles as referents. Compared with infants with lower IGF-I levels (≤3rd tertile), those with higher IGF-I levels (>3rd tertile) were 130?g heavier at birth, ( , , ), after adjusting for gender, race/ethnicity, gestational age, delivery route, maternal BMI and smoking. Stratified analyses suggested that these associations are more pronounced in infants born to African American women and women with BMI ≥30?kg/m2; the cross product term for IGF-I and maternal BMI was statistically significant ( ). Our findings suggest that the association between IGF-I levels and birth weight depends more on maternal obesity than African American race/ethnicity. 1. Introduction Low birth weight (LBW) and high birth weight (HBW) are both important indicators of suboptimal intrauterine development and have been linked to risk of several chronic diseases later in life. HBW has been associated with childhood and adult obesity [1] and some cancers, including breast [2] and prostate cancer [3], whereas LBW is a consistently identified risk factor for cardiovascular disease (CVD) [4, 5] and type 2 diabetes (T2D) [6, 7]. IGF-I is a mitogenic and antiapoptotic paracrine growth factor expressed in all fetal organs [8, 9], and is essential in fetal and neonatal growth, differentiation and development [10–14]. Several lines of evidence suggest that IGF-I levels are associated with birth weight [15–26]; furthermore higher IGF-I levels are associated with higher BW, but not with lower birth weight [16, 17, 26]. In adulthood, elevated concentrations of IGF-I are associated with an increased risk of obesity and many cancers, including breast, lung, head and neck, colorectal, pancreas, synovial sarcoma, and prostate cancer [26–31]. Although concentrations of circulating IGF-I levels vary considerably by race/ethnicity and maternal prepregnancy obesity, few studies
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
Association between Common Germline Genetic Variation in 94 Candidate Genes or Regions and Risks of Invasive Epithelial Ovarian Cancer
Lydia Quaye, Jonathan Tyrer, Susan J. Ramus, Honglin Song, Eva Wozniak, Richard A. DiCioccio, Valerie McGuire, Estrid H?gdall, Claus H?gdall, Jan Blaakaer, Ellen L. Goode, Joellen M. Schildkraut, Douglas F. Easton, Susanne Krüger-Kjaer, Alice S. Whittemore, Simon A. Gayther, Paul D. P. Pharoah
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0005983
Abstract: Background Recent studies have identified several single nucleotide polymorphisms (SNPs) in the population that are associated with variations in the risks of many different diseases including cancers such as breast, prostate and colorectal. For ovarian cancer, the known highly penetrant susceptibility genes (BRCA1 and BRCA2) are probably responsible for only 40% of the excess familial ovarian cancer risks, suggesting that other susceptibility genes of lower penetrance exist. Methods We have taken a candidate approach to identifying moderate risk susceptibility alleles for ovarian cancer. To date, we have genotyped 340 SNPs from 94 candidate genes or regions, in up to 1,491 invasive epithelial ovarian cancer cases and 3,145 unaffected controls from three different population based studies from the UK, Denmark and USA. Results After adjusting for population stratification by genomic control, 18 SNPs (5.3%) were significant at the 5% level, and 5 SNPs (1.5%) were significant at the 1% level. The most significant association was for the SNP rs2107425, located on chromosome 11p15.5, which has previously been identified as a susceptibility allele for breast cancer from a genome wide association study (P-trend = 0.0012). When SNPs/genes were stratified into 7 different pathways or groups of validation SNPs, the breast cancer associated SNPs were the only group of SNPs that were significantly associated with ovarian cancer risk (P-heterogeneity = 0.0003; P-trend = 0.0028; adjusted (for population stratification) P-trend = 0.006). We did not find statistically significant associations when the combined data for all SNPs were analysed using an admixture maximum likelihood (AML) experiment-wise test for association (P-heterogeneity = 0.051; P-trend = 0.068). Conclusion These data suggest that a proportion of the SNPs we evaluated were associated with ovarian cancer risk, but that the effect sizes were too small to detect associations with individual SNPs.
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.
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