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1. Genome-wide DNA methylation differences according to oestrogen receptor beta status in colorectal cancer

Author: Sonja Neumeyer, Odilia Popanda, Dominic Edelmann, Katja Butterbach, Csaba Toth, Wilfried Roth, Hendrik Bläker, Ruijingfang Jiang, Esther Herpel, Cornelia Jäkel, Peter Schmezer, Lina Jansen, Elizabeth Alwers, Axel Benner, Barbara Burwinkel, Michael Hoffmeister, Hermann Brenner, and Jenny Chang-Claude
Subjects: colon, ewas, differential methylation, erβ, sex hormones, methylation profiling, epigenetics, Genetics, QH426-470
Abstract: Involvement of sex hormones in colorectal cancer (CRC) development has been linked to oestrogen receptor β (ERβ). Expression of ERβ is found reduced in tumour tissue and inversely related to mortality. However, mechanisms are not well understood. Our study aimed to detect differentially methylated genes associated with ERβ expression, which could point to mechanisms by which ERβ could influence risk and prognosis of CRC. Epigenome-wide DNA methylation profiling was performed using Illumina HumanMethylation450k BeadChip arrays in two independent tumour sample sets of CRC patients recruited in 2003–2010 by the German DACHS study (discovery cohort n = 917, replication cohort n = 907). ERβ expression was measured using immunohistochemistry and scored as negative, moderate and high. Differentially methylated CpG sites and genomic regions were determined using limma in the R-package RnBeads. For the comparison of tumours with moderate/high ERβ versus negative expression, differentially methylated CpG sites were identified but not confirmed by replication. Comparing tumours of high with tumours of negative ERβ expression revealed 2,904 differentially methylated CpG sites of which 403 were replicated (FDR adjusted p-value
Published: 2019
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2. Association analyses identify 31 new risk loci for colorectal cancer susceptibility

Author: Philip J. Law, Maria Timofeeva, Ceres Fernandez-Rozadilla, Peter Broderick, James Studd, Juan Fernandez-Tajes, Susan Farrington, Victoria Svinti, Claire Palles, Giulia Orlando, Amit Sud, Amy Holroyd, Steven Penegar, Evropi Theodoratou, Peter Vaughan-Shaw, Harry Campbell, Lina Zgaga, Caroline Hayward, Archie Campbell, Sarah Harris, Ian J. Deary, John Starr, Laura Gatcombe, Maria Pinna, Sarah Briggs, Lynn Martin, Emma Jaeger, Archana Sharma-Oates, James East, Simon Leedham, Roland Arnold, Elaine Johnstone, Haitao Wang, David Kerr, Rachel Kerr, Tim Maughan, Richard Kaplan, Nada Al-Tassan, Kimmo Palin, Ulrika A. Hänninen, Tatiana Cajuso, Tomas Tanskanen, Johanna Kondelin, Eevi Kaasinen, Antti-Pekka Sarin, Johan G. Eriksson, Harri Rissanen, Paul Knekt, Eero Pukkala, Pekka Jousilahti, Veikko Salomaa, Samuli Ripatti, Aarno Palotie, Laura Renkonen-Sinisalo, Anna Lepistö, Jan Böhm, Jukka-Pekka Mecklin, Daniel D. Buchanan, Aung-Ko Win, John Hopper, Mark E. Jenkins, Noralane M. Lindor, Polly A. Newcomb, Steven Gallinger, David Duggan, Graham Casey, Per Hoffmann, Markus M. Nöthen, Karl-Heinz Jöckel, Douglas F. Easton, Paul D. P. Pharoah, Julian Peto, Federico Canzian, Anthony Swerdlow, Rosalind A. Eeles, Zsofia Kote-Jarai, Kenneth Muir, Nora Pashayan, The PRACTICAL consortium, Andrea Harkin, Karen Allan, John McQueen, James Paul, Timothy Iveson, Mark Saunders, Katja Butterbach, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Iva Kirac, Petar Matošević, Philipp Hofer, Stefanie Brezina, Andrea Gsur, Jeremy P. Cheadle, Lauri A. Aaltonen, Ian Tomlinson, Richard S. Houlston, and Malcolm G. Dunlop
Subjects: Science
Abstract: In colorectal cancer (CRC), finding loci associated with risk may give insight into disease aetiology. Here, the authors report a genome-wide association analysis in Europeans of 34,627 CRC cases and 71,379 controls, and find 31 new risk loci and 17 new risk SNPs at previously reported loci.
Published: 2019
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3. Pathway analysis of genetic variants in folate‐mediated one‐carbon metabolism‐related genes and survival in a prospectively followed cohort of colorectal cancer patients

Author: Jennifer Ose, Akke Botma, Yesilda Balavarca, Katharina Buck, Dominique Scherer, Nina Habermann, Jolantha Beyerle, Katrin Pfütze, Petra Seibold, Elisabeth J. Kap, Axel Benner, Lina Jansen, Katja Butterbach, Michael Hoffmeister, Hermann Brenner, Alexis Ulrich, Martin Schneider, Jenny Chang‐Claude, Barbara Burwinkel, and Cornelia M. Ulrich
Subjects: Colorectal cancer, one‐carbon metabolism, polymorphisms, survival, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Folate‐mediated one‐carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5‐fluorouracil (5‐FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM‐related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM‐related genes for associations with overall‐ (OS) and disease‐free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol). We investigated effect modification by 5‐FU‐based chemotherapy and assessed pathway‐specific effects. Correction for multiple testing was performed using false discovery rates (FDR). After a median follow‐up time of 5.0 years, 585 patients were deceased. For one candidate SNP in MTHFR and two in TYMS, we observed significant inverse associations with OS (MTHFR: rs1801133, C677T: HRhet = 0.81, 95% CI: 0.67–0.97; TYMS: rs1001761: HRhet = 0.82, 95% CI: 0.68–0.99 and rs2847149: HRhet = 0.82, 95% CI: 0.68–0.99). After FDR correction, one polymorphism in paraoxonase 1 (PON1; rs3917538) was significantly associated with OS (HRhet = 1.28, 95% CI: 1.07–1.53; HRhzv = 2.02, 95% CI:1.46–2.80; HRlogAdd = 1.31, pFDR = 0.01). Adjusted pathway analyses showed significant associations for pyrimidine biosynthesis (P = 0.04) and fluorouracil drug metabolism (P
Published: 2018
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4. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author: Cristian Pattaro, Alexander Teumer, Mathias Gorski, Audrey Y. Chu, Man Li, Vladan Mijatovic, Maija Garnaas, Adrienne Tin, Rossella Sorice, Yong Li, Daniel Taliun, Matthias Olden, Meredith Foster, Qiong Yang, Ming-Huei Chen, Tune H. Pers, Andrew D. Johnson, Yi-An Ko, Christian Fuchsberger, Bamidele Tayo, Michael Nalls, Mary F. Feitosa, Aaron Isaacs, Abbas Dehghan, Pio d’Adamo, Adebowale Adeyemo, Aida Karina Dieffenbach, Alan B. Zonderman, Ilja M. Nolte, Peter J. van der Most, Alan F. Wright, Alan R. Shuldiner, Alanna C. Morrison, Albert Hofman, Albert V. Smith, Albert W. Dreisbach, Andre Franke, Andre G. Uitterlinden, Andres Metspalu, Anke Tonjes, Antonio Lupo, Antonietta Robino, Åsa Johansson, Ayse Demirkan, Barbara Kollerits, Barry I. Freedman, Belen Ponte, Ben A. Oostra, Bernhard Paulweber, Bernhard K. Krämer, Braxton D. Mitchell, Brendan M. Buckley, Carmen A. Peralta, Caroline Hayward, Catherine Helmer, Charles N. Rotimi, Christian M. Shaffer, Christian Müller, Cinzia Sala, Cornelia M. van Duijn, Aude Saint-Pierre, Daniel Ackermann, Daniel Shriner, Daniela Ruggiero, Daniela Toniolo, Yingchang Lu, Daniele Cusi, Darina Czamara, David Ellinghaus, David S. Siscovick, Douglas Ruderfer, Christian Gieger, Harald Grallert, Elena Rochtchina, Elizabeth J. Atkinson, Elizabeth G. Holliday, Eric Boerwinkle, Erika Salvi, Erwin P. Bottinger, Federico Murgia, Fernando Rivadeneira, Florian Ernst, Florian Kronenberg, Frank B. Hu, Gerjan J. Navis, Gary C. Curhan, George B. Ehret, Georg Homuth, Stefan Coassin, Gian-Andri Thun, Giorgio Pistis, Giovanni Gambaro, Giovanni Malerba, Grant W. Montgomery, Gudny Eiriksdottir, Gunnar Jacobs, Guo Li, H-Erich Wichmann, Harry Campbell, Helena Schmidt, Henri Wallaschofski, Henry Völzke, Hermann Brenner, Heyo K. Kroemer, Holly Kramer, Honghuang Lin, I. Mateo Leach, Ian Ford, Idris Guessous, Igor Rudan, Inga Prokopenko, Ingrid Borecki, Iris M. Heid, Ivana Kolcic, Ivana Persico, J. Wouter Jukema, James F. Wilson, Janine F. Felix, Jasmin Divers, Jean-Charles Lambert, Jeanette M. Stafford, Jean-Michel Gaspoz, Jennifer A. Smith, Jessica D. Faul, Jie Jin Wang, Jingzhong Ding, Joel N. Hirschhorn, John Attia, John B. Whitfield, John Chalmers, Jorma Viikari, Josef Coresh, Joshua C. Denny, Juha Karjalainen, Jyotika K. Fernandes, Karlhans Endlich, Katja Butterbach, Keith L. Keene, Kurt Lohman, Laura Portas, Lenore J. Launer, Leo-Pekka Lyytikäinen, Loic Yengo, Lude Franke, Luigi Ferrucci, Lynda M. Rose, Lyudmyla Kedenko, Madhumathi Rao, Maksim Struchalin, Marcus E. Kleber, Margherita Cavalieri, Margot Haun, Marilyn C. Cornelis, Marina Ciullo, Mario Pirastu, Mariza de Andrade, Mark A. McEvoy, Mark Woodward, Martin Adam, Massimiliano Cocca, Matthias Nauck, Medea Imboden, Melanie Waldenberger, Menno Pruijm, Marie Metzger, Michael Stumvoll, Michele K. Evans, Michele M. Sale, Mika Kähönen, Mladen Boban, Murielle Bochud, Myriam Rheinberger, Niek Verweij, Nabila Bouatia-Naji, Nicholas G. Martin, Nick Hastie, Nicole Probst-Hensch, Nicole Soranzo, Olivier Devuyst, Olli Raitakari, Omri Gottesman, Oscar H. Franco, Ozren Polasek, Paolo Gasparini, Patricia B. Munroe, Paul M. Ridker, Paul Mitchell, Paul Muntner, Christa Meisinger, Johannes H. Smit, ICBP Consortium, AGEN Consortium, CARDIOGRAM, CHARGe-Heart Failure Group, ECHOGen Consortium, Peter Kovacs, Philipp S. Wild, Philippe Froguel, Rainer Rettig, Reedik Mägi, Reiner Biffar, Reinhold Schmidt, Rita P. S. Middelberg, Robert J. Carroll, Brenda W. Penninx, Rodney J. Scott, Ronit Katz, Sanaz Sedaghat, Sarah H. Wild, Sharon L. R. Kardia, Sheila Ulivi, Shih-Jen Hwang, Stefan Enroth, Stefan Kloiber, Stella Trompet, Benedicte Stengel, Stephen J. Hancock, Stephen T. Turner, Sylvia E. Rosas, Sylvia Stracke, Tamara B. Harris, Tanja Zeller, Tatijana Zemunik, Terho Lehtimäki, Thomas Illig, Thor Aspelund, Tiit Nikopensius, Tonu Esko, Toshiko Tanaka, Ulf Gyllensten, Uwe Völker, Valur Emilsson, Veronique Vitart, Ville Aalto, Vilmundur Gudnason, Vincent Chouraki, Wei-Min Chen, Wilmar Igl, Winfried März, Wolfgang Koenig, Wolfgang Lieb, Ruth J. F. Loos, Yongmei Liu, Harold Snieder, Peter P. Pramstaller, Afshin Parsa, Jeffrey R. O’Connell, Katalin Susztak, Pavel Hamet, Johanne Tremblay, Ian H. de Boer, Carsten A. Böger, Wolfram Goessling, Daniel I. Chasman, Anna Köttgen, W. H. Linda Kao, and Caroline S. Fox
Subjects: Science
Abstract: Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.
Published: 2016
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5. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

Author: Mengmeng Du, Shuo Jiao, Stephanie A Bien, Manish Gala, Goncalo Abecasis, Stephane Bezieau, Hermann Brenner, Katja Butterbach, Bette J Caan, Christopher S Carlson, Graham Casey, Jenny Chang-Claude, David V Conti, Keith R Curtis, David Duggan, Steven Gallinger, Robert W Haile, Tabitha A Harrison, Richard B Hayes, Michael Hoffmeister, John L Hopper, Thomas J Hudson, Mark A Jenkins, Sébastien Küry, Loic Le Marchand, Suzanne M Leal, Polly A Newcomb, Deborah A Nickerson, John D Potter, Robert E Schoen, Fredrick R Schumacher, Daniela Seminara, Martha L Slattery, Li Hsu, Andrew T Chan, Emily White, Sonja I Berndt, and Ulrike Peters
Subjects: Medicine, Science
Abstract: Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).
Published: 2016
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6. Supplementary Methods and Tables from The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Author: Douglas F. Easton, Jacques Simard, Stephen J. Chanock, Georgia Chenevix-Trench, Paul D.P. Pharoah, Antonis C. Antoniou, Daniela Seminara, Elizabeth Gillanders, Michael F. Seldin, Rosalind A. Eeles, Ulrike Peters, Ali Amin Al Olama, Jonathan Marchini, Rayjean J. Hung, Laura Ottini, Rita Schmutzler, Mads Thomassen, Kenneth Offit, Sue K. Park, John K. Field, Jack A. Taylor, Christopher K. Edlund, Tameka Shelford, Stephanie L. Schmit, Sylvie Laboissiere, Andrew Berchuck, Sune F. Nielsen, Marc T. Goodman, Deborah J. Thompson, Yongyong Shi, Hongbing Shen, Tracy A. O'Mara, Marjorie Riggan, Paul Brennan, Linda E. Kelemen, Sara Benlloch, Catherine M. Phelan, James D. McKay, Marcia Adams, Sara Lindström, Liesel FitzGerald, Peter Kraft, Zsofia Kote-Jarai, Katja Butterbach, Julie M. Cunningham, Judith Manz, Penny Soucy, Karoline Kuchenbaecker, Andrew Lee, Lesley McGuffog, Hua Ling, Belynda D. Hicks, Irene Brüske-Hohlfeld, Melanie Waldenberger, Angela Risch, Heike Bickeböller, David V. Conti, Graham G. Giles, Judith L. Forman, Fergus J. Couch, David E. Goldgar, Stephen Demetriades, Stefanie Nelson, David J. Van Den Berg, François Bacot, Daniel Vincent, Daniel Tessier, Craig Luccarini, Ahsan Kamal, Christopher A. Haiman, Charlisse Caga-Anan, Stig E. Bojesen, Dennis J. Hazelett, Gerhard A. Coetzee, Elizabeth Pugh, Jane Romm, Xiangjun Xiao, Yafang Li, Amanda B. Spurdle, Kimberly Doheny, Laura Fachal, Kyriaki Michailidou, Alison M. Dunning, Stephen B. Gruber, Thomas A. Sellers, David J. Hunter, Graham Casey, Simon A. Gayther, Fredrick R. Schumacher, Jinyoung Byun, Zhaoming Wang, Joe Dennis, and Christopher I. Amos
Abstract: Supplementary Methods and Tables
Published: 2023

7. Data from The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Author: Douglas F. Easton, Jacques Simard, Stephen J. Chanock, Georgia Chenevix-Trench, Paul D.P. Pharoah, Antonis C. Antoniou, Daniela Seminara, Elizabeth Gillanders, Michael F. Seldin, Rosalind A. Eeles, Ulrike Peters, Ali Amin Al Olama, Jonathan Marchini, Rayjean J. Hung, Laura Ottini, Rita Schmutzler, Mads Thomassen, Kenneth Offit, Sue K. Park, John K. Field, Jack A. Taylor, Christopher K. Edlund, Tameka Shelford, Stephanie L. Schmit, Sylvie Laboissiere, Andrew Berchuck, Sune F. Nielsen, Marc T. Goodman, Deborah J. Thompson, Yongyong Shi, Hongbing Shen, Tracy A. O'Mara, Marjorie Riggan, Paul Brennan, Linda E. Kelemen, Sara Benlloch, Catherine M. Phelan, James D. McKay, Marcia Adams, Sara Lindström, Liesel FitzGerald, Peter Kraft, Zsofia Kote-Jarai, Katja Butterbach, Julie M. Cunningham, Judith Manz, Penny Soucy, Karoline Kuchenbaecker, Andrew Lee, Lesley McGuffog, Hua Ling, Belynda D. Hicks, Irene Brüske-Hohlfeld, Melanie Waldenberger, Angela Risch, Heike Bickeböller, David V. Conti, Graham G. Giles, Judith L. Forman, Fergus J. Couch, David E. Goldgar, Stephen Demetriades, Stefanie Nelson, David J. Van Den Berg, François Bacot, Daniel Vincent, Daniel Tessier, Craig Luccarini, Ahsan Kamal, Christopher A. Haiman, Charlisse Caga-Anan, Stig E. Bojesen, Dennis J. Hazelett, Gerhard A. Coetzee, Elizabeth Pugh, Jane Romm, Xiangjun Xiao, Yafang Li, Amanda B. Spurdle, Kimberly Doheny, Laura Fachal, Kyriaki Michailidou, Alison M. Dunning, Stephen B. Gruber, Thomas A. Sellers, David J. Hunter, Graham Casey, Simon A. Gayther, Fredrick R. Schumacher, Jinyoung Byun, Zhaoming Wang, Joe Dennis, and Christopher I. Amos
Abstract: Background: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits.Methods: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background.Results: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis.Conclusions: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures.Impact: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126–35. ©2016 AACR.
Published: 2023

8. Genetic Predictors of Circulating 25-Hydroxyvitamin D and Prognosis after Colorectal Cancer

Author: Haifa Maalmi, JoAnn E. Manson, Michael Hoffmeister, Lori C. Sakoda, Sonja I. Berndt, Jane C. Figueiredo, Amit Joshi, Edward Giovannucci, Sonja Neumeyer, Barbara L. Banbury, Katja Butterbach, Ulrike Peters, Aung Ko Win, Emily White, John L. Hopper, Mingyang Song, Peter T. Campbell, Shuji Ogino, Martha L. Slattery, Robert E. Schoen, Rowan T. Chlebowski, Marjorie L. McCullough, Jenny Chang-Claude, Hermann Brenner, Finlay A. Macrae, Polly A. Newcomb, and Andrew T. Chan
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, Colorectal cancer, Genome-wide association study, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Vitamin D and neurology, Genetic predisposition, Humans, Vitamin D, Survival analysis, business.industry, Proportional hazards model, Cancer, Prognosis, medicine.disease, Survival Analysis, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Colorectal Neoplasms, business
Abstract: Background: Low serum 25-hydroxyvitamin D [25(OH)D] concentrations in patients with colorectal cancer have been consistently associated with higher mortality in observational studies. It is unclear whether low 25(OH)D levels directly influence colorectal cancer mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and colorectal cancer–specific survival. Methods: Six genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. On the basis of data from the International Survival Analysis in Colorectal Cancer Consortium, the individual genetic variants and a weighted genetic risk score were tested for association with overall and colorectal cancer–specific survival using Cox proportional hazards models in 7,657 patients with stage I to IV colorectal cancer, of whom 2,438 died from any cause and 1,648 died from colorectal cancer. Results: The 25(OH)D decreasing allele of SNP rs2282679 (GC gene, encodes group-specific component/vitamin D–binding protein) was associated with poorer colorectal cancer–specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed nonsignificant associations with increased overall [HR = 1.54; confidence interval (CI), 0.86–2.78] and colorectal cancer–specific mortality (HR = 1.76; 95% CI, 0.86–3.58). A significant increased risk of overall mortality was observed in women (HR = 3.26; 95% CI, 1.45–7.33; Pheterogeneity = 0.01) and normal-weight individuals (HR = 4.14; 95% CI, 1.50–11.43, Pheterogeneity = 0.02). Conclusions: Our results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or colorectal cancer–specific survival, although power might have been an issue. Impact: Further studies are warranted to investigate the association in specific subgroups.
Published: 2020

9. DNA methylation profiling to explore colorectal tumor differences according to menopausal hormone therapy use in women

Author: Dominic Edelmann, Katja Butterbach, Hendrik Bläker, Wilfried Roth, Axel Benner, Michael Hoffmeister, Hermann Brenner, Barbara Burwinkel, Esther Herpel, Odilia Popanda, Peter Schmezer, Sonja Neumeyer, Csaba Toth, Jenny Chang-Claude, and Cornelia Jäkel
Subjects: Cancer Research, medicine.drug_class, Colorectal cancer, medicine.medical_treatment, Estrogen receptor, Biology, chemistry.chemical_compound, Genetics, medicine, Estrogen Receptor beta, Humans, Gene, Aged, Aged, 80 and over, Estrogen Replacement Therapy, Hormone replacement therapy (menopause), DNA Methylation, Middle Aged, medicine.disease, chemistry, CpG site, Estrogen, DNA methylation, Cancer research, CpG Islands, Female, Menopause, Colorectal Neoplasms, DNA
Abstract: Aim: Use of menopausal hormone therapy (MHT) has been associated with a reduced risk for colorectal cancer, but mechanisms underlying this relationship are not well understood. In the colon, MHT appears to act through estrogen receptor β (ERβ) which may influence DNA methylation by binding to DNA. Using genome-wide methylation profiling data, we aimed to identify genes that may be differentially methylated according to MHT use. Materials & methods: DNA methylation was measured using Illumina HumanMethylation450k arrays in two independent tumor sample sets of colorectal cancer patients. Differential methylation was determined using R/limma. Results: In the discovery analysis, two CpG sites showed differential DNA methylation according to MHT use, both were not replicated. In stratified analyses, 342 CpG sites were associated with current MHT use only in ERβ-positive tumors. Conclusion: The suggestive findings of differential methylation according to current MHT use in ERβ-positive tumors warrant further investigation.
Published: 2019

10. Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Author: Katja Butterbach, Julyann Pérez-Mayoral, Douglas F. Easton, Stefanie Brezina, Ben Zhang, Frank J. Manion, Hansong Wang, Sanford D. Markowitz, Liesel M. FitzGerald, Sun Ha Jee, Michelle Cotterchio, Daniel D. Buchanan, Timothy R. Church, Wolfgang Lieb, Xiao-Ou Shu, John L. Hopper, Stephanie A. Bien, Manuela Gago-Dominguez, Jian Gong, Laurence N. Kolonel, Graham G. Giles, Leon Raskin, Yingchang Lu, Kristen Anton, Charles S. Fuchs, Fränzel J.B. van Duijnhoven, Hermann Brenner, Yi Lin, Clicerio Gonzalez-Villalpando, Yong-Bing Xiang, Aaron K. Aragaki, Daniela Seminara, Stephanie M. Gogarten, Gad Rennert, Jose E. Castelao, Rocky Fischer, Antonio J. Molina, Jarmo Virtamo, Tabitha A. Harrison, Volker Arndt, Lee Soo Chin, Michael Hoffmeister, Mark A. Jenkins, Shu Chen Huang, Chris S. Carlson, Stéphane Bézieau, Rebecca D. Jackson, Bhramar Mukherjee, Darin Taverna, Bridget M. Riggs, Christopher K. Edlund, Christopher A. Haiman, Melissa C. Southey, Anna H. Wu, Marilena Melas, Antonia Trichopoulou, Hedy S. Rennert, Gianluca Severi, Stephen B. Gruber, Noralane M. Lindor, Gerhard A. Coetzee, Richard B. Hayes, Sarah J. Plummer, Keitaro Matsuo, Mathieu Lemire, Philipp Hofer, Neil Murphy, José María Huerta, Paul D.P. Pharoah, Erin M. Siegel, Sébastien Küry, Thomas J. Hudson, Annika Lindblom, Marcia Cruz Correa, Michael O. Woods, Sophia Harlid, Tilman Kuehn, David Shibata, Christopher I. Li, Stephen N. Thibodeau, Stephen J. Chanock, Jochen Hampe, Flavio Lejbkowicz, Jeroen R. Huyghe, Suminori Kono, Jenny Chang-Claude, Aung Ko Win, Brent W. Zanke, Alicja Wolk, David V. Conti, Elena M. Gonzalez-Villalpando, Christopher I. Amos, Shuo Jiao, Domenico Palli, Vicente Martín, Jesus P. Paredes Cotoré, Stephanie J. Weinstein, Andrea Gsur, William M. Grady, Koichi Matsuda, Loic Le Marchand, Hanane Omichessan, Marc J. Gunter, Graham Casey, Li Li, Zsofia K. Stadler, Eric J. Jacobs, Kevin McDonnell, Dallas R. English, Demetrius Albanes, Amit Joshi, Wei Zheng, Mariana C. Stern, Cecelia A. Laurie, Jing Ma, Cornelia M. Ulrich, Stephanie L. Schmit, Victor Moreno, John D. Potter, Chenxu Qu, Bette J. Caan, Heinz-Josef Lenz, M. Henar Alonso, Andrea Z. LaCroix, Christoph Mancao, John F. Harju, Yun Ru Liu, Jane C. Figueiredo, Gregory Idos, Kana Wu, Duncan C. Thomas, Motoki Iwasaki, W. James Gauderman, Thomas A. Sellers, David Van Den Berg, Barbara K. Fortini, David N. Levine, James M. Church, Ya Wen Cheng, Edith J. M. Feskens, Edward Giovannucci, Manish Gala, Polly A. Newcomb, Charles Kooperberg, Iona Cheng, David J. Hunter, Martha L. Slattery, Roger L. Milne, Lars G. Fritsche, Niha Zubair, Steven Gallinger, Yi Xin Zeng, Wei Shi, Andrew T. Chan, Fotios Loupakis, Vittorio Krogh, Clemens Schafmayer, Sun-Seog Kweon, Bethany van Guelpan, Amanda Bloomer, Kenneth Offit, Stephanie Tring, Shoichiro Tsugane, David Duggan, Fredrick R. Schumacher, Joseph Vijai, Weihua Jia, Marie-Christine Boutron-Ruault, Joel K. Greenson, Frank Luh, Ulrike Peters, Keith R. Curtis, Juergen Boehm, Robert E. Schoen, Sonja I. Berndt, Elizabeth L. Barry, Sebastian Stintzing, Li Hsu, Emily White, Conghui Qu, Peter T. Campbell, Caroline McNeil, and Yun Yen
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Genotype, Nutrition and Disease, Colorectal cancer, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Càncer colorectal, Internal medicine, Voeding en Ziekte, Ethnicity, medicine, Genetic predisposition, Genetics, Humans, Life Science, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Allele, Allele frequency, Genetic association, VLAG, Global Nutrition, Wereldvoeding, Oncology And Carcinogenesis, Case-control study, Articles, Prognosis, medicine.disease, United States, 3. Good health, Genetic Loci, Case-Control Studies, 030220 oncology & carcinogenesis, Colorectal Neoplasms, Genètica, Follow-Up Studies, Genome-Wide Association Study
Abstract: Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
Published: 2019

11. Discovery of common and rare genetic risk variants for colorectal cancer

Author: Charles M. Connolly, Deborah A. Nickerson, Jian Gong, Sébastien Küry, Barbara Pardini, Brent W. Zanke, Andrea Gsur, Jochen Hampe, Coral Arnau-Collell, M. Henar Alonso, Elio Riboli, Annika Lindblom, Ulrike Peters, Gad Rennert, Tabitha A. Harrison, Lori C. Sakoda, Caroline McNeil, Flavio Lejbkowicz, Hyun Min Kang, David J. Hunter, Martha L. Slattery, Miguel Rodríguez-Barranco, Christina Bamia, Satu Männistö, Timothy J. Key, W. James Gauderman, Gonçalo R. Abecasis, Sanford D. Markowitz, Laurence N. Kolonel, Mark A. Jenkins, Yi Lin, Robin Myte, Hedy S. Rennert, Neil Murphy, Antonia Trichopoulou, Christopher I. Li, Ross L. Prentice, Sai Chen, Stephanie J. Weinstein, Kristin E. Anderson, Hua Ling, Mitul Shah, Philipp Hofer, Wen Yi Huang, Sergi Castellví-Bel, Susanna C. Larsson, Maria Dolores Chirlaque, Wei Zheng, Stephanie L. Schmit, Cecelia A. Laurie, Soo-Chin Lee, David Forman, Andrea N. Burnett-Hartman, Giovanna Masala, Sarah C. Nelson, Michael O. Woods, Charles Kooperberg, Qing Zhang, Sonja I. Berndt, Christopher S. Carlson, Katja Butterbach, Hyeong Rok Kim, Rebecca D. Jackson, David Van Den Berg, Michael C. Bassik, Amanda J. Cross, Sushma S. Thomas, Clemens Schafmayer, Anna H. Wu, Douglas F. Easton, Robert W. Haile, Ludmila Vodickova, Graham G. Giles, Yu Ru Su, Jenny Chang-Claude, Lorena Moreno, Peter C. Scacheri, Stefanie Brezina, Min-Ho Shin, Steven Gallinger, Bethany Van Guelpen, Daniel D. Buchanan, Roger L. Milne, Stephen J. Chanock, Tin Louie, Tameka Shelford, Emily White, Kala Visvanathan, Loic Le Marchand, Veronika Vymetalkova, Roxann G. Ingersoll, Temitope O. Keku, Stephanie A. Bien, Fredrick R. Schumacher, Wan-Ling Hsu, Amanda E. Toland, John S. Grove, Noralane M. Lindor, Faye Elliott, Leon Raskin, Heather Hampel, Joshua D. Smith, Vicente Martín, David V. Conti, Sjoerd G. Elias, Henk J. van Kranen, Manish Gala, Daniela Seminara, Syed H.E. Zaidi, Suzanne M. Leal, Tilman Kühn, Korbinian Weigl, Marc J. Gunter, Cornelia M. Ulrich, Peyton Greenside, Victor Moreno, John D. Potter, Michael Hoffmeister, Eric J. Jacobs, Catherine M. Tangen, Jihyoun Jeon, Fränzel J.B. Van Duijnhoven, Andrew T. Chan, Stephen B. Gruber, John A. Baron, Alicja Wolk, Edith J. M. Feskens, Demetrius Albanes, Amit Joshi, Bette J. Caan, Polly A. Newcomb, Stéphane Bézieau, Elizabeth M. Gillanders, Anshul Kundaje, Elizabeth A. Platz, Michael Wainberg, Sun-Seog Kweon, C. Roland Wolf, Gemma Ibáñez-Sanz, Shuji Ogino, Emiko Kobayashi, Richard B. Hayes, Patrick S. Parfrey, Katarina Cuk, Stephen N. Thibodeau, Kenneth Offit, David Duggan, Sophia Harlid, Pavel Vodicka, Juergen Boehm, Christa Stegmaier, Jeroen R. Huyghe, Joseph Vijai, Sang-Hee Cho, Elizabeth W. Pugh, Rachel Pearlman, Alessio Naccarati, Marilena Melas, Graham Casey, Jane Romm, Stephan Buch, Phyllis J. Goodman, Albert de la Chapelle, John L. Hopper, Zsofia K. Stadler, Corinne E. Joshu, Liesel M. FitzGerald, Wolfgang Lieb, Aung Ko Win, Keith R. Curtis, Hermann Brenner, Christopher K. Edlund, Li Hsu, Conghui Qu, Peter T. Campbell, Robert E. Schoen, Heiner Boeing, D. Timothy Bishop, Kimberly F. Doheny, Sabina Sieri, Barbara L. Banbury, Mathieu Lemire, Jane C. Figueiredo, Gregory Idos, Katerina Shulman, Thomas J. Hudson, Melissa C. Southey, Duncan C. Thomas, Paul D.P. Pharoah, Mila Pinchev, Vittorio Perduca, Rocky Fischer, Volker Arndt, William M. Grady, Nasa Sinnott-Armstrong, N. Charlotte Onland-Moret, David M. Levine, Li Li, Dallas R. English, Health Research Board - Ireland, Department of Medical Genetics, HMNC Brain Health, Case Western Reserve University [Cleveland], National Cancer Institute, NIH, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Service de Génétique, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Division of Cancer Epidemiology, Cancer Genome Project, The Wellcome Trust Sanger Institute [Cambridge], Division of Signaling Biology, Ontario Cancer Institute, Consorcio de Investigación Biomédica en Red especializado en Epidemiología y Salud Pública (CIBERESP), Los Centros de Investigación Biomédica en Red (CIBER), National Institute of Standards and Technology [Gaithersburg] (NIST), Ohio State University [Columbus] (OSU), Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Cancer Epidemiology Centre, Cancer Council Victoria, Division of Human Nutrition, Wageningen University and Research [Wageningen] (WUR), Division of Public Health Sciences, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Northern and Yorkshire Cancer Registry and Information Service, Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), University of Melbourne, Nutrition and Metabolism Section, International Agency for Cancer Research (IACR), Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, London School of Hygiene and Tropical Medicine (LSHTM), Fraunhofer Institute for Manufacturing Engineering and Automation (Fraunhofer IPA), Fraunhofer (Fraunhofer-Gesellschaft), Centre for Molecular , Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne-Centre for Molecular, Melbourne School of Population Health, Department of Mathematics, University of Warwick, Warwick Mathematics Institute (WMI), University of Warwick [Coventry]-University of Warwick [Coventry], Department of Statistics, Penn State University, University of Pennsylvania [Philadelphia], Tata Memorial Centre, Cancer Epidemiology Unit, University of Oxford [Oxford], Thermo Fisher Scientific, Thermo Fisher Scientific Inc., Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, National University Health System, Department of Community Medicine and Epidemiology, CHS National Cancer Control Center, Ontario Institute for Cancer Research [Canada] (OICR), Ontario Institute for Cancer Research, Laboratoire de Génie Electrique de Grenoble (G2ELab), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare [Helsinki], Dell-EMC, Molecular and Nutritional Epidemiology Unit (ISPO), Cancer Research and Prevention Institute, Clinical Genetics Service, Memorial Sloane Kettering Cancer Center [New York], Department of Pathology, Brigham and Women's Hospital [Boston], University Medical Center [Utrecht], Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), Department of Oncology, Department of Epidemiology and Biostatistics, Imperial College London, Department of Visceral and Thoracic Surgery [Kiel, Germany], University Hospital Schleswig-Holstein [Kiel, Germany], Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, entre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, Department of Laboratory Medicine and Department of Pathology, Mayo Clinic College of Medicine, Department of Molecular Virology, Immunology and Medical Genetics [Colombus], Ohio State University [Columbus] (OSU)-College of Medicine and Public Health [Colombus], Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School [Athens], Department of Medical Biosciences and Pathology, Umeå University, Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Dundee Technopole, CXR Biosciences Ltd, Karolinska Institutet [Stockholm], CINTRA / SEEE Nanyang Technological University, Nanyang Technological University [Singapour], Center for Astrophysical Sciences [Baltimore], Johns Hopkins University (JHU), Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology (MIT), Department of Preventive Medicine, University of Southern California (USC), Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Medstar Research Institute, Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Department of Internal Medicine, Epidemiology, Human Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Wageningen University and Research Centre [Wageningen] (WUR), Mount Sinai Hospital (MSH), Fraunhofer Institute for Manufacturing Engineering and Automation [Stuttgart] (IPA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Czech Academy of Sciences [Prague] (ASCR), Huyghe, Jeroen R [0000-0001-6027-9806], Harrison, Tabitha A [0000-0002-4173-7530], Chen, Sai [0000-0003-3106-5643], Schmit, Stephanie L [0000-0001-5931-1194], Jeon, Jihyoun [0000-0001-7003-3412], Schumacher, Fredrick R [0000-0002-3073-7463], Nelson, Sarah C [0000-0002-2109-6465], Sinnott-Armstrong, Nasa A [0000-0003-4490-0601], Alonso, M Henar [0000-0003-0285-5451], Arndt, Volker [0000-0001-9320-8684], Bézieau, Stéphane [0000-0003-0095-1319], Bishop, D Timothy [0000-0002-8752-8785], Brezina, Stefanie [0000-0001-5238-6900], Buchanan, Daniel D [0000-0003-2225-6675], Chanock, Stephen J [0000-0002-2324-3393], de la Chapelle, Albert [0000-0001-9345-9248], Easton, Douglas F [0000-0003-2444-3247], Hampe, Jochen [0000-0002-2421-6127], Hayes, Richard B [0000-0002-0918-661X], Hofer, Philipp [0000-0003-2550-6019], Huang, Wen-Yi [0000-0002-4440-3368], Hudson, Thomas J [0000-0002-1376-4849], Jacobs, Eric J [0000-0002-8458-7659], Jenkins, Mark A [0000-0002-8964-6160], Joshi, Amit D [0000-0001-7581-6934], Küry, Sébastien [0000-0001-5497-0465], Larsson, Susanna C [0000-0003-0118-0341], Laurie, Cecelia A [0000-0001-6569-2501], Martín, Vicente [0000-0003-0552-2804], Masala, Giovanna [0000-0002-5758-9069], Milne, Roger L [0000-0001-5764-7268], Naccarati, Alessio [0000-0001-5774-0905], Newcomb, Polly A [0000-0001-8786-0043], Pardini, Barbara [0000-0001-9571-4257], Perduca, Vittorio [0000-0003-0339-0473], Pharoah, Paul DP [0000-0001-8494-732X], Raskin, Leon [0000-0003-1195-7214], Rennert, Gad [0000-0002-8512-068X], Shin, Min-Ho [0000-0002-2217-5624], Toland, Amanda E [0000-0002-0271-1792], Vijai, Joseph [0000-0002-7933-151X], Weigl, Korbinian [0000-0003-4453-2036], Win, Aung Ko [0000-0002-2794-5261], Wolk, Alicja [0000-0001-7387-6845], Zheng, Wei [0000-0003-1226-070X], Bassik, Michael C [0000-0001-5185-8427], Moreno, Victor [0000-0002-2818-5487], Peters, Ulrike [0000-0001-5666-9318], and Apollo - University of Cambridge Repository
Subjects: Male, Nutrition and Disease, Colorectal cancer, IDENTIFIES 6, Genome-wide association study, 0302 clinical medicine, Risk Factors, Voeding en Ziekte, Genotype, ComputingMilieux_MISCELLANEOUS, Avaluació del risc per la salut, Genetics & Heredity, Genetics, 0303 health sciences, COLON-CANCER, 11 Medical And Health Sciences, Middle Aged, 3. Good health, Medical genetics, Female, RNA, Long Noncoding, Colorectal Neoplasms, Life Sciences & Biomedicine, Signal Transduction, EXPRESSION, medicine.medical_specialty, SUSCEPTIBILITY LOCI, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, Article, Health risk assessment, 03 medical and health sciences, QUALITY-CONTROL, Càncer colorectal, Journal Article, medicine, Life Science, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, VLAG, Aged, 030304 developmental biology, Global Nutrition, [SDV.GEN]Life Sciences [q-bio]/Genetics, Wereldvoeding, Science & Technology, ORGAN SIZE, MUTATIONS, Haplotype, Case-control study, 06 Biological Sciences, medicine.disease, Genetic architecture, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Human genome, LYSOPHOSPHATIDIC ACID, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract: To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P, Reporting Summary. Further information on experimental design is available in the Life Sciences Reporting Summary linked to this article.
Published: 2018

12. Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts

Author: Miguel Inacio da Silva Filho, Juan Sainz, Vicente Martín Sánchez, Manuel Martínez-Bueno, Kari Hemminki, Asta Försti, Pedro Sánchez-Rovira, Jose Manuel Sánchez-Maldonado, Katja Butterbach, Ludmila Vodickova, Paula Ludovico, Abhishek Kumar, Pavel Vodicka, Rob ter Horst, Stefanie Brezina, Victor Moreno, Yang Li, Hermann Brenner, Mihai G. Netea, Belém Sampaio-Marques, Andrea Gsur, Manuel Jurado, Anna Díez-Villanueva, Veronika Vymetalkova, Michael Hoffmeister, Francisco García-Verdejo, Jenny Chang-Claude, [et al.], CiiM, Zentrum für individualisierte Infektionsmedizin, Feodor-Lynen-Str.7, 30625 Hannover., and Universidade do Minho
Subjects: 0301 basic medicine, Cancer Research, Genetic variants, autophagy, Colorectal cancer, ATG5, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Genome-wide association study, colorectal cancer, CD38, Biology, Peripheral blood mononuclear cell, lcsh:RC254-282, Article, susceptibility, 03 medical and health sciences, 0302 clinical medicine, Autofàgia, Càncer colorectal, Genetic susceptibility, medicine, Autophagy, Allele, B cell, Science & Technology, genetic variants, Cancer, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Oncology, Susceptibility, 030220 oncology & carcinogenesis, Cancer research
Abstract: Simple Summary We investigated the influence of autophagy-related variants in modulating colorectal cancer (CRC) risk through a meta-analysis of genome-wide association study (GWAS) data from four large European cohorts. We found that genetic variants within the DAPK2 and ATG5 loci were associated with CRC risk. This study also shed some light onto the functional mechanisms behind the observed associations and demonstrated the impact of DAPK2rs11631973 and ATG5rs546456 polymorphisms on the modulation of host immune responses, blood derived-cell counts and serum inflammatory protein levels, which might be involved in promoting cancer development. No effect of the DAPK2 and ATG5 polymorphisms on the autophagy flux was observed, Acknowledgments: We kindly thank all individuals who agreed to participate in the DACHS, CRCGen, CORSA and Czech Republic Colorectal Cancer studies, as well as all cooperating physicians and students. We thank Hugo Sousa for the collection of healthy donors for the autophagy in vitro studies, Data Availability Statement: The genotype data used in the present study are available from the corresponding authors upon reasonable request. Functional data used in this project have been meticulously catalogued and archived in the BBMRI-NL data infrastructure (https://hfgp.bbmri.nl/, accessed on 13 December 2019) using the MOLGENIS open-source platform for scientific data [52]. This allows flexible data querying and download, including sufficiently rich metadata and interfaces for machine processing (R statistics, REST API) and using FAIR principles to optimise findability, accessibility, interoperability and reusability [53,54]., Funding: This work was partially supported by grants from the Instituto de Salud Carlos III (Madrid, Spain; PI12/02688 and PI17/02256). CORSA was funded by the Austrian Research Promotion Agency (FFG) BRIDGE grant (no. 829675, to Andrea Gsur), the “Herzfelder’sche Familienstiftung” (grant to Andrea Gsur). Czech Republic CCS was funded by GACR grants (18–09709S, 19–10543S and 20–03997S), ProgresQ28/1.LF and UNCE/MED/006 grants. This article is based upon work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology). A.K. is a recipient of a Ramalingaswami Re-Retry Faculty Fellowship (Grant; BT/RLF/Re-entry/38/2017) from the Department of Biotechnology (DBT), Government of India (GOI). V.M. received funding from the Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723, the Instituto de Salud Carlos III, co-funded by FEDER funds–a way to build Europe–grants PI14-00613, PI17-00092 and the Spanish Association Against Cancer (AECC) Scientific Foundation grant GCTRA18022MORE. K.H. was supported by European Union Horizon 2020 grant No. 856620. We thank the CERCA Programme, Generalitat de Catalunya for institutional support., The role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome-wide association study (GWAS) data from four independent European cohorts (8006 CRC cases and 7070 controls), two loci, DAPK2 (p = 2.19 × 10−5) and ATG5 (p = 6.28 × 10−4) were associated with the risk of CRC. Mechanistically, the DAPK2rs11631973G allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with Staphylococcus aureus (p = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood (p = 0.0038) and serum levels of en-RAGE (p = 0.0068). ATG5rs546456T allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS (p = 0.0088 and p = 0.0076, respectively), CD14+CD16− cell levels in blood (p = 0.0068) and serum levels of CCL19 and cortisol (p = 0.0052 and p = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the DAPK2 and ATG5 loci in the pathogenesis of CRC, likely through the modulation of host immune responses., Instituto de Salud Carlos III (Madrid, Spain; PI12/02688 and PI17/02256), CORSA was funded by the Austrian Research Promotion Agency (FFG), BRIDGE grant (no. 829675, to Andrea Gsur), Czech Republic CCS was funded by GACR grants (18–09709S, 19–10543S and 20–03997S), ProgresQ28/1.LF and UNCE/MED/006 grants, COST Action CA17118, supported by COST (European Cooperation in Science and Technology), A.K. is a recipient of a Ramalingaswami Re-Retry Faculty Fellowship (Grant; BT/RLF/Re-entry/38/2017) from the Department of Biotechnology (DBT), Government of India (GOI), Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723, the Instituto de Salud Carlos III, co-funded by FEDER funds–a way to build Europe–grants PI14-00613, PI17-00092 and the Spanish Association Against Cancer (AECC) Scientific Foundation grant GCTRA18022MORE., European Union Horizon 2020 grant No. 856620, CERCA Programme, Generalitat de Catalunya for institutional support
Published: 2021

13. Evidence for PTGER4 ,PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level

Author: Jesús Espinel, Ines Gockel, Daniela Collette, Thomas Schmidt, Gisela Keller, Katja Butterbach, Yogesh K. Vashist, Martin Kruschewski, Michael Knapp, P. Malfertheiner, Anne C. Böhmer, Angel Lanas, Elisabeth Mangold, Rafael Campo, Oliver Pech, Lutz Hamann, Markus Moehler, Jessica Becker, Aksana Höblinger, Jan Gehlen, Concha Thomson, Maria Asuncion Garcia-Gonzalez, Katharina Weise, Peter P. Grimminger, Hakan Alakus, Hermann Brenner, Hans Lippert, Jakob R. Izbicki, Sebastian J. Hofer, Hauke Lang, Evita Gasenko, Philipp Lingohr, Nicole Kreuser, Timo Hess, Fernando Geijo, Markus M. Nöthen, Marino Venerito, Iurii Krasniuk, Florian Lordick, Michael Vieth, Karsten Ridwelski, Claus Schildberg, Alexander F. Hagel, Christiane J. Bruns, Ralf R. Schumann, Katharina Messerle, Lothar Veits, Johannes Schumacher, Katja Ott, Julia Schröder, Marcis Leja, Vitalia Schüller, Limas Kupčinskas, Federico Sopena, Ernst Rodermann, Juozas Kupcinskas, Nikolaos Vassos, Ángeles Pérez-Aisa, Monika Ludwig, Ugne Gyvyte, Luis Bujanda, and Sophie K. M. Heinrichs
Subjects: Male, 0301 basic medicine, Cancer Research, Genotype, Quantitative Trait Loci, eQTL study, Biology, GPI-Linked Proteins, Polymorphism, Single Nucleotide, Genome, Transcriptome, 03 medical and health sciences, Antigens, Neoplasm, Stomach Neoplasms, Gene expression, medicine, Humans, SNP, Genetic Predisposition to Disease, Radiology, Nuclear Medicine and imaging, Gene, Genetic Association Studies, Original Research, Cancer Biology, Genetics, Gene Expression Profiling, Chromosome Mapping, Membrane Proteins, Chromosome, Cancer, medicine.disease, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Oncology, genetic association study, Case-Control Studies, Expression quantitative trait loci, gene expression, Chromosomes, Human, Pair 5, Female, Receptors, Prostaglandin E, EP4 Subtype, Acyltransferases, Chromosomes, Human, Pair 8
Abstract: Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 x 10(-04)) and on chromosome 8q24 at rs2585176 (P = 1.09 x 10(-09)). On chromosome 5p13 we found cis-eQTL effects with an up-regulation of PTGER4 expression in GC risk allele carrier (P = 9.27 x 10(-11)). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 x 10(-47)). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 x 10(-09)). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms.
Published: 2018

14. Mendelian randomisation study of age at menarche and age at menopause and the risk of colorectal cancer

Author: Sonja Neumeyer, Kenneth Offit, William M. Grady, Katja Butterbach, Stéphane Bézieau, Mingyang Song, Robert E. Schoen, Andrew T. Chan, Cornelia M. Ulrich, Victor Moreno, Anna H. Wu, Sonja I. Berndt, John D. Potter, Li Li, Graham G. Giles, Annika Lindblom, Daniel D. Buchanan, Michael Hoffmeister, Steven Gallinger, Jenny Chang-Claude, Bette J. Caan, Stephen J. Chanock, Paul D. Pharaoh, Hermann Brenner, Amit Joshi, Barbara L. Banbury, Mathieu Lemire, Lihong Qi, Clemens Schafmayer, Stephen B. Gruber, Volker Arndt, Gad Rennert, Li Hsu, Peter T. Campbell, John L. Hopper, Polly A. Newcomb, Edward Giovannucci, Susanna C. Larsson, Loic Le Marchand, Ulrike Peters, Martha L. Slattery, Michael O. Woods, Jochen Hampe, Emily White, James Y. Dai, Mark A. Jenkins, Yi Lin, Alicja Wolk, Graham Casey, Aung Ko Win, Stephanie A. Bien, Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, Cancer Research, Aging, 0302 clinical medicine, Medicine, 2.1 Biological and endogenous factors, Registries, Aetiology, Cancer, 2. Zero hunger, Confounding, Age Factors, Single Nucleotide, 3. Good health, Colo-Rectal Cancer, Menopause, 030220 oncology & carcinogenesis, Menarche, Public Health and Health Services, Female, Colorectal Neoplasms, Menopausa, medicine.medical_specialty, Oncology and Carcinogenesis, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Clinical Research, Càncer colorectal, Internal medicine, Genetics, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Polymorphism, business.industry, Contraception/Reproduction, Prevention, Case-control study, Odds ratio, Mendelian Randomization Analysis, medicine.disease, Estrogen, Colorectal cancer, Confidence interval, digestive system diseases, 030104 developmental biology, Good Health and Well Being, Logistic Models, Genetic epidemiology, Case-Control Studies, business, Digestive Diseases, Body mass index
Abstract: BACKGROUND: Substantial evidence supports an association between use of menopausal hormone therapy and decreased colorectal cancer (CRC) risk, indicating a role of exogenous sex hormones in CRC development. However, findings on endogenous oestrogen exposure and CRC are inconsistent. METHODS: We used a Mendelian randomisation approach to test for a causal effect of age at menarche and age at menopause as surrogates for endogenous oestrogen exposure on CRC risk. Weighted genetic risk scores based on 358 single-nucleotide polymorphisms associated with age at menarche and 51 single-nucleotide polymorphisms associated with age at menopause were used to estimate the association with CRC risk using logistic regression in 12,944 women diagnosed with CRC and 10,741 women without CRC from three consortia. Sensitivity analyses were conducted to address pleiotropy and possible confounding by body mass index. RESULTS: Genetic risk scores for age at menarche (odds ratio per year 0.98, 95% confidence interval: 0.95-1.02) and age at menopause (odds ratio 0.98, 95% confidence interval: 0.94-1.01) were not significantly associated with CRC risk. The sensitivity analyses yielded similar results. CONCLUSIONS: Our study does not support a causal relationship between genetic risk scores for age at menarche and age at menopause and CRC risk.
Published: 2018

15. Pathway analysis of genetic variants in folate‐mediated one‐carbon metabolism‐related genes and survival in a prospectively followed cohort of colorectal cancer patients

Author: Elisabeth J. Kap, Jenny Chang-Claude, Michael Hoffmeister, Nina Habermann, Katja Butterbach, Katrin Pfütze, Alexis Ulrich, Jolantha Beyerle, Yesilda Balavarca, Barbara Burwinkel, Jennifer Ose, Akke Botma, Martin Schneider, Katharina Buck, Petra Seibold, Lina Jansen, Cornelia M. Ulrich, Dominique Scherer, Hermann Brenner, and Axel Benner
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, Single-nucleotide polymorphism, survival, 03 medical and health sciences, 0302 clinical medicine, Polymorphism (computer science), Internal medicine, medicine, one‐carbon metabolism, Radiology, Nuclear Medicine and imaging, RC254-282, Original Research, biology, Proportional hazards model, business.industry, Paraoxonase, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Clinical Cancer Research, medicine.disease, PON1, 3. Good health, 030104 developmental biology, Fluorouracil, 030220 oncology & carcinogenesis, Methylenetetrahydrofolate reductase, biology.protein, business, polymorphisms, medicine.drug
Abstract: Folate‐mediated one‐carbon metabolism (FOCM) is a key pathway essential for nucleotide synthesis, DNA methylation, and repair. This pathway is a critical target for 5‐fluorouracil (5‐FU), which is predominantly used for colorectal cancer (CRC) treatment. A comprehensive assessment of polymorphisms in FOCM‐related genes and their association with prognosis has not yet been performed. Within 1,739 CRC cases aged ≥30 years diagnosed from 2003 to 2007 (DACHS study), we investigated 397 single nucleotide polymorphisms (SNPs) and 50 candidates in 48 FOCM‐related genes for associations with overall‐ (OS) and disease‐free survival (DFS) using multiple Cox regression (adjusted for age, sex, stage, grade, BMI, and alcohol). We investigated effect modification by 5‐FU‐based chemotherapy and assessed pathway‐specific effects. Correction for multiple testing was performed using false discovery rates (FDR). After a median follow‐up time of 5.0 years, 585 patients were deceased. For one candidate SNP in MTHFR and two in TYMS, we observed significant inverse associations with OS (MTHFR: rs1801133, C677T: HR het = 0.81, 95% CI: 0.67–0.97; TYMS: rs1001761: HR het = 0.82, 95% CI: 0.68–0.99 and rs2847149: HR het = 0.82, 95% CI: 0.68–0.99). After FDR correction, one polymorphism in paraoxonase 1 (PON1; rs3917538) was significantly associated with OS (HR het = 1.28, 95% CI: 1.07–1.53; HR hzv = 2.02, 95% CI:1.46–2.80; HR logAdd = 1.31, pFDR = 0.01). Adjusted pathway analyses showed significant associations for pyrimidine biosynthesis (P = 0.04) and fluorouracil drug metabolism (P
Published: 2018

16. Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation

Author: Domenica Gioffreda, Yasuhiro Shimizu, Serena Stigliano, Hidemi Ito, Kay-Tee Khaw, Carlo Lombardo, Martin Oliverius, Ioannis Papaconstantinou, Irena Valantiene, Pavel Soucek, Claudio Pasquali, Kazuo Hara, Verena Katzke, Federico Canzian, Hendrik Strothmann, Andrea Mambrini, Paola Fogar, Gabriele Capurso, Raffaele Pezzilli, Katarina Cuk, Anna Latiano, Olivier R. Busch, Chiara Valsuani, Katja Butterbach, Oliver Strobel, Jakob R. Izbicki, Pavel Vodicka, Thilo Hackert, William Greenhalf, Cosimo Sperti, Anna Katharina König, Angelo Andriulli, Francesca Tavano, Petra H.M. Peeters, Renata Talar-Wojnarowska, Willem Niesen, Giulia Martina Cavestro, Keitaro Matsuo, Beatrice Mohelnikova-Duchonova, Frederike Dijk, Yogesh K. Vashist, Stefano Landi, Maurizio Cantore, Hermann Brenner, Roberto Valente, Daniele Campa, Manuela Pastore, H. Bas Bueno-de-Mesquita, Carlo Federico Zambon, Roberto Salvia, Milena Di Leo, Maria Gazouli, Theron Johnson, Ewa Małecka-Panas, Timothy J. Key, Peter Macinga, Rudolf Kaaks, and Juozas Kupcinskas
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Pancreatic disease, endocrine system diseases, business.industry, Case-control study, Context (language use), medicine.disease, Bioinformatics, digestive system diseases, Minor allele frequency, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Pancreatic cancer, Internal medicine, medicine, Genetic predisposition, Pancreatitis, chronic, Risk factor, business
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share a consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639, rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous = 1.19, 95% CI 1.02-1.38, p = 0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous = 0.51, 95% CI 0.39-0.67, p = 1.10 × 10-6 ) and MORC4-rs 12837024 (ORhomozygous = 2.07 (1.55-2.77, ptrend = 0.7 × 10-11 ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639, rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants.
Published: 2017

17. Genetic polymorphisms in genes of class switch recombination and multiple myeloma risk and survival: an IMMEnSE study

Author: Stefanie Huhn, Krzysztof Jamroziak, Katalin Kadar, Daria Zawirska, Katja Butterbach, Herlander Marques, Joaquin Martinez-Lopez, Edyta Subocz, Federico Canzian, Ben Schöttker, Marc S. Raab, Victor Moreno, Ramón García Sanz, Vibeke Andersen, Ulla Vogel, Maximilian Merz, Rafael Rios, Hartmut Goldschmidt, Alessandro Martino, Anna Suska, Agnieszka Druzd-Sitek, Marcin Kruszewski, Andres Jerez, Gabriele Buda, Rui Manuel Reis, Jan Maciej Zaucha, Torben Barington, Aleksandra Butrym, Angelica Macauda, Judit Várkonyi, Emeline Perrial, Artur Jurczyszyn, Grzegorz Mazur, Grzegorz Helbig, Marek Dudziński, Juan Sainz, Eva Haastrup, Charles Dumontet, Annette Juul Vangsted, Hermann Brenner, Marcin Rymko, Marzena Wątek, Daniele Campa, Elżbieta Iskierka-Jażdżewska, Gergely Szombath, Fabienne Lesueur, Norbert Grzasko, and Universidade do Minho
Subjects: Male, Cancer Research, Medicina Básica [Ciências Médicas], Plasma cell, Lymphocyte Activation, susceptibility, Cohort Studies, DNA Ligase ATP, 0302 clinical medicine, Multiple myeloma, Overall survival, Genetics, Classswitch recombination, Progression-free survival, Hematology, Middle Aged, Prognosis, Gene Expression Regulation, Neoplastic, Survival Rate, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Ciências Médicas::Medicina Básica, Female, class switch recombination, Adult, overall survival, genetic polymorphisms, progression-free survival, Biology, Genetic polymorphisms, 03 medical and health sciences, Cytidine Deaminase, Biomarkers, Tumor, medicine, Humans, Maturation process, Gene, Aged, Polymorphism, Genetic, Science & Technology, Genetic variants, medicine.disease, Immunoglobulin Class Switching, Immunoglobulin class switching, Susceptibility, Case-Control Studies, Follow-Up Studies, 030215 immunology
Abstract: Genetic variants in genes acting during the maturation process of immature B-cell to differentiated plasma cell could influence the risk of developing multiple myeloma (MM). During B-cell maturation, several programmed genetic rearrangements occur to increase the variation of the immunoglobulin chains. Class switch recombination (CSR) is one of the most important among these mechanisms. Germline polymorphisms altering even subtly this process could play a role in the etiology and outcome of MM. We performed an association study of 30 genetic variants in the key CSR genes, using 2632 MM patients and 2848 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the Heidelberg MM Group and the ESTHER cohort. We found an association between LIG4-rs1555902 and decreased MM risk, which approached statistical significance, as well as significant associations between AICDA-rs3794318 and better outcome. Our results add to our knowledge on the genetic component of MM risk and survival., Partially supported by intramural funds of DKFZ, by grants PI12/02688 and PI17/02276 from Fondo de Investigaciones Sanitarias (Madrid, Spain), Instituto de Salud Carlos III, co-funded by FEDER funds –a way to build Europe– grant PI14-00613 and Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723. The ESTHER study was funded by grants from the Baden-Württemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany) and the Saarland Ministry of Social Affairs, Health, Women and Family (Saarbrücken, Germany)
Published: 2019

18. Genome-wide DNA methylation differences according to oestrogen receptor beta status in colorectal cancer

Author: Hermann Brenner, Wilfried Roth, Dominic Edelmann, Sonja Neumeyer, Elizabeth Alwers, Csaba Toth, Jenny Chang-Claude, Michael Hoffmeister, Odilia Popanda, Barbara Burwinkel, Cornelia Jäkel, Hendrik Bläker, Lina Jansen, Katja Butterbach, Esther Herpel, Ruijingfang Jiang, Axel Benner, and Peter Schmezer
Subjects: 0301 basic medicine, Adult, Male, Cancer Research, Colorectal cancer, Biology, Genome, Epigenesis, Genetic, 03 medical and health sciences, Tumour tissue, 0302 clinical medicine, medicine, Biomarkers, Tumor, Estrogen Receptor beta, Humans, Epigenetics, Oestrogen receptor, Beta (finance), Promoter Regions, Genetic, Molecular Biology, Aged, Aged, 80 and over, DNA Methylation, Middle Aged, medicine.disease, Prognosis, Gene Expression Regulation, Neoplastic, Survival Rate, 030104 developmental biology, 030220 oncology & carcinogenesis, Case-Control Studies, DNA methylation, Cancer research, Female, Colorectal Neoplasms, Hormone, Follow-Up Studies, Genome-Wide Association Study, Research Paper
Abstract: Involvement of sex hormones in colorectal cancer (CRC) development has been linked to oestrogen receptor β (ERβ). Expression of ERβ is found reduced in tumour tissue and inversely related to mortality. However, mechanisms are not well understood. Our study aimed to detect differentially methylated genes associated with ERβ expression, which could point to mechanisms by which ERβ could influence risk and prognosis of CRC. Epigenome-wide DNA methylation profiling was performed using Illumina HumanMethylation450k BeadChip arrays in two independent tumour sample sets of CRC patients recruited in 2003–2010 by the German DACHS study (discovery cohort n = 917, replication cohort n = 907). ERβ expression was measured using immunohistochemistry and scored as negative, moderate and high. Differentially methylated CpG sites and genomic regions were determined using limma in the R-package RnBeads. For the comparison of tumours with moderate/high ERβ versus negative expression, differentially methylated CpG sites were identified but not confirmed by replication. Comparing tumours of high with tumours of negative ERβ expression revealed 2,904 differentially methylated CpG sites of which 403 were replicated (FDR adjusted p-value
Published: 2019

19. Epigenome-wide search for association of serum 25-hydroxyvitamin D concentration with leukocyte DNA methylation in a large cohort of older men

Author: Ben Schöttker, Katja Butterbach, Melanie Bewerunge-Hudler, Hermann Brenner, and Ines Florath
Subjects: Epigenomics, Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Biology, Bioinformatics, White People, 03 medical and health sciences, symbols.namesake, Germany, Internal medicine, Leukocytes, Genetics, medicine, Vitamin D and neurology, Humans, Vitamin D, Aged, Confounding, dNaM, DNA Methylation, Middle Aged, 030104 developmental biology, Bonferroni correction, CpG site, Multiple comparisons problem, DNA methylation, symbols, CpG Islands, Cohort study
Abstract: Aim: We aimed for an epigenome-wide identification of vitamin D-associated CpG sites in leukocyte DNA. Materials & methods: Infinium HumanMethylation450BeadChip measurements in 402 Caucasian older men were evaluated for significant association with 25-hydroxy-vitamin (25(OH)D) using Spearman's correlation and median regression to adjust for confounding variables. A cross-validation approach as well as a bootstrapping procedure were implemented to determine the replicability of significant associations. Multiple testing was corrected for by Benjamini–Hochberg or Bonferroni. Results: Although in the screening subcohorts significant associations of DNAm with 25(OH)D were observed in the validation cohorts these associations were not replicated after adjustment for potential confounders. At none of the 361,945 CpGs a significant association of DNAm with 25(OH)D was found in all 100 random bootstrap samples, but in comparison at 462 CpGs for the well-established association with age. Conclusion: Leukocyte DNAm was not associated with 25(OH)D levels after validation and consideration of confounders.
Published: 2016

20. Smoking-Associated DNA Methylation Biomarkers and Their Predictive Value for All-Cause and Cardiovascular Mortality

Author: Ute Mons, Ines Florath, Katja Butterbach, Ben Schöttker, Bernd Holleczek, Hermann Brenner, Christian Stock, and Yan Zhang
Subjects: Male, Health, Toxicology and Mutagenesis, MEDLINE, Bioinformatics, Text mining, Humans, Medicine, Prospective Studies, Prospective cohort study, Aged, Proportional Hazards Models, Cardiovascular mortality, Proportional hazards model, business.industry, Research, Smoking, Public Health, Environmental and Occupational Health, Methylation, DNA Methylation, Middle Aged, Cardiovascular Diseases, DNA methylation, Female, business, Biomarkers, All cause mortality
Abstract: Background With epigenome-wide mapping of DNA methylation, a number of novel smoking-associated loci have been identified. Objectives We aimed to assess dose–response relationships of methylation at the top hits from the epigenome-wide methylation studies with smoking exposure as well as with total and cause-specific mortality. Methods In a population-based prospective cohort study in Germany, methylation was quantified in baseline blood DNA of 1,000 older adults by the Illumina 450K assay. Deaths were recorded during a median follow-up of 10.3 years. Dose–response relationships of smoking exposure with methylation at nine CpGs were modeled by restricted cubic spline regression. Associations of individual and aggregate methylation patterns with all-cause, cardiovascular, and cancer mortality were assessed by multiple Cox regression. Results Clear dose–response relationships with respect to current and lifetime smoking intensity were consistently observed for methylation at six of the nine CpGs. Seven of the nine CpGs were also associated with mortality outcomes to various extents. A methylation score based on the top two CpGs (cg05575921 and cg06126421) showed the strongest associations with all-cause, cardiovascular, and cancer mortality, with adjusted hazard ratios (95% CI) of 3.59 (2.10, 6.16), 7.41 (2.81, 19.54), and 2.48 (1.01, 6.08), respectively, for participants with methylation levels in the lowest quartile at both CpGs. Adding methylation at those two CpGs into a model that included the variables of the Systematic Coronary Risk Evaluation chart for fatal cardiovascular risk prediction improved the predictive discrimination. Conclusion The novel methylation biomarkers are highly informative for both smoking exposure and smoking-related mortality outcomes. In particular, these biomarkers may substantially improve cardiovascular risk prediction. Nevertheless, the findings of the present study need to be further validated in additional large longitudinal studies. Citation Zhang Y, Schöttker B, Florath I, Stock C, Butterbach K, Holleczek B, Mons U, Brenner H. 2016. Smoking-associated DNA methylation biomarkers and their predictive value for all-cause and cardiovascular mortality. Environ Health Perspect 124:67–74; http://dx.doi.org/10.1289/ehp.1409020
Published: 2016

21. CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk

Author: Robert E. Schoen, Carolyn M. Hutter, Martha L. Slattery, W. James Gauderman, Stephanie A. Rosse, Brent W. Zanke, Xabier García-Albéniz, Anja Rudolph, Jane C. Figueiredo, Michael Hoffmeister, Edward Giovannucci, Graham Casey, Ulrike Peters, Mathieu Lemire, Cornelia M. Ulrich, Thomas J. Hudson, Sonja I. Berndt, Mark D. Thornquist, Shuo Jiao, Noralane M. Lindor, Katja Butterbach, Jenny Chang-Claude, Stephen N. Thibodeau, Stephen J. Chanock, Marc J. Gunter, Andrew T. Chan, Bethann M. Pflugeisen, Li Hsu, John A. Baron, Shuji Ogino, Conghui Qu, Laurence N. Kolonel, Michelle Cotterchio, Hermann Brenner, Peter T. Campbell, Mark A. Jenkins, Greg S. Warnick, Richard B. Hayes, Christopher S. Carlson, John D. Potter, Yi Lin, Tabitha A. Harrison, John L. Hopper, Jian Gong, Robert W. Haile, Bette J. Caan, Deanna L. Stelling, Charles S. Fuchs, Emily White, Jennifer Y. Lin, David Duggan, Polly A. Newcomb, Loic Le Marchand, Daniela Seminara, Mengmeng Du, and Fredrick R. Schumacher
Subjects: 0301 basic medicine, Oncology, Cancer Research, Colorectal cancer, Genome-wide association study, Genetics & Genomics, Wald test, Prostate cancer, 0302 clinical medicine, Risk Factors, GWAS, Gene–environment interaction, Vitamin D3 24-Hydroxylase, gene–environment interaction, Estrogen Replacement Therapy, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, Drug Therapy, Combination, Female, Colorectal Neoplasms, Liver cancer, medicine.medical_specialty, Genotype, cytochrome P450, menopausal hormone therapy, colorectal cancer, Adenocarcinoma, Polymorphism, Single Nucleotide, 03 medical and health sciences, Breast cancer, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Aged, business.industry, Case-control study, Bayes Theorem, Estrogens, medicine.disease, Logistic Models, 030104 developmental biology, Case-Control Studies, Gene-Environment Interaction, Progestins, polymorphisms, business, Genome-Wide Association Study
Abstract: Background: Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene–environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT. Methods: We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen–progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case–control logistic regression as primary tests. The Cocktail test was used as secondary test. Results: The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52–0.72), P=4.8 × 10−9). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52–0.78), P=1.2 × 10−5 (alpha threshold=3.1 × 10−4). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61–1.50); A/C, 0.61 (0.39–0.95) and A/A, 0.40 (0.22–0.73), respectively. Conclusions: Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.
Published: 2016

22. Mendelian randomization analysis of C-reactive protein on colorectal cancer risk

Author: Martha L. Slattery, Edward Giovannucci, Petra Schrotz-King, Flavio Lejbkowicz, Susanna C. Larsson, Jenny Chang-Claude, Douglas F. Easton, Li Hsu, Emily White, Peter T. Campbell, Polly A. Newcomb, Robert E. Schoen, Mila Pinchev, Vicente Martín, Daniel D. Buchanan, Zhengyi Chen, Anna H. Wu, Sonja I. Berndt, Mingyang Song, Stephen B. Gruber, Mark A. Jenkins, Graham G. Giles, Annika Lindblom, Amit Joshi, Alicja Wolk, Paul D.P. Pharoah, Andrew T. Chan, Michelle Cotterchio, Walid Saliba, Michael Hoffmeister, Victor Moreno, Stephanie J. Weinstein, Demetrius Albanes, Hedy S. Rennert, Loic Le Marchand, Roger L. Milne, Johanna W. Lampe, Kenneth Offitt, James Y. Dai, Gad Rennert, Shuji Ogino, John L. Hopper, Volker Arndt, Xiaoliang Wang, William M. Grady, Ulrike Peters, Michael O. Woods, Li Li, Hermann Brenner, Graham Casey, Christa Stegmaier, Katja Butterbach, Stéphane Bézieau, Clemens Schafmayer, John D. Potter, Bette J. Caan, Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Cooperative Family Registry, Risk factors in diseases, Epidemiology, Colorectal cancer, colorectal cancer, Polymorphism, Single Nucleotide, Epidemiologia genètica, 03 medical and health sciences, 0302 clinical medicine, Càncer colorectal, Mendelian Randomization, Epidemiology of cancer, medicine, Cancer Family, Humans, Genetic epidemiology, Genetic Predisposition to Disease, 030212 general & internal medicine, Human services, Aged, Cancer prevention, Factors de risc en les malalties, business.industry, Proteins, Cancer, General Medicine, Mendelian Randomization Analysis, Middle Aged, medicine.disease, 3. Good health, Causality, 030104 developmental biology, C-Reactive Protein, Logistic Models, Family medicine, Female, business, Colorectal Neoplasms, Proteïnes
Abstract: GECCO (Genetics and Epidemiology of Colorectal Cancer Consortium) is supported by the National Cancer Institute (NCI), National Institutes of Health (NIH), U.S. Department of Health and Human Services (U01 CA137088; R01 CA059045; U01 CA164930). ASTERISK was funded by a Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte Contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC). COLO2&3 (Hawai’i Colorectal Cancer Studies 2 & 3) is supported by the NIH (R01 CA60987). DACHS (Darmkrebs: Chancen der Verhutung durch Screening) was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1 and BR 1704/17-1), the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A and 01ER1505B). DALS (Diet, Activity and Lifestyle Survey) is supported by the NIH (R01 CA48998 to P.A. Slattery). HPFS (Health Professionals Follow-up Study) is supported by the NIH (P01 CA055075, UM1 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003), NHS (Nurses’ Health Study) by the NIH (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003) and PHS (Physician’s Health Study) by the NIH (R01 CA042182). MEC (Multiethnic Cohort Study) is supported by the NIH (R37 CA54281, P01 CA033619, and R01 CA63464). OFCCR (the Ontario Registry for Studies of Familial Colorectal Cancer) was supported by NIH (U01 CA074783; see CCFR section above), and additional funding toward genetic analyses of OFCCR was supported by a GL2 grant from the Ontario Research Fund, Canadian Institutes of Health Research and a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. PLCO (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial) is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. PMH-CCFR (Postmenopausal Hormone Study-Colon Cancer Family Registry) is supported by the NIH (R01 CA076366 to P.A. Newcomb). VITAL (VITamins And Lifestyle) is supported by the NIH (K05 CA154337 to E.White). WHI (Women’s Health Initiative) is supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. X.Wang and E. White were also supported by the NCI (R25 CA094880). CORECT (the Colorectal Transdisciplinary Study) is supported by the NCI under RFA # CA-09-002 as part of the GAME-ON consortium (US NIH, U19 CA148107) with additional support from the NCI grants (R01 CA81488 and P30 CA14089), the National Human Genome Research Institute at the US NIH (T32 HG000040) and the National Institute of Environmental Health Sciences at the US NIH (T32 ES013678). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in CORECT, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or CORECT. CCFR (the Colon Cancer Family Registry) is supported by grant UM1 CA167551 from the US NCI and through cooperative agreements with members of the CCFR and principal investigators of the Australasian Colorectal Cancer Family Registry (US NIH, U01 CA074778 and U01/U24 CA097735), University of South California Consortium Colorectal Cancer Family Registry for Colon Cancer Studies (US NIH, U01/U24 CA074799), the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (US NIH, U01/U24 CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (US NIH, U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (US NIH, U01/U24 CA074794), and the University of Hawaii Colorectal Cancer Family Registry (US NIH, U01/U24 CA074806). The Colon CFR Illumina GWAS was supported by NCI/NIH grant U01 CA122839 and R01 CA143237 to G Casey. CPSII (the Cancer Prevention Study-II Nutrition Cohort) is funded by the American Cancer Society. MECC was supported by the NIH, U.S. Department of Health and Human Services (R01 CA81488 to SB Gruber and G Rennert). The MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria, GALEON: FIS Intrasalud (PI13/01136). The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553 and 504711, and by infrastructure provided by Cancer Council Victoria. The NFCCR (Newfoundland Colorectal Cancer Registry) was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the NIH, U.S. Department of Health and Human Serivces (U01 CA74783); and National Cancer Institute of Canada grants (18223 and 18226). The Kentucky study was supported by the US NCI R01 CA136726, and the Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8). The Spain study was supported by Instituto de Salud Carlos III, co-funded by FEDER funds –a way to build Europe– grants PI14-613 and PI09-1286. SEARCH was supported by the Cancer Research UK (C490/A16561). The Sweden-Wolk was supported by grants from the Swedish Research Council/Infrastructure grant, the Swedish Cancer Foundation and Karolinska Institute’s Distinguished Professor Award to Alicja Wolk. The ATBC Study is supported by the Intramural Research Program of the U.S. NCI and by U.S. Public Health Service contract HHSN261201500005C from the NCI, Department of Health and Human Services. The ColoCare-heidelberg and the ColoCare-Seattle studies were funded by the US NIH (grants 2P30CA015704-40, R01 CA189184 and U01 CA152756), the Matthias Lackas-Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. ESTER_VERDI was supported by grants from the Baden-Wϋrttemberg Ministry of Science. The work at MSKCC (Memorial Sloan Kettering Cancer Center in New York) was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. D. Buchanan is also supported by University of Melbourne Research at Melbourne Accelerator Program (R@MAP) and NHMRC R.D. Wright Career Development Fellowship. Dr. M. Song was supported by the American Cancer Society (Grant number MRSG-17-220-01 – NEC to M.S.); by the 2017 AACR-AstraZeneca Fellowship in Immuno-oncology Research (Grant Number 17-40-12-SONG to M.S.); by the U.S. National Institutes of Health (NIH) grants [K99 CA215314 to M.S.].
Published: 2018

23. Discovery of a novel epigenetic cancer marker related to the oxidative status of human blood

Author: Kai Uwe Saum, Yan Zhang, Bernd Holleczek, Melanie Bewerunge-Hudler, Katja Butterbach, Eugène H.J.M. Jansen, Jonathan A Heiss, Ben Schöttker, and Hermann Brenner
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Cancer, Methylation, Biology, Bioinformatics, medicine.disease, medicine.disease_cause, 3. Good health, CpG site, Internal medicine, DNA methylation, Genetics, medicine, Biomarker (medicine), Body region, Epigenetics, Oxidative stress
Abstract: Long-lasting oxidative stress exposure may lead to relatively stable epigenetic modifications of the DNA in order to activate anti-oxidative defence mechanisms. Oxidative stress related DNA methylation may therefore be associated (causally or as a by-product) with cancer. We measured derivatives of reactive oxygen metabolites (D-ROM), total thiol levels (TTL) and DNA methylation with the Illumina Infinium 450K BeadChip in three samples of German individuals aged ≥50 years: n = 1,000 ESTHER study baseline participants (DNA methylation only), n = 99 ESTHER eight-year follow-up participants and n = 142 participants of the BLITZ study. The correlation coefficient of methylation at cg10342304 and D-ROM in the ESTHER 8-year follow-up sample (r = −0.427; P = 1 × 10−5) was replicated with a P-value indicating statistical significance after correction for multiple testing in the BLITZ sample (r = −0.192; P = 0.022). The association was robust to adjusting for potential confounders. In the ESTHER baseline sample, the hazard ratio for cancer development in 11 years of follow-up comparing bottom and top quartile of DNA methylation at cg10342304 was 1.86 (95%-confidence-interval 1.01–3.43). In summary, this first epigenome-wide screening and replication study with oxidative status markers observed a negative correlation of D-ROM levels and DNA methylation at cg10342304 in two independent cohorts. This CpG site is located in the body region of the nucleoredoxin gene. The nucleoredoxin protein is a redox-dependent inhibitor of the Wnt/s-catenin signaling pathway, a well-characterized cancer pathway. If the observed CpG-cancer association can be successfully replicated by other studies, this epigenetic marker could be an interesting biomarker of cancer risk. © 2015 Wiley Periodicals, Inc.
Published: 2015

24. Prediction of individual genetic risk to prostate cancer using a polygenic score

Author: Cezary Cybulski, Rosalind A. Eeles, Douglas F. Easton, Robert Szulkin, Nora Pashayan, Timothy J. Key, B. E. Henderson, G.G. Giles, Hardev Pandha, Jenny L Donovan, Zsofia Kote-Jarai, Henrik Grönberg, Jong Y. Park, Johanna Schleutker, Kenneth Muir, Melissa C. Southey, Fredrick R. Schumacher, Manuel Luedeke, Markus Aly, David E. Neal, Paul D.P. Pharoah, Ruth C. Travis, Børge G. Nordestgaard, Jyotsna Batra, D J Schaid, Fredrik Wiklund, Judith A. Clements, Amanda B. Spurdle, Katja Butterbach, Lisa A. Cannon-Albright, Janet L. Stanford, Kathleen Herkommer, Adam S. Kibel, W. Vogel, Wojciech Kluźniak, Vanio Mitev, Paula Paulo, Liesel M. FitzGerald, Hermann Brenner, T A Sellers, Shannon K. McDonnell, Tammela Tlj., Lin H-Y., Freddie C. Hamdy, Ali Amin Al Olama, Jan Lubinski, Manuel R. Teixeira, C. Slavov, S. N. Thibodeau, Tom Whitington, C. Stegmaier, Andrzej M. Kierzek, Agnieszka Michael, Christiane Maier, Christopher A. Haiman, Sofia Maia, Khaw K-T., Tiina Wahlfors, Martin Eklund, Radka Kaneva, and Sara Benlloch
Subjects: Linkage disequilibrium, education.field_of_study, business.industry, Urology, Population, Area under the curve, Disease, Bioinformatics, medicine.disease, Prostate cancer, Oncology, Genetic marker, Cohort, Genetic variation, Medicine, business, education
Abstract: BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. METHODS: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.
Published: 2015

25. TERTgene harbors multiple variants associated with pancreatic cancer susceptibility

Author: Juozas Kupcinskas, Beatrice Mohelnikova-Duchonova, Franco Bambi, Ewa Małecka-Panas, Charles Kooperberg, Sergio Pedrazzoli, Katja Butterbach, Gabriele Capurso, Paola Pacetti, Eithne Costello, Federico Canzian, Niccola Funel, Stephen J. Chanock, Harvey A. Risch, Audrius Ivanauskas, Carlo Federico Zambon, Maria Gazouli, Wei Zheng, Stefano Landi, Maurizio Cantore, Claudio Pasquali, Laufey T. Amundadottir, Eric J. Jacobs, Thilo Hackert, William Greenhalf, Paige M. Bracci, Raffaele Pezzilli, Cosimo Sperti, Francesca Tavano, Nicholas J. Wareham, Alan A. Arslan, Ludmila Vodickova, Sara H. Olson, Pavel Vodicka, Claudio Bassi, Melissa A. Austin, Nathalia A. Giese, Rachael S. Stolzenberg-Solomon, Aldo Scarpa, Donghui Li, Kala Visvanathan, Miroslav Ryska, Julie E. Buring, Renata Talar-Wojnarowska, Paola Fogar, Charles S. Fuchs, Domenica Gioffreda, Timothy J. Key, Hermann Brenner, Sean P. Cleary, Daniele Campa, Ada Piepoli, George Theodoropoulos, Patricia Hartge, Jens Werner, Peter Kraft, Pavel Soucek, Brian M. Wolpin, Alison P. Klein, Krzysztof Jamroziak, Cosmeri Rizzato, Andrea Mambrini, Gloria M. Petersen, Howard D. Sesso, Gianfranco Delle Fave, Oliver Strobel, Aida Karina Dieffenbach, H. B. Bueno-De-Mesquita, Zhaoming Wang, and Ivana Holcatova
Subjects: Genetics, Cancer Research, Telomerase, Linkage disequilibrium, Pancreatic disease, Single-nucleotide polymorphism, Biology, medicine.disease, Telomerase RNA component, Oncology, Genetic marker, Pancreatic cancer, medicine, Cancer research, Telomerase reverse transcriptase
Abstract: A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio=0.85; 95% confidence interval=0.80-0.90, p=8.3 × 10-8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2=0.07, D′=0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p=3.0 × 10-5), rs4583925 (p=4.0 × 10-5) and rs2735948 (p=5.0 × 10-5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants. What's new? Most pancreatic cancer patients do not survive long after diagnosis, and, so far, there are not many genetic markers to help screen for the disease. In search of genetic predictors of pancreatic cancer, the authors zoomed in on a region linked to susceptibility to the disease. They measured the frequency of different variants of two genes, telomerase reverse transcriptase and telomerase RNA component, among thousands of pancreatic cancer patients and controls. They identified several variants of the TERT gene that indicate a boosted pancreatic cancer risk, and which may develop into useful prognostic tools.
Published: 2015

26. F2RL3methylation, lung cancer incidence and mortality

Author: Rongxi Yang, Yan Zhang, Katja Butterbach, José M Ordóñez-Mena, Bernd Holleczek, Ben Schöttker, Hermann Brenner, and Barbara Burwinkel
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Proportional hazards model, business.industry, Incidence (epidemiology), Hazard ratio, Methylation, medicine.disease, F2RL3, Internal medicine, Immunology, medicine, Lung cancer, Prospective cohort study, business, Cohort study
Abstract: © 2015 UICC.Smoking accounts for a large share of lung cancer. F2RL3 methylation was recently identified as a biomarker closely reflecting both current and past smoking exposure. We aimed to assess the associations of F2RL3 methylation with lung cancer incidence and mortality. In a large population-based cohort study, F2RL3 methylation was measured in baseline blood samples of 4,987 participants by MassARRAY. Associations of F2RL3 methylation and smoking with lung cancer incidence/mortality during a median follow-up of 10.9 years were assessed by Cox regression, controlling for potential confounders. The ability of F2RL3 methylation to predict lung cancer was examined by Harrell's C statistics. Hypomethylation at F2RL3 was strongly associated with both lung cancer incidence and mortality, with age- and sex-adjusted hazard ratios (HR; 95% CI) of 9.99 (5.61-17.79) and 16.86 (8.53-33.34), respectively, for participants whose methylation intensity were ≤0.54 compared with whose methylation intensity were ≥0.75. Strongly elevated HRs of 2.88 (1.42-5.84) and 5.17 (2.28-11.70) persisted even after controlling for multiple covariates including smoking status and pack-years. With fully adjusted HRs of 9.92 (2.88-34.12) and 16.48 (4.10-66.15), the associations between methylation and the two outcomes were particularly strong among participants≥65 years. Combination of F2RL3 methylation and pack-years predicted lung cancer incidence with high accuracy (optimism-corrected Harrell's C statistics=0.86 for participants≥65 years). These findings suggested that F2RL3 methylation is a very strong predictor of lung cancer risk and mortality, particularly at older age. The potential implications of F2RL3 methylation for early detection, risk stratification and prevention of lung cancer warrant further exploration.
Published: 2015

27. Evidence for PTGER4, PSCA and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level

Author: Ines Gockel, Thomas Schmidt, Markus M. Nöthen, Markus Möhler, Karsten Ridwelski, Florian Lordick, Claus Schildberg, Yogesh K. Vashist, Alexander F. Hagel, MA Gonzalez-Carmona, Michael Vieth, Hans Lippert, Angel Lanas, Ralf R. Schumann, Limas Kupčinskas, Philipp Lingohr, Iurii Krasniuk, Peter P. Grimminger, M Ludwig, Johannes Schumacher, Martin Kruschewski, Oliver Pech, Ugne Gyvyte, Timo Hess, A Höblinger, Sophie K. M. Heinrichs, P. Malfertheiner, E. Mangold, J. R. Izbicki, Lutz Hamann, M.W. Büchler, Christiane J. Bruns, Marcis Leja, Katja Ott, Lothar Veits, Marino Venerito, Maria Asuncion Garcia-Gonzalez, Hermann Brenner, Katja Butterbach, E Rodermann, J Becker, Juozas Kupcinskas, Gisela Keller, and Michael Knapp
Subjects: Transcriptome, Genetics, medicine, Cancer, Biology, medicine.disease, Gene, Genome
Published: 2017

28. Association analysis identifies 65 new breast cancer risk loci

Author: Michael Jones, Dong-Young Noh, Martha J. Shrubsole, Chen-Yang Shen, Xiaoqing Chen, Esther M. John, Patricia Harrington, Quinten Waisfisz, Sue K. Park, Miriam Dwek, Christa Stegmaier, Sibylle Loibl, Wing-Yee Lo, Suleeporn Sangrajrang, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Christof Sohn, Keun-Young Yoo, Arja Jukkola-Vuorinen, Kathrin Thöne, James McKay, John J. Spinelli, Brian D. Carter, Elza Khusnutdinova, Francois Bacot, Paul L. Auer, Anna H. Wu, Christopher I. Amos, Johanna I. Kiiski, Hans Wildiers, Manjeet K. Bolla, Soo Hwang Teo, Julie M. Cunningham, Zhaoming Wang, Dieter Flesch-Janys, Argyrios Ziogas, Ann Smeets, Min Hyuk Lee, Xiaohong R. Yang, Carl Blomqvist, Natalia Antonenkova, Vassilios Georgoulias, Siranoush Manoukian, Anne Lise Børresen-Dale, Montserrat Garcia-Closas, Priyanka Sharma, Michael J. Kerin, Loic Le Marchand, Yoshio Kasuga, Michael Untch, Thomas Brüning, Natalia Bogdanova, Juliet D. French, Mark E. Sherman, Diana Eccles, Don M. Conroy, Marcia Adams, Pascal Guénel, Jonine D. Figueroa, Somchai Thanasitthichai, Jonathan Beesley, Paolo Peterlongo, Angela Cox, Graham G. Giles, Hans Christiansen, Irene L. Andrulis, Caroline Baynes, V. Shane Pankratz, Kristine Jones, Wei Zheng, Motoki Iwasaki, Rita K. Schmutzler, Julian Peto, Sara Margolin, Hedy S. Rennert, Hidemi Ito, Caroline Seynaeve, Jirong Long, Rachel Lloyd, Mark S. Goldberg, Javier Benitez, Børge G. Nordestgaard, Kathleen E. Malone, A. Heather Eliassen, Valerie Rhenius, Kristan J. Aronson, Maartje J. Hooning, Ursula Eilber, Christopher A. Haiman, Ji Yeob Choi, Jaana M. Hartikainen, Ian W. Brock, Barbara Burwinkel, Brigitte Rack, Mitul Shah, Matthias W. Beckmann, Belynda Hicks, Bernardo Bonanni, Alexander Hein, Leslie Bernstein, Christine L. Clarke, Emilie Cordina-Duverger, Sabine Behrens, Hoda Anton-Culver, Angela Brooks-Wilson, Bin Zhu, Gord Glendon, Banu Arun, José A. García-Sáenz, Jose Ignacio Arias Perez, Anne Grundy, Ans M.W. van den Ouweland, Nadege Presneau, Volker Arndt, Mikael Eriksson, Simon S. Cross, Craig Luccarini, Anthony J. Swerdlow, Veli-Matti Kosma, Hui Miao, Ming-Feng Hou, Hiroji Iwata, Christi J. van Asperen, Henrik Flyger, Jennifer Stone, Qin Wang, Penny Soucy, Heli Nevanlinna, Jane Heyworth, Shoichiro Tsugane, Annika Lindblom, Curtis Olswold, Trinidad Caldés, Laura Fachal, Ed Dicks, Shirley Hui, Katja Butterbach, Alison M. Dunning, Peter Devilee, Qiuyin Cai, Antonis C. Antoniou, Diether Lambrechts, Katarzyna Kaczmarek, Katri Pylkäs, Fredrick R. Schumacher, Arif B. Ekici, Aaron D. Norman, Jolanta Lissowska, Daniel C. Tessier, N Hamel, Paolo Radice, Håkan Olsson, Vessela N. Kristensen, Ling Tong, Harald Surowy, Rulla M. Tamimi, Jonathan Tyrer, Michael P. Lux, Stacey L. Edwards, Kathryn J. Ruddy, Giske Ursin, Myrto Barrdahl, Xiao-Ou Shu, Primitiva Menéndez, Sara Y. Brucker, Elad Ziv, Kenneth Muir, Eric Hahnen, Andy C. H. Lee, Rodney J. Scott, Lothar Haeberle, Darya Prokofyeva, Isabel dos-Santos-Silva, Peter Kraft, David G. Cox, Jong Won Lee, Sunil R. Lakhani, Kelly-Anne Phillips, Douglas F. Easton, Melissa C. Southey, Jan Lubinski, Jose E. Castelao, Hanne Meijers-Heijboer, Ivana Maleva Kostovska, Siddhartha Kar, Renske Keeman, Celine M. Vachon, Diana Torres, Stephen J. Chanock, Jack A. Taylor, Emiel J. Th. Rutgers, Chuen Neng Lee, Jason Vollenweider, Gadi Rennert, Jane Romm, Amy E. McCart Reed, Kee Seng Chia, Thomas Rüdiger, Anja Rudolph, Catriona McLean, David Van Den Berg, Christopher G. Scott, Mervi Grip, Lucy Xia, Georgia Chenevix-Trench, Robert Winqvist, Mary Beth Terry, Jenny Chang-Claude, Hans-Ulrich Ulmer, Mikael Hartman, Dona N. Ho, Maria Kabisch, Christoph Engel, Claire Mulot, Grethe I. Grenaker Alnæs, Arto Mannermaa, Nazneen Rahman, Tjoung-Won Park-Simon, Atocha Romero, Lin Fritschi, Manuela Gago-Dominguez, Matthias Ruebner, Valerie Gaborieau, Keitaro Matsuo, Asha Rostamianfar, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, J.-P. Meyer, Sara Lindström, Annegien Broeks, Audrey Lemaçon, Tsun Leung Chan, Tongguang Cheng, Robert J. MacInnis, Habibul Ahsan, Federico Canzian, Paul Brennan, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Jacek Gronwald, Sung-Won Kim, Daehee Kang, Daniel O. Stram, Nichola Johnson, Rob B. van der Luijt, Sten Cornelissen, Camilla Wendt, Dylan M. Glubb, Olufunmilayo I. Olopade, Usha Menon, David J. Hunter, Kristiina Aittomäki, Jamie Allen, Chiu-Chen Tseng, Keith Humphreys, Edmond S. K. Ma, Peter Hillemanns, Hiltrud Brauch, Chia-Ni Hsiung, Sheila Seal, Junko Ishiguro, Dale P. Sandler, Peter Schürmann, Gary D. Bader, Sarah Stewart-Brown, Flavio Lejbkowicz, Marike Gabrielson, Wolfgang Janni, Judith S. Brand, Jingmei Li, Ava Kwong, Stig E. Bojesen, Ying Zheng, Mila Pinchev, Yu Tang Gao, Susan E. Hankinson, Elinor J. Sawyer, Per Broberg, Sofia Khan, Grace Sheng, Alfons Meindl, Margriet Collée, Jyh-Cherng Yu, Ute Krüger, Louise A. Brinton, Elizabeth W. Pugh, Thilo Dörk, Hilary K. Finucane, Peter A. Fasching, Shan Wang-Gohrke, Jenna Lilyquist, Muriel A. Adank, Marjanka K. Schmidt, Susan M. Gapstur, Sune F. Nielsen, Maya Ghoussaini, Minouk J. Schoemaker, Roger L. Milne, Jacques Simard, Clarice R. Weinberg, Kyriaki Michailidou, Shivaani Mariapun, Rob A. E. M. Tollenaar, Lizet E. van der Kolk, Nicola Miller, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Ross L. Prentice, Anna Marie Mulligan, Jason S. Carroll, Taiki Yamaji, Carolina Ellberg, Mingajeva Elvira, Olivia Fletcher, Arnaud Droit, Per Hall, Maria Elena Martinez, Maria Tengström, Hui Cai, Xia Jiang, Janet E. Olson, Julia A. Knight, Nick Orr, Angel Carracedo, Guanmengqian Huang, Martine Dumont, Cheng Har Yip, Tom Maishman, Mary B. Daly, Artitaya Lophatananon, Niclas Håkansson, Steven N. Hart, Nur Aishah Taib, Andreas Schneeweiss, Daniel F. Schmidt, Daniel Vincent, Antoinette Hollestelle, Dimitrios Mavroudis, JoAnn E. Manson, Joe Dennis, Walter C. Willett, Rudolf Kaaks, Karen McCue, Enes Makalic, Kimberly F. Doheny, Eunjung Lee, Robert N. Hoover, Fergus J. Couch, Ute Hamann, Alice S. Whittemore, Hermann Brenner, Lorraine Durcan, Kamila Czene, Patrick Neven, John L. Hopper, Clinical Genetics, Medical Oncology, Human Genetics, CCA - Cancer biology and immunology, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Tyrer, Jonathan [0000-0003-3724-4757], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Allen, Jamie [0000-0002-8677-2225], Fachal Vilar, Laura [0000-0002-7256-9752], Carroll, Jason [0000-0003-3643-0080], Rhenius, Valerie [0000-0003-4215-3235], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Multifactorial Inheritance, Genome-wide association study, Regulatory Sequences, Nucleic Acid, skin and connective tissue diseases, Cancer genetics, Genetics, Multidisciplinary, medicine.diagnostic_test, 3. Good health, Europe, annotation, Medical genetics, Female, Asian Continental Ancestry Group, medicine.medical_specialty, Asia, architecture, European Continental Ancestry Group, ABCTB Investigators, Locus (genetics), Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, White People, NBCS Collaborators, 03 medical and health sciences, Breast cancer, Asian People, SDG 3 - Good Health and Well-being, Genetic variation, ConFab/AOCS Investigators, expression, medicine, Genetic predisposition, Journal Article, Humans, Computer Simulation, Genetic Predisposition to Disease, biological pathways, Genetic association, Genetic testing, Genetic association study, Binding Sites, interaction networks, medicine.disease, comprehensive molecular portraits, mutations, susceptibility loci, 030104 developmental biology, Genetic Loci, genome-wide association, protein, Transcription Factors, Genome-Wide Association Study
Abstract: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P
Published: 2017

29. Frailty and telomere length: Cross-sectional analysis in 3537 older adults from the ESTHER cohort

Author: Katja Butterbach, Kai Uwe Saum, Heiko Müller, Aida Karina Dieffenbach, Hermann Stammer, Federico Canzian, Klaus Hauer, Hermann Brenner, Matthias Schick, Petra Boukamp, Christa Stegmaier, Bernd Holleczek, and Aysel Müezzinler
Subjects: Genetic Markers, Male, Gerontology, Aging, Cross-sectional study, Frail Elderly, Gene Dosage, Frailty Index, Polymerase Chain Reaction, Biochemistry, Correlation, Age Distribution, Sex Factors, Endocrinology, Predictive Value of Tests, Germany, Genetics, Humans, Medicine, Sex Distribution, Geriatric Assessment, Molecular Biology, Telomere Shortening, Aged, business.industry, Age Factors, Cell Biology, Baseline data, Middle Aged, Telomere, Uncorrelated, Cross-Sectional Studies, Cohort, Female, business, Cohort study, Demography
Abstract: Both telomere length and frailty were observed to be associated with aging. Whether and to what extent telomere length is related to frailty is essentially unknown. In this cross-sectional analysis of baseline data of 3537 community-dwelling adults aged 50 to 75 years of a large German cohort study, we assessed the hypothesis that shorter telomere length might be a biological marker for frailty. Using whole blood DNA we examined mean telomere repeat copy to single gene copy number (T/S ratio) using quantitative PCR. Construction of a frailty index (FI) was based on a deficit accumulation approach, which quantifies frailty as ratio of the deficits present divided by the total number of deficits considered. Mean FI was determined according to age by tertiles of T/S ratio. Furthermore, we used correlation analyses stratified for gender and age groups to examine the association of the T/S ratio with frailty. Mean FI value was similar across tertiles of the T/S ratio (0.24±0.14, 0.24±0.14 and 0.23±0.14, respectively (p=0.09)), and FI and the T/S ratio were uncorrelated in gender- and age-specific analyses. In conclusion, T/S ratio and frailty were unrelated in this large sample of older adults. T/S ratio may therefore not be a meaningful biological marker for frailty.
Published: 2014

30. Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

Author: Artur Jurczyszyn, Juan Sainz, Charles Dumontet, Niels Weinhold, Annette Juul Vangsted, Ulla Vogel, Katja Butterbach, Aida Karina Dieffenbach, Enrico Orciuolo, Judit Várkonyi, Daniele Campa, Stefano Landi, Krzysztof Jamroziak, Alessandro Martino, Svend Erik Hove Jacobsen, Federica Gemignani, Gabriele Buda, Anna Maria Rossi, Hartmut Goldschmidt, Vibeke Andersen, Joaquin Martinez-Lopez, María José Moreno, Marek Dudziński, Rafael Rios, Marzena Wątek, Mario Petrini, Anna Stępień, Federico Canzian, Herlander Marques, Victor Moreno, Ramón García-Sanz, Fabienne Lesueur, Jens Hillengass, Manuel Jurado, Rui Manuel Reis, and Hermann Brenner
Subjects: Genetics, Oncology, 0303 health sciences, Cancer Research, medicine.medical_specialty, Telomerase, 4. Education, Biology, medicine.disease, 3. Good health, Telomere, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, Christian ministry, Gene, Multiple myeloma, 030304 developmental biology
Abstract: Grant sponsor: Polish Ministry of Science and Higher Education; Grant number: NN402178334; Grant sponsors: Research Fund at Region Sjaelland, DK; Baden-Wurttemberg State Ministry of Science, Research and Arts; CRIS Foundation
Published: 2014

31. Vitamin D Receptor Genotype rs731236 (Taq1) and Breast Cancer Prognosis

Author: Heiko Müller, Katja Butterbach, Barbara Burwinkel, Ben Schöttker, Bernd Holleczek, Hermann Brenner, Ulrike Haug, Laura Perna, and Volker Arndt
Subjects: Oncology, medicine.medical_specialty, Genotype, Epidemiology, medicine.medical_treatment, Breast Neoplasms, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Calcitriol receptor, Cohort Studies, Breast cancer, Germany, Internal medicine, Biomarkers, Tumor, Vitamin D and neurology, Humans, Medicine, Genetic Predisposition to Disease, Family history, skin and connective tissue diseases, Radical mastectomy, Aged, Neoplasm Staging, Gynecology, business.industry, Proportional hazards model, Cancer, DNA, Neoplasm, Middle Aged, Prognosis, medicine.disease, Survival Rate, Receptors, Calcitriol, Female, business, Body mass index, Follow-Up Studies
Abstract: Several studies have suggested that the anticancerogenous effects of vitamin D might be modulated by genetic variants in the vitamin D receptor (VDR) gene. The association of VDR polymorphisms with breast cancer–specific and all-cause mortality after a breast cancer diagnosis remains, however, largely unexplored. We assessed the association of genetic variants in VDR (rs731236, rs1989969, rs2228570, and 11568820) with breast cancer survival in a sample of 498 patients with breast cancer with a mean age at diagnosis of 61 years from Saarland, Germany, who were followed for up to 5 years with respect to total and breast cancer–specific mortality (56 and 48 events, respectively). Adjusted HRs with 95% confidence intervals (CI) were estimated by Cox regression models. We found that patients with breast cancer homozygous for the rare allele of rs731236 (15% of the women in our cohort) had a tendency toward an increased risk for breast cancer–specific mortality. The HR (95% CI) adjusted for age and breast cancer stage was 2.8 (1.1–7.2) for breast cancer–specific mortality and 2.1 (0.9–4.9) for total mortality. Additional adjustment for family history of breast cancer, radical mastectomy, and body mass index only marginally changed the estimates. No association was found for rs1989969, rs2228570, and rs11568820. Our analysis suggests that VDR polymorphism rs731236 might be associated with breast cancer–specific mortality, and if our findings are confirmed in future bigger studies rs731236 might deserve consideration as a prognostic factor in clinical care of patients with breast cancer. Cancer Epidemiol Biomarkers Prev; 22(3); 437–42. ©2012 AACR.
Published: 2013

32. PRRC2A and BCL2L11 gene variants influence risk of non-Hodgkin lymphoma: results from the InterLymph consortium

Author: Danica R. Skibola, Lenka Foretova, Lindsay M. Morton, James R. Cerhan, Sophia S. Wang, John J. Spinelli, Eran Halperin, Stephen J. Chanock, Stephen M. Ansell, Paul Brennan, Luz Agana, Mark P. Purdue, Alexandra Nieters, Anne Kricker, Alice H. Wang, Marc Maynadié, Silvia de Sanjosé, Paige M. Bracci, Lucia Conde, Katja Butterbach, Richard K. Severson, Yawei Zhang, Jacques Riby, Anneclaire J. De Roos, Christine F. Skibola, Patricia Hartge, Wendy Cozen, Anne J. Novak, Claire M. Vajdic, Qing Lan, Susan L. Slager, Nathaniel Rothman, Yolanda Benavente, Nikolaus Becker, Anthony Staines, Pierluigi Cocco, Tait D. Shanafelt, Andrew E. Grulich, Bruce K. Armstrong, Tongzhang Zheng, Paolo Boffetta, Martyn T. Smith, Angela Brooks-Wilson, Nieters, A., Conde, L., Slager, S.L., Brooks-Wilson, A., Morton, L., Skibola, D.R., Novak, A.J., Riby, J., Ansell, S.M., Halperin, E., Shanafelt, T.D., Agana, L., Wang, A.H., De Roos, A.J., Severson, R.K., Cozen, W., Spinelli, J., Butterbach, K., Becker, N., De Sanjose, S., Benavente, Y., Cocco, P., Staines, A., Maynadié, M., Foretova, L., Boffetta, P., Brennan, P., Lan, Q., Zhang, Y., Zheng, T., Purdue, M., Armstrong, B., Kricker, A., Vajdic, C.M., Grulich, A., Smith, M.T., Bracci, P.M., Chanock, S.J., Hartge, P., Cerhan, J.R., Wang, S.S., Rothman, N., and Skibola, C.F.
Subjects: Male, Genotype, Immunology, Follicular lymphoma, Single-nucleotide polymorphism, Genome-wide association study, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, Biochemistry, PRRC2A, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Meta-Analysis as Topic, Risk Factors, immune system diseases, Proto-Oncogene Proteins, hemic and lymphatic diseases, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, Genotyping, Non-Hodgkin lymphoma, InterLymph consortium, 030304 developmental biology, 0303 health sciences, Lymphoid Neoplasia, Bcl-2-Like Protein 11, Lymphoma, Non-Hodgkin, Case-control study, Membrane Proteins, Proteins, Cell Biology, Hematology, Odds ratio, medicine.disease, 3. Good health, Lymphoma, BCL2L11, Case-Control Studies, 030220 oncology & carcinogenesis, Female, Apoptosis Regulatory Proteins
Abstract: Many common genetic variants have been associated with non-Hodgkin lymphoma (NHL), but individual study results are often conflicting. To confirm the role of putative risk alleles in B-cell NHL etiology, we performed a validation genotyping study of 67 candidate single nucleotide polymorphisms within InterLymph, a large international consortium of NHL case-control studies. A meta-analysis was performed on data from 5633 B-cell NHL cases and 7034 controls from 8 InterLymph studies. rs3789068 in the proapoptotic BCL2L11 gene was associated with an increased risk for B-cell NHL (odds ratio = 1.21, P random = 2.21 × 10−11), with similar risk estimates for common B-cell subtypes. PRRC2A rs3132453 in the HLA complex class III region conferred a reduced risk of B-cell NHL (odds ratio = 0.68, P random = 1.07 × 10−9) and was likewise evident for common B-cell subtypes. These results are consistent with the known biology of NHL and provide insights into shared pathogenic components, including apoptosis and immune regulation, for the major B-cell lymphoma subtypes.
Published: 2012

33. Smoking, variation in N-acetyltransferase 1 (NAT1) and 2 (NAT2), and risk of non-Hodgkin lymphoma: a pooled analysis within the InterLymph consortium

Author: Karin E. Smedby, Katja Butterbach, Susan L. Slager, Brian C.-H. Chiu, Silvia de Sanjosé, Nikolaus Becker, Hatef Darabi, Todd M. Gibson, Jacques Riby, Anneclaire J. De Roos, Christine F. Skibola, Yawei Zhang, Lindsay M. Morton, James R. Cerhan, Elizabeth A. Holly, Anne Kricker, Alexandra Nieters, Carol Kolar, Paige M. Bracci, Dennis D. Weisenburger, Theodore R. Holford, Nathaniel Rothman, Yolanda Benavente, Wendy Cozen, David W. Hein, Claire M. Vajdic, Joshua N. Sampson, Sophia S. Wang, Lucia Conde, Tongzhang Zheng, Casey Palmers, Henrik Hjalgrim, and Bruce K. Armstrong
Subjects: Adult, Male, Cancer Research, medicine.medical_specialty, Arylamine N-Acetyltransferase, Follicular lymphoma, Polymorphism, Single Nucleotide, Article, Young Adult, Hàbit de fumar, Risk Factors, immune system diseases, hemic and lymphatic diseases, Molecular genetics, Genetic variation, medicine, Humans, Young adult, Aged, Aged, 80 and over, business.industry, Lymphoma, Non-Hodgkin, Smoking, Case-control study, Genetic Variation, Cancer, Middle Aged, medicine.disease, Malaltia de Hodgkin, Lymphoma, Isoenzymes, Oncology, Case-Control Studies, Meta-analysis, Immunology, Female, Hodgkin's disease, business
Abstract: Studies of smoking and risk of non-Hodgkin lymphoma (NHL) have yielded inconsistent results, possibly due to subtype heterogeneity and/or genetic variation impacting the metabolism of tobacco-derived carcinogens, including substrates of the N-acetyltransferase enzymes NAT1 and NAT2.We conducted a pooled analysis of 5,026 NHL cases and 4,630 controls from seven case-control studies in the international lymphoma epidemiology consortium to examine associations between smoking, variation in the N-acetyltransferase genes NAT1 and NAT2, and risk of NHL subtypes. Smoking data were harmonized across studies, and genetic variants in NAT1 and NAT2 were used to infer acetylation phenotype of the NAT1 and NAT2 enzymes, respectively. Pooled odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for risk of NHL and subtypes were calculated using joint fixed effects unconditional logistic regression models.Current smoking was associated with a significant 30 % increased risk of follicular lymphoma (n = 1,176) but not NHL overall or other NHL subtypes. The association was similar among NAT2 slow (OR 1.36; 95 % CI 1.07-1.75) and intermediate/rapid (OR 1.27; 95 % CI 0.95-1.69) acetylators (p (interaction) = 0.82) and also did not differ by NAT1*10 allelotype. Neither NAT2 phenotype nor NAT1*10 allelotype was associated with risk of NHL overall or NHL subtypes.The current findings provide further evidence for a modest association between current smoking and follicular lymphoma risk and suggest that this association may not be influenced by variation in the N-acetyltransferase enzymes.
Published: 2012

34. The OncoArray Consortium: a network for understanding the genetic architecture of common cancers

Author: Katja Butterbach, Daniel C. Tessier, Dennis J. Hazelett, Stephen J. Chanock, Paul Brennan, Zhaoming Wang, Marc T. Goodman, Ali Amin Al Olama, Daniela Seminara, Tracy A. O'Mara, Craig Luccarini, Lesley McGuffog, David Van Den Berg, Andy C. H. Lee, James McKay, Stephen B. Gruber, Sue K. Park, Jack A. Taylor, Graham G. Giles, Michael F. Seldin, Alison M. Dunning, Zsofia Kote-Jarai, Sara Lindström, David E. Goldgar, Irene Brüske-Hohlfeld, Stig E. Bojesen, Paul D.P. Pharoah, Jonathan Marchini, Rosalind A. Eeles, Karoline Kuchenbaecker, Laura Fachal, Penny Soucy, Rayjean J. Hung, Ahsan Kamal, Marjorie J. Riggan, Xiangjun Xiao, Fergus J. Couch, Francois Bacot, Georgia Chenevix-Trench, John K. Field, Amanda B. Spurdle, Christopher A. Haiman, Julie M. Cunningham, Andrew Berchuck, Fredrick R. Schumacher, Elizabeth M. Gillanders, Simon A. Gayther, Belynda Hicks, Laura Ottini, David J. Hunter, Peter Kraft, Charlisse Caga-Anan, Jane Romm, Sylvie Laboissiere, Heike Bickeböller, Catherine M. Phelan, Jacques Simard, Graham Casey, Stephanie L. Schmit, Yafang Li, Sune F. Nielsen, Thomas A. Sellers, Hua Ling, Christopher K. Edlund, Yongyong Shi, Liesel M. FitzGerald, Stefanie A. Nelson, Rita K. Schmutzler, Gerhard A. Coetzee, Linda E. Kelemen, Kimberly F. Doheny, Elizabeth W. Pugh, Antonis C. Antoniou, Melanie Waldenberger, Judith L. Forman, Angela Risch, Ulrike Peters, Joe Dennis, David V. Conti, Daniel Vincent, Stephen Demetriades, Jinyoung Byun, Sara Benlloch, Tameka Shelford, Hongbing Shen, Douglas F. Easton, Mads Thomassen, Marcia Adams, Christopher I. Amos, Kenneth Offit, Kyriaki Michailidou, Judith Manz, Deborah J. Thompson, Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Fachal Vilar, Laura [0000-0002-7256-9752], Lee, Andrew [0000-0003-0677-0252], Thompson, Deborah [0000-0003-1465-5799], Amin Al Olama, Ali [0000-0002-7178-3431], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Male, 0301 basic medicine, epistasis, genetic epidemiology, Genotype, Epidemiology, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Genetic Predisposition to Disease/epidemiology, Genetic variation, Mendelian randomization, Prevalence, Humans, cancer, Genetic Predisposition to Disease, Selection, Genetic, Genotyping, Genetics, ancestry, Genetic Variation, Polymorphism, Single Nucleotide/genetics, Prognosis, Genetic architecture, 3. Good health, 030104 developmental biology, Genetic Variation/genetics, Oncology, 030220 oncology & carcinogenesis, OncoArray Consortium, genetic architecture, cancers, Genome-Wide Association Study/methods, Female, DNA microarray, Neoplasms/epidemiology, Genome-Wide Association Study, genetic susceptibility
Abstract: Background: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers and cancer related traits. Methods: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. Results: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. Conclusions: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental and lifestyle related exposures. Impact: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. TRICL (Transdisciplinary Research for Cancer of Lung) and International Lung Cancer Consortium (ILCCO): National Institute of Health U19 CA148127-01 (C.I. Amos, J. Byun, Y. Li, X. Xiao, J. L. Forman, A. Risch, H. Bickeböller, M. Waldenberger, I. Brüske, J. Manz, P. Brennan, R. Hung, H. Shen, Y. Shi, A. Kamal, C. I. Amos, J.K. Field), Canadian Cancer Society Research Institute (no. 020214, R. Hung). DRIVE (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer): National Institute of Health U19 CA148065 (D.J. Hazelett, D. F. Easton, S. Lindström, P. Kraft, J. Dennis, A. Dunning, K. Michailidou, L. Fachal, S. Benlloch, J. Cunningham, K. Butterbach, K. Offit, R. Schmutzler, L. Ottini, D. Vincent). CORECT (ColoRectal Transdisciplinary Study): National Institute of Health U19 CA148107; R01 CA81488, P30 CA014089 (S. Gruber, U. Peters, G. Casey). ELLIPSE (ELLIPSE, Elucidating Loci in Prostate Cancer Susceptibility): This work was support by U19 CA148537(F. Schumacher, S.A. Gayther, S.L. Schmit, C.K. Edlund, D.J. Hazelett, G.A. Coetzee, C. Haiman, S. Demetriades, D. Van Den Berg). FOCI (Transdisciplinary Cancer Genetic Association and Interacting Studies): National Institutes of Health U19 CA148112- 01 (T.A. Sellers, C. Phelan), R01-CA122443(B. Hicks) ) P50-CA116201, CA192393 (F. Couch), P50-CA136393(J. Cunningham, F. Couch), OCAC - CA-149429 (C. Phelan). , P30-CA15083 (B. Hicks), Cancer Research UK (C490/A8339(A. Antoniou, P. Pharoah, A. Dunning), C490/A16561(P. Pharoah, A. Dunning), C490/A10119 (A. Dunning, P. Pharoah), C490/A10124 (A. Dunning, P. Pharoah)). ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC) (F. Bacot). DACHS: German Research Council (Deutsche Downloaded from cebp.aacrjournals.org on October 31, 2016. © 2016 American Association for Cancer Research. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on October 3, 2016; DOI: 10.1158/1055-9965.EPI-16-0106 Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, and CH 117/1-1, C.K. Edlund), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). Prostate Lung Colon Ovarian Screening trial: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837, coordinator: R. Schmutzler, Cologne). The PERSPECTIVE (J. Simard) project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (MOP-86727, L.E. Kelemen), the Ministère de l’Économie, Innovation et Exportation du Québec through Genome Québec, and thee Quebec Breast Cancer Foundation, including additional funding from the Canadian Breast Cancer Foundation and the National Cancer Institute USA through Breast Cancer Family Registry Cohort (#1UM1CA164920-01A1). European Union Framework Programme for Research and Innovation (MSCA-IF-2014-EF-656144)(L. Fachal). The Breast Cancer Research Foundation, P30 CA08748, Andrew Sabin Foundation (K. Offit). CIDR genotyping for the Oncoarray was conducted under contract 268201200008I to K.Doheny and through grant 1X01HG007491- 01 to C.I. Amos. This is the author accepted manuscript. The final version is available from American Association for Cancer Research via http://dx.doi.org/10.1158/1055-9965.EPI-16-0106
Published: 2016

35. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants

Author: Sonja I. Berndt, Katja Butterbach, Stephanie A. Bien, Stéphane Bézieau, Michael Hoffmeister, John L. Hopper, Steven Gallinger, Christopher S. Carlson, Suzanne M. Leal, Martha L. Slattery, Gonçalo R. Abecasis, Ulrike Peters, Mark A. Jenkins, John D. Potter, Jenny Chang-Claude, Tabitha A. Harrison, Daniela Seminara, Shuo Jiao, Manish Gala, Bette J. Caan, David Duggan, Loic Le Marchand, Polly A. Newcomb, Thomas J. Hudson, David V. Conti, Andrew T. Chan, Richard B. Hayes, Li Hsu, Emily White, Robert E. Schoen, Deborah A. Nickerson, Fredrick R. Schumacher, Mengmeng Du, Keith R. Curtis, Robert W. Haile, Graham Casey, Hermann Brenner, and Sébastien Küry
Subjects: 0301 basic medicine, Male, lcsh:Medicine, Genome-wide association study, Genome browser, 030105 genetics & heredity, Database and Informatics Methods, Cell Signaling, Risk Factors, Medicine and Health Sciences, Registries, lcsh:Science, Genetics, Aged, 80 and over, Multidisciplinary, Chromosome Mapping, Hep G2 Cells, Genomics, Middle Aged, Genomic Databases, 3. Good health, Functional Genomics, Oncology, Female, Colorectal Neoplasms, Functional genomics, Genomic Signal Processing, Research Article, Signal Transduction, Adult, Genotype, Bioinformatics, Single-nucleotide polymorphism, Biology, Research and Analysis Methods, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, 1000 Genomes Project, Alleles, Genetic association, Aged, Colorectal Cancer, lcsh:R, Computational Biology, Genetic Variation, Cancers and Neoplasms, Biology and Life Sciences, Human Genetics, Cell Biology, HCT116 Cells, Genome Analysis, Human genetics, 030104 developmental biology, Biological Databases, A549 Cells, Genetic Loci, lcsh:Q, Caco-2 Cells, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s). National Institutes of Health; National Cancer Institute; U.S. Department of Health and Human Services
Published: 2016

36. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author: Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. Nalls, Erik Ingelsson, Mario A. Morken, Susana Eyheramendy, Christopher Newton-Cheh, Igor Rudan, D. G. Vinay, Christopher P. Nelson, Ervin R. Fox, Xiuqing Guo, Jing Hua Zhao, Rick Twee-Hee Ong, Margaret M. Redfield, Oscar H. Franco, Yongmei Liu, Fulvio Ricceri, Mark A. Hlatky, Bernhard Paulweber, Mingyao Li, Themistocles L. Assimes, Karl Winkler, Inês Barroso, Sylvia E. Rosas, M Walker, Richard W Morris, Bo Hedblad, Hakon Hakonarson, Sonny Dandona, Peter H. Whincup, Martin Adam, Vilmundur Gudnason, Daniel Ackermann, Qiong Yang, Cuno S. P. M. Uiterwaal, Paul M. Ridker, George Davey Smith, Li Chen, C. Sinning, Terri L. Young, Jer-Yuarn Wu, Walter Palmas, Will Longstreth, Joe Devaney, Pavel Hamet, Xiaofeng Zhu, Fredrik Nyberg, Wilfried Renner, Anuj Goel, L. Adrienne Cupples, Nish Chaturvedi, Iftikhar J. Kullo, Nicholas D. Hastie, Aude Saint-Pierre, Panos Deloukas, Smita R. Kulkarni, Eric Boerwinkle, Wolfram Goessling, Gian Andri Thun, Eric J.G. Sijbrands, Shih-Jen Hwang, Carole Proust, Hirotsugu Ueshima, Kristian Hveem, Pierre Meneton, Joshua C. Denny, Olivier Devuyst, Kerri L. Wiggins, Ming-Huei Chen, Robert W. Lawrence, Robert L. Wilensky, Andre Franke, Nicole Soranzo, Simon Heath, Margot Haun, Karlhans Endlich, David Altshuler, Harald Grallert, Laurence Tiret, Luigi Ferrucci, Caroline Hayward, Sudha Seshadri, Bénédicte Stengel, Lynne E. Wagenknecht, John Attia, Andreas Ziegler, Renate B. Schnabel, Stefan Schreiber, Santosh Dahgam, Kurt Lohman, Christian M. Shaffer, Barbara Ludwig, Katalin Susztak, Chien-Hsiun Chen, Michele K. Evans, Paolo Vineis, Guo Li, Thomas J. Wang, Meena Kumari, Heather M. Stringham, Bruce M. Psaty, Norman Klopp, Halit Ongen, Ben A. Oostra, Stefan Coassin, Petra Bruse, Wei-Min Chen, Unnur Thorsteinsdottir, Charles N. Rotimi, Robert J. Carroll, Muredach P. Reilly, Niek Verweij, Dena G. Hernandez, Amy J. Swift, Barbara Kollerits, Hyung Lae Kim, Cristian Pattaro, Ivana Kolcic, Ronit Katz, John M. C. 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R., Fortmann, Stephen, Go, Alan, Hlatky, Mark, Iribarren, Carlo, Knowles, Joshua, Myers, Richard, Quertermous, Thoma, Sidney, Steven, Risch, Neil, Tang, Hua, Blankenberg, Stefan, Schnabel, Renate, Sinning, Christoph, Lackner, Karl J., Tiret, Laurence, Nicaud, Viviane, Cambien, Francoi, Bickel, Christoph, Rupprecht, Hans J., Perret, Claire, Proust, Carole, Münzel, Thomas F., Barbalic, Maja, Chen, Ida Yii Der, Demissie Banjaw, Serkalem, Folsom, Aaron, Lumley, Thoma, Marciante, Kristin, Taylor, Kent D., Volcik, Kelly, Gretarsdottir, Solveig, Gulcher, Jeffrey R., Kong, Augustine, Stefansson, Kari, Thorgeirsson, Gudmundur, Andersen, Karl, Fischer, Marcu, Grosshennig, Anika, Linsel Nitschke, Patrick, Stark, Klau, Schreiber, Stefan, Aherrahrou, Zouhair, Bruse, Petra, Doering, Angela, Klopp, Norman, Diemert, Patrick, Loley, Christina, Medack, Anja, Nahrstedt, Janja, Peters, Annette, Wagner, Arnika K., Willenborg, Christina, Böhm, Bernhard O., Dobnig, Harald, Grammer, Tanja B., Hoffmann, Michael M., Meinitzer, Andrea, Winkelmann, Bernhard R., Pilz, Stefan, Renner, Wilfried, Scharnagl, Hubert, Stojakovic, Tatjana, Tomaschitz, Andrea, Winkler, Karl, Guiducci, Candace, Burtt, Noel, Gabriel, Stacey B., Dandona, Sonny, Jarinova, Olga, Qu, Liming, Wilensky, Robert, Matthai, William, Hakonarson, Hakon H., Devaney, Joe, Burnett, Mary Susan, Pichard, Augusto D., Kent, Kenneth M., Satler, Lowell, Lindsay, Joseph M., Waksman, Ron, Knouff, Christopher W., Waterworth, Dawn M., Walker, Max C., Epstein, Stephen E., Rader, Daniel J., Nelson, Christopher P., Wright, Benjamin J., Balmforth, Anthony J., Ball, Stephen G., Loehr, Laura R., Rosamond, Wayne D., Benjamin, Emelia, Haritunians, Talin, Couper, David, Murabito, Joanne, Wang, Ying A., Stricker, Bruno H., Chang, Patricia P., Willerson, James T., Felix, Stephan B., Watzinger, Norbert, Aragam, Jayashri, Zweiker, Robert, Lind, Lar, Rodeheffer, Richard J., Greiser, Karin Halina, Deckers, Jaap W., Stritzke, Jan, Ingelsson, Erik, Kullo, Iftikhar, Haerting, Johanne, Reffelmann, Thorsten, Redfield, Margaret M., Werdan, Karl, Mitchell, Gary F., Arnett, Donna K., Gottdiener, John S., Blettner, Maria, Friedrich, Nele, Kovacs, Peter, Wild, Philipp S., Froguel, Philippe, Rettig, Rainer, Mägi, Reedik, Biffar, Reiner, Schmidt, Reinhold, Middelberg, Rita P. S., Carroll, Robert J., Penninx, Brenda W., Scott, Rodney J., Katz, Ronit, Sedaghat, Sanaz, Wild, Sarah H., Kardia, Sharon L. R., Ulivi, Sheila, Hwang, Shih Jen, Enroth, Stefan, Kloiber, Stefan, Trompet, Stella, Stengel, Benedicte, Hancock, Stephen J., Turner, Stephen T., Rosas, Sylvia E., Stracke, Sylvia, Harris, Tamara B., Zeller, Tanja, Zemunik, Tatijana, Lehtimäki, Terho, Illig, Thoma, Aspelund, Thor, Nikopensius, Tiit, Esko, Tonu, Tanaka, Toshiko, Gyllensten, Ulf, Völker, Uwe, Emilsson, Valur, Vitart, Veronique, Aalto, Ville, Gudnason, Vilmundur, Chouraki, Vincent, Chen, Wei Min, Igl, Wilmar, März, Winfried, Koenig, Wolfgang, Lieb, Wolfgang, Loos, Ruth J. F., Liu, Yongmei, Snieder, Harold, Pramstaller, Peter P., Parsa, Afshin, O'Connell, Jeffrey R., Susztak, Katalin, Hamet, Pavel, Tremblay, Johanne, De Boer, Ian H., Böger, Carsten A., Goessling, Wolfram, Chasman, Daniel I., Köttgen, Anna, Kao, W. H. Linda, Fox, Caroline S., RS: CARIM - R1.06 - Genetic Epidemiology and Genomics of cardiovascular diseases, Biochemie, RS: FHML MaCSBio, Ehret, Georg Benedikt, Guessous, Idris, Gaspoz, Jean-Michel, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Polymer Chemistry and Bioengineering, Value, Affordability and Sustainability (VALUE), Stem Cell Aging Leukemia and Lymphoma (SALL), Epidemiology, Public Health, Internal Medicine, Clinical Genetics, Erasmus MC other, Genetic Identification, ICBP Consortium, AGEN Consortium, CHARGe-Heart Failure Group, ECHOGen Consortium, CARDIOGRAM, Abecasis, GR., Adair, LS., Alexander, M., Altshuler, D., Amin, N., Arking, DE., Arora, P., Aulchenko, Y., Bakker, SJ., Bandinelli, S., Barroso, I., Beckmann, JS., Beilby, JP., Bergman, RN., Bergmann, S., Bis, JC., Boehnke, M., Bonnycastle, LL., Bornstein, SR., Bots, ML., Bragg-Gresham, JL., Brand, SM., Brand, E., Braund, PS., Brown, MJ., Burton, PR., Casas, JP., Caulfield, MJ., Chakravarti, A., Chambers, JC., Chandak, GR., Chang, YP., Charchar, FJ., Chaturvedi, N., Shin Cho, Y., Clarke, R., Collins, FS., Collins, R., Connell, JM., Cooper, JA., Cooper, MN., Cooper, RS., Corsi, AM., Dörr, M., Dahgam, S., Danesh, J., Davey Smith, G., Day, IN., Deloukas, P., Denniff, M., Dominiczak, AF., Dong, Y., Doumatey, A., Elliott, P., Elosua, R., Erdmann, J., Eyheramendy, S., Farrall, M., Fava, C., Forrester, T., Fowkes, FG., Fox, ER., Frayling, TM., Galan, P., Ganesh, SK., Garcia, M., Gaunt, TR., Glazer, NL., Go, MJ., Goel, A., Grässler, J., Grobbee, DE., Groop, L., Guarrera, S., Guo, X., Hadley, D., Hamsten, A., Han, BG., Hardy, R., Hartikainen, AL., Heath, S., Heckbert, SR., Hedblad, B., Hercberg, S., Hernandez, D., Hicks, AA., Hilton, G., Hingorani, AD., Bolton, JA., Hopewell, JC., Howard, P., Humphries, SE., Hunt, SC., Hveem, K., Ikram, MA., Islam, M., Iwai, N., Jarvelin, MR., Jackson, AU., Jafar, TH., Janipalli, CS., Johnson, T., Kathiresan, S., Khaw, KT., Kim, HL., Kinra, S., Kita, Y., Kivimaki, M., Kooner, JS., Kumar, MJ., Kuh, D., Kulkarni, SR., Kumari, M., Kuusisto, J., Kuznetsova, T., Laakso, M., Laan, M., Laitinen, J., Lakatta, EG., Langefeld, CD., Larson, MG., Lathrop, M., Lawlor, DA., Lawrence, RW., Lee, JY., Lee, NR., Levy, D., Li, Y., Longstreth, WT., Luan£££Jian'an£££ J., Lucas, G., Ludwig, B., Mangino, M., Mani, KR., Marmot, MG., Mattace-Raso, FU., Matullo, G., McArdle, WL., McKenzie, CA., Meitinger, T., Melander, O., Meneton, P., Meschia, JF., Miki, T., Milaneschi, Y., Mohlke, KL., Mooser, V., Morken, MA., Morris, RW., Mosley, TH., Najjar, S., Narisu, N., Newton-Cheh, C., Nguyen, KD., Nilsson, P., Nyberg, F., O'Donnell, CJ., Ogihara, T., Ohkubo, T., Okamura, T., Ong, RT., Ongen, H., Onland-Moret, NC., O'Reilly, PF., Org, E., Orru, M., Palmas, W., Palmen, J., Palmer, LJ., Palmer, ND., Parker, AN., Peden, JF., Peltonen, L., Perola, M., Pihur, V., Platou, CG., Plump, A., Prabhakaran, D., Psaty, BM., Raffel, LJ., Rao, DC., Rasheed, A., Ricceri, F., Rice, KM., Rosengren, A., Rotter, JI., Rudock, ME., Sõber, S., Salako, T., Saleheen, D., Salomaa, V., Samani, NJ., Schwartz, SM., Schwarz, PE., Scott, LJ., Scott, J., Scuteri, A., Sehmi, JS., Seielstad, M., Seshadri, S., Sharma, P., Shaw-Hawkins, S., Shi, G., Shrine, NR., Sijbrands, EJ., Sim, X., Singleton, A., Sjögren, M., Smith, NL., Soler Artigas, M., Spector, TD., Staessen, JA., Stancakova, A., Steinle, NI., Strachan, DP., Stringham, HM., Sun, YV., Swift, AJ., Tabara, Y., Tai, ES., Talmud, PJ., Taylor, A., Terzic, J., Thelle, DS., Tobin, MD., Tomaszewski, M., Tripathy, V., Tuomilehto, J., Tzoulaki, I., Uda, M., Ueshima, H., Uiterwaal, CS., Umemura, S., van der Harst, P., van der Schouw YT., van Gilst WH., Vartiainen, E., Vasan, RS., Veldre, G., Verwoert, GC., Viigimaa, M., Vinay, DG., Vineis, P., Voight, BF., Vollenweider, P., Wagenknecht, LE., Wain, LV., Wang, X., Wang, TJ., Wareham, NJ., Watkins, H., Weder, AB., Whincup, PH., Wiggins, KL., Witteman, JC., Wong, A., Wu, Y., Yajnik, CS., Yao, J., Young, JH., Zelenika, D., Zhai, G., Zhang, W., Zhang, F., Zhao, JH., Zhu, H., Zhu, X., Zitting, P., Zukowska-Szczechowska, E., Okada, Y., Wu, JY., Gu, D., Takeuchi, F., Takahashi, A., Maeda, S., Tsunoda, T., Chen, P., Lim, SC., Wong, TY., Liu, J., Young, TL., Aung, T., Teo, YY., Kim, YJ., Kang, D., Chen, CH., Tsai, FJ., Chang, LC., Fann, SJ., Mei, H., Hixson, JE., Chen, S., Katsuya, T., Isono, M., Albrecht, E., Yamamoto, K., Kubo, M., Nakamura, Y., Kamatani, N., Kato, N., He, J., Chen, YT., Tanaka, T., Reilly, MP., Schunkert, H., Assimes, TL., Hall, A., Hengstenberg, C., König, IR., Laaksonen, R., McPherson, R., Thompson, JR., Thorsteinsdottir, U., Ziegler, A., Absher, D., Chen, L., Cupples, LA., Halperin, E., Li, M., Musunuru, K., Preuss, M., Schillert, A., Thorleifsson, G., Wells, GA., Holm, H., Roberts, R., Stewart, AF., Fortmann, S., Go, A., Hlatky, M., Iribarren, C., Knowles, J., Myers, R., Quertermous, T., Sidney, S., Risch, N., Tang, H., Blankenberg, S., Schnabel, R., Sinning, C., Lackner, KJ., Tiret, L., Nicaud, V., Cambien, F., Bickel, C., Rupprecht, HJ., Perret, C., Proust, C., Münzel, TF., Barbalic, M., Chen, IY., Demissie-Banjaw, S., Folsom, A., Lumley, T., Marciante, K., Taylor, KD., Volcik, K., Gretarsdottir, S., Gulcher, JR., Kong, A., Stefansson, K., Thorgeirsson, G., Andersen, K., Fischer, M., Grosshennig, A., Linsel-Nitschke, P., Stark, K., Schreiber, S., Aherrahrou, Z., Bruse, P., Doering, A., Klopp, N., Diemert, P., Loley, C., Medack, A., Nahrstedt, J., Peters, A., Wagner, AK., Willenborg, C., Böhm, BO., Dobnig, H., Grammer, TB., Hoffmann, MM., Meinitzer, A., Winkelmann, BR., Pilz, S., Renner, W., Scharnagl, H., Stojakovic, T., Tomaschitz, A., Winkler, K., Guiducci, C., Burtt, N., Gabriel, SB., Dandona, S., Jarinova, O., Qu, L., Wilensky, R., Matthai, W., Hakonarson, HH., Devaney, J., Burnett, MS., Pichard, AD., Kent, KM., Satler, L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Epstein, SE., Rader, DJ., Nelson, CP., Wright, BJ., Balmforth, AJ., Ball, SG., Loehr, LR., Rosamond, WD., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, YA., Stricker, BH., Chang, PP., Willerson, JT., Felix, SB., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, RJ., Greiser, KH., Deckers, JW., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, MM., Werdan, K., Mitchell, GF., Arnett, DK., Gottdiener, JS., Blettner, M., and Friedrich, N.
Subjects: 0301 basic medicine, Nephrology, Genetics and Molecular Biology (all), estimated glomerular filtration rate, estimated glomerular filtration rate, chronic kidney disease, genetic determinants, General Physics and Astronomy, Kidney development, Genome-wide association study, Biochemistry, Settore MED/14 - NEFROLOGIA, Renal Insufficiency, Chronic, Genetics, AGEN Consortium, ddc:616, education.field_of_study, Kidney, Stage renal-disease, Multidisciplinary, Genome-wide association, CHARGe-Heart Failure Group, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic, Genetic Predisposition to Disease, Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all), Metaanalysis, Renal Insufficiency, Chronic/genetics, Biological sciences, Serum creatinine, medicine.anatomical_structure, Efficient, Ronyons -- Fisiologia, Hypertension, ICBP Consortium, Transmembrane transporter activity, genetic association, loci, kidney function, CARDIOGRAM, Human, medicine.medical_specialty, Science, Population, Renal function, ECHOGen Consortium, Replication, Biology, Environment, Research Support, General Biochemistry, Genetics and Molecular Biology, N.I.H, genetic determinants, 03 medical and health sciences, GENOME-WIDE ASSOCIATION, FALSE DISCOVERY RATES, STAGE RENAL-DISEASE, SERUM CREATININE, METAANALYSIS, VARIANTS, INDIVIDUALS, POPULATION, RISK, HYPERTENSION, Kidney function, Research Support, N.I.H., Extramural, Internal medicine, MD Multidisciplinary, medicine, Journal Article, eGFRcrea, eGFRcys, ddc:610, Genetik, Mortality, education, ddc:613, urogenital system, Individuals, Extramural, General Chemistry, ta3121, medicine.disease, R1, 030104 developmental biology, 570 Life sciences, biology, Genètica, chronic kidney disease, Kidney disease, Meta-Analysis
Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.
Published: 2016

37. Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Author: Martine Tranchant, Fergus J. Couch, Meeri Otsukka, Sabine Behrens, Jirong Long, Nadia Obi, Kamila Czene, John L. Hopper, Heather Thorne, Robert Pilarski, Anja Rudolph, Simon S. Cross, Volker Harth, Gabrielle Colleran, Hatef Darabi, Thomas Van Brussel, Eunjung Lee, Anne Lotz, E. Krol-Warmerdam, M. Pilar Zamora, Qin Wang, Andy C. H. Lee, Annie Fung, Kara Sargus, Melissa C. Southey, Katja Butterbach, Nuria Álvarez, Francois Bacot, Jeffrey G. Meyer, Ian W. Brock, Jessica Clague De Hart, Pierre Laurent-Puig, Irene L. Andrulis, Pei Chao, Arnaud Droit, Per Hall, Daniel C. Tessier, Paolo Radice, Frederic Robidoux, Don M. Conroy, Irja Erkkilä, Daniel Vincent, Antoinette Hollestelle, Christopher A. Hilker, Alicia Beeghly-Fadiel, Muhabbet Celik, Peggy Reynolds, Caroline Baynes, Sophia S. Wang, Katri Pylkäs, Kang In Nee, Robert Winqvist, Henrik Flyger, Annette Heemskerk, Sara Margolin, Hui Cai, Julie M. Cunningham, Prat Boonyawongviroj, Bernardo Bonanni, Anthony J. Swerdlow, Dan Connley, Huiyan Ma, Valerie Gaborieau, David O. Nelson, Keitaro Matsuo, Sylvie La Boissière, Pornthep Siriwanarungsan, Hidemi Ito, Ursula Eilber, Matthias W. Beckmann, Sylvia Rabstein, Natalia Bogdanova, Anna Jakubowska, Yves Raoul, Robert A.E.M. Tollenaar, Frans B. L. Hogervorst, Hannah L Park, Pierre Kerbrat, Ying Zheng, Paul D.P. Pharoah, Wanqing Wen, Judith Heinz, Annika Lindblom, Christa Stegmaier, Manjeet K. Bolla, Loris Bernard, Anna H. Wu, Alison M. Dunning, Hermann Brenner, A. Green, Thilo Dörk, Chia-Ni Hsiung, Dennis Deapen, Michael G. Schrauder, Gilian Peuteman, S.E. Higham, Sabapathy P. Balasubramanian, Irene Feroce, Christina Justenhoven, Angela Jones, William J. Blot, Nichola Johnson, Petra Seibold, D. Bowtell, Jiajun Shi, Wei Zheng, U Hamann, Pascal Guenel, P. Webb, Soo Hwang Teo, Daniela Zaffaroni, J. Blom, Rita K. Schmutzler, Douglas F. Easton, Yani Lu, Witold Zatonski, Phuah Sze Yee, Susan L. Neuhausen, Kenneth Muir, Sofia Khan, Daehee Kang, Silke Landrith, Helena Kemiläinen, Maggie Angelakos, Rich Pinder, Javier Benitez, Til Olchers, Senno Verhoef, Fred Schumacher, Martha J. Shrubsole, Teresa Selander, Teh Yew Ching, Christof Sohn, Patrick Arveux, Dorota M. Gertig, Saila Kauppila, Mervi Grip, Florentia Fostira, Jenny Chang-Claude, Michael Stagner, Kathleen Corthouts, Ellen Van Der Schoot, H Nevanlinna, Peter Bugert, Christian Baisch, Eija Myöhänen, Sonja Wolf, Hoda Anton-Culver, Nicola Miller, Cheng Har Yip, Neonila Szeszenia-Dabrowska, Nicholas K. Hayward, Dieter Flesch-Janys, Barbara Burwinkel, J. Molenaar, Eileen Williams, Marjanka K. Schmidt, Yon Ko, Anja Nieuwlaat, Chen-Yang Shen, Veli-Matti Kosma, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Artitaya Lophatananon, Mikael Hartman, Jonathan Beesley, Bernard Peissel, Paolo Peterlongo, Ji Yeob Choi, Craig Luccarini, Rosalind A. Eeles, Niall M. McInerney, Bernard Thienpont, Xiao-Ou Shu, Léa Héguy, Maya Ghoussaini, Sander Canisius, Wing-Yee Lo, Suleeporn Sangrajrang, Nur Aishah Taib, June Yashiki, Kirsimari Aaltonen, Louise A. Brinton, Elinor J. Sawyer, Alina Vrieling, Angela Cox, Frederik Marmé, Matthias Rübner, Graham G. Giles, Sonja Oeser, Hans Christiansen, Andrew Rowan, Ed Dicks, Andeas Schneeweiß, Catriona McLean, Antonis C. Antoniou, B. Pesch, Eveline Niedermayr, Volker Arndt, Janet E. Olson, Dominiek Smeets, Jingmei Li, Georgia Chenevix-Trench, Claire Mulot, Siranoush Manoukian, Hans Fischer, Ellen Crepin, Arto Mannermaa, Ali Amin Al Olama, Helen Cramp, Ans M.W. van den Ouweland, Olivia Fletcher, Sharon A. Windebank, Peter Hillemanns, Nayana Weerasooriya, James V. Lacey, Leslie Bernstein, Romuald Le Scodan, Giulietta Scuvera, P. Parsons, Thomas C. Putti, Elaine Ryder-Mills, Sara Benlloch, Beata Peplonska, Stig E. Bojesen, Kimberley Chua, Stefan Nickels, Nick Orr, Roger L. Milne, Tuomas Heikkinen, Christopher A. Haiman, Natalia Antonenkova, Volker Hermann, Maria Kabisch, Kenneth Offit, Julia A. Knight, Angela Maniscalco, Arja Jukkola-Vuorinen, Hartwig Ziegler, Chenjie Zeng, Jacques Simard, Pamela L. Horn-Ross, Daphne S.C. Lee, Xingyi Guo, Jan Lubinski, Michael J. Kerin, Loic Le Marchand, Sune F. Nielsen, Peter Devilee, A. De Fazio, Qiuyin Cai, Annie Turgeon, Yoon Sook-Yee, Silje Nord, Petra Bos, Hiltrud Brauch, Kyriaki Michailidou, Shivaani Mariapun, Kari Mononen, Alfons Meindl, Peter B. Kang, Siddhartha Kar, Alessandra Rossi, G. Chenevix-Trench, Diether Lambrechts, Karl von Smitten, Zsofia Kote-Jarai, Emiel J. Th. Rutgers, Chiu-Chen Tseng, Peter A. Fasching, Lesley McGuffog, Annegien Broekss, Johann H. Karstens, Montserrat Garcia-Closas, Thomas Brüning, David C. Whiteman, Judi Maskiell, Clinical Genetics, Cardiothoracic Surgery, Medical Oncology, and Obstetrics & Gynecology
Subjects: Genetic Markers, Linkage disequilibrium, Epidemiology, Locus (genetics), Genome-wide association study, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, Breast cancer, SDG 3 - Good Health and Well-being, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Gene, Genetics, Molecular epidemiology, Case-control study, Chromosome Mapping, medicine.disease, Logistic Models, Oncology, Genetic marker, Genetic Loci, Case-Control Studies, Female, Chromosomes, Human, Pair 4, Genome-Wide Association Study
Abstract: Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1680–91. ©2015 AACR.
Published: 2015

38. Association of JAK-STAT pathway related genes with lymphoma risk: results of a European case-control study (EpiLymph)

Author: Paul Brennan, Silvia de Sanjosé, Pierluigi Cocco, Lars Beckmann, Alexandra Nieters, Yolanda Benavente, Paolo Boffetta, Nikolaus Becker, Marc Maynadié, Katja Butterbach, Lenka Foretova, and Anthony Staines
Subjects: Genetics, 0303 health sciences, medicine.medical_specialty, Hematology, Haplotype, JAK-STAT signaling pathway, Single-nucleotide polymorphism, Biology, medicine.disease, Lymphoma, STAT5A, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, 030220 oncology & carcinogenesis, Internal medicine, IL12A, Cancer research, medicine, SNP, 030304 developmental biology
Abstract: Previous studies have suggested an important role for the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling pathway in tumour development. Therefore, we explored genetic variants in JAK-STAT pathway associated genes with lymphoma risk. In samples of the EpiLymph case-control study we genotyped 1536 single nucleotide polymorphisms (SNPs) using GoldenGate BeadArray™ Technology (Illumina, San Diego, CA, USA). Here, we report the associations between selected SNPs and haplotypes of the JAK-STAT pathway and risk of Hodgkin lymphoma (HL), B-cell non-Hodgkin lymphoma (B-NHL) and most frequent B-NHL subtypes. Among 210 relevant JAK-STAT pathway-related SNPs, polymorphisms in nine genes (BMF, IFNG, IL12A, SOCS1, STAT1, STAT3, STAT5A, STAT6, TP63) were significantly associated with lymphoma risk. At a study-wise significance level, we obtained a risk reduction of 28% among carriers of the heterozygous genotype of the STAT3 variant (rs1053023) for B-NHL. For six other variants within the STAT3 gene we observed an inverse association with different lymphoma subtypes. A reduced risk for HL was observed for the heterozygous genotype of the STAT6 SNP (rs324011). This is an explorative investigation to examine associations between JAK-STAT signalling related genes and lymphoma risk. The results implicate a relevant role of certain pathway-related genes in lymphomagenesis, but still need to be approved by independent studies.
Published: 2011

39. Correction: Corrigendum: Genome-wide association study of colorectal cancer identifies six new susceptibility loci

Author: Manish Gala, Stéphane Bézieau, Eric J. Jacobs, Kevin McDonnell, Amit Joshi, Leon Raskin, Shu Chen Huang, W. James Gauderman, Brian E. Henderson, Shoichiro Tsugane, Sonja I. Berndt, Marilena Melas, Jane C. Figueiredo, Christopher P. Fischer, Gregory Idos, Kana Wu, Hermann Brenner, Wei Zheng, Ulrike Peters, Stephen J. Chanock, N. M. Lindor, David J. Hunter, Martha L. Slattery, Charles Kooperberg, Cathy C. Laurie, Ben Zhang, Jing Ma, Cecelia A. Laurie, Rebecca D. Jackson, Gianluca Severi, Graham Casey, Katja Butterbach, David Van Den Berg, Frank J. Manion, Hansong Wang, Daniela Seminara, Christopher S. Carlson, Stephanie M. Gogarten, Karen W. Makar, Duncan C. Thomas, Stephen B. Gruber, David K. Levine, Barbara K. Fortini, Caroline McNeil, Flavio Lejbkowicz, Charles S. Fuchs, Motoki Iwasaki, Robert W. Haile, John D. Potter, Stephanie A. Rosse, Shuo Jiao, Keitaro Matsuo, Wei Hua Jia, Cornelia M. Ulrich, Stephanie L. Schmit, Victor Moreno, Bhramar Mukherjee, Darin Taverna, John L. Hopper, Sun Ha Jee, Dee W. West, Bette J. Caan, Andrea Z. LaCroix, Brent W. Zanke, Robert E. Schoen, Sébastien Küry, Keith R. Curtis, Loic Le Marchand, Aaron K. Aragaki, Steven Gallinger, Gad Rennert, Tabitha A. Harrison, Laurence N. Kolonel, Li Li, David V. Conti, John F. Harju, Polly A. Newcomb, David Duggan, Mathieu Lemire, Christopher K. Edlund, Thomas J. Hudson, Roger C. Green, Wei Shi, Li Hsu, Conghui Qu, Peter T. Campbell, Fredrick R. Schumacher, Mark A. Jenkins, Andrew T. Chan, Yong-Bing Xiang, Richard B. Hayes, Suminori Kono, Jenny Chang-Claude, Gerhard A. Coetzee, Carolyn M. Hutter, Hedy S. Rennert, Emily White, Graham G. Giles, Michael Hoffmeister, Xiao-Ou Shu, and Edward Giovannucci
Subjects: Genetics, Multidisciplinary, Colorectal cancer, medicine, Susceptibility locus, General Physics and Astronomy, Genome-wide association study, General Chemistry, Biology, Bioinformatics, medicine.disease, General Biochemistry, Genetics and Molecular Biology
Abstract: Corrigendum: Genome-wide association study of colorectal cancer identifies six new susceptibility loci
Published: 2015

40. Body mass index and leukocyte telomere length dynamics among older adults: Results from the ESTHER cohort

Author: Aysel Müezzinler, Kai Uwe Saum, Christa Stegmaier, Hermann Stammer, Aida Karina Dieffenbach, Matthias Schick, Bernd Holleczek, Katja Butterbach, Petra Boukamp, Hermann Brenner, and Ute Mons
Subjects: 0301 basic medicine, Gerontology, Male, Aging, Time Factors, Population, Weight Gain, Biochemistry, Polymerase Chain Reaction, Body Mass Index, 03 medical and health sciences, Endocrinology, Risk Factors, Bayesian multivariate linear regression, Germany, Genetics, medicine, Leukocytes, Humans, Longitudinal Studies, Obesity, Risk factor, education, Molecular Biology, Telomere Shortening, Adiposity, Aged, education.field_of_study, business.industry, Age Factors, Cell Biology, Middle Aged, Telomere, medicine.disease, 030104 developmental biology, Cross-Sectional Studies, Ageing, Cohort, Female, business, Body mass index, Demography, Cohort study
Abstract: Telomere length (TL) has been proposed as a biomarker of ageing, which might be used to identify individuals at higher risk of age-related diseases. Obesity is a well-known risk factor for several diseases. This study aims to analyse the associations of BMI with TL and the rate of TL change in older adults.Leukocyte TL (LTL) was measured by quantitative PCR in blood samples of 3600 older adults aged 50-75 years obtained at the baseline examination of a population-based cohort study in Germany. For longitudinal analyses, measurements were repeated in blood samples obtained at 8-year follow-up from 1000 participants. Multivariate linear regression models were used to estimate associations of BMI with LTL and changes in LTL over time.LTL was inversely associated with age (r = -0.090, p0.0001). BMI and LTL associations varied according to age (p for interaction = 0.021). BMI was significantly inversely associated with LTL in those younger than 60 years (-6 basepairs per 1 kg/m(2) difference in BMI). In particular, weight gain during adulthood was inversely associated with LTL in a dose-response manner in this age group, with those having gained ≥ 30 kg having significantly shorter telomeres (-209 basepairs) than those who maintained their weight. No clear patterns were observed between any of BMI-related variables and the rate of LTL change.Our cross-sectional analysis supports suggestions that weight gain during adulthood and obesity may contribute to shorter telomere length below 60 years of age, but this relationship could not be shown longitudinally.
Published: 2015

41. Prediction of Individual Genetic Risk to Prostate Cancer Using a Polygenic Score

Author: Robert, Szulkin, Thomas, Whitington, Martin, Eklund, Markus, Aly, Rosalind A, Eeles, Douglas, Easton, Z Sofia, Kote-Jarai, Ali, Amin Al Olama, Sara, Benlloch, Kenneth, Muir, Graham G, Giles, Melissa C, Southey, Liesel M, Fitzgerald, Brian E, Henderson, Fredrick, Schumacher, Christopher A, Haiman, Johanna, Schleutker, Tiina, Wahlfors, Teuvo L J, Tammela, Børge G, Nordestgaard, Tim J, Key, Ruth C, Travis, David E, Neal, Jenny L, Donovan, Freddie C, Hamdy, Paul, Pharoah, Nora, Pashayan, Kay-Tee, Khaw, Janet L, Stanford, Stephen N, Thibodeau, Shannon K, McDonnell, Daniel J, Schaid, Christiane, Maier, Walther, Vogel, Manuel, Luedeke, Kathleen, Herkommer, Adam S, Kibel, Cezary, Cybulski, Jan, Lubiński, Wojciech, Kluźniak, Lisa, Cannon-Albright, Hermann, Brenner, Katja, Butterbach, Christa, Stegmaier, Jong Y, Park, Thomas, Sellers, Hui-Yi, Lin, Hui-Yi, Lim, Chavdar, Slavov, Radka, Kaneva, Vanio, Mitev, Jyotsna, Batra, Judith A, Clements, Amanda, Spurdle, Manuel R, Teixeira, Paula, Paulo, Sofia, Maia, Hardev, Pandha, Agnieszka, Michael, Andrzej, Kierzek, Henrik, Gronberg, and Danielle M, Karyadi
Subjects: Genetic Markers, Male, Risk Factors, Genetic Variation, Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Linkage Disequilibrium, Article
Abstract: BACKGROUND. Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. METHODS. We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS. The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5 E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. CONCLUSIONS. Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.
Published: 2015

42. Type 2 diabetes and leucocyte DNA methylation: an epigenome-wide association study in over 1,500 older adults

Author: Yan Zhang, Jonathan A Heiss, Ines Florath, Katja Butterbach, Ben Schöttker, Melanie Bewerunge-Hudler, and Hermann Brenner
Subjects: 0301 basic medicine, Oncology, Blood Glucose, Male, medicine.medical_specialty, Cross-sectional study, Endocrinology, Diabetes and Metabolism, Genome-wide association study, Type 2 diabetes, Bioinformatics, Body Mass Index, Epigenesis, Genetic, Cohort Studies, 03 medical and health sciences, Internal medicine, Diabetes mellitus, Surveys and Questionnaires, Internal Medicine, Leukocytes, Medicine, Humans, Genetic Predisposition to Disease, 3' Untranslated Regions, Aged, business.industry, Smoking, dNaM, DNA Methylation, Middle Aged, medicine.disease, 030104 developmental biology, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Cohort, CpG Islands, Female, business, Carrier Proteins, Body mass index, Cohort study, Genome-Wide Association Study
Abstract: Development of type 2 diabetes depends on environmental and genetic factors. We investigated the epigenome-wide association of prevalent diabetes with DNA methylation (DNAm) in peripheral blood. DNAm was measured in whole blood with the Illumina Infinium HumanMethylation450 BeadChip in two subsamples of participants from the ESTHER cohort study. Cohort 1 included 988 participants, who were consecutively recruited between July and October 2000 and cohort 2 included 527 randomly selected participants. The association of DNAm with prevalent type 2 diabetes at recruitment was estimated using median regression analysis adjusting for sex, age, BMI, smoking behaviour, cell composition and batch at 361,922 CpG sites. Type 2 diabetes was prevalent in 16% of the participants, and diabetes was poorly controlled in 45% of the diabetic patients. In cohort 1 (discovery) DNAm at 39 CpGs was significantly associated with prevalent diabetes after correction for multiple testing. In cohort 2 (replication) at one of these CpGs, DNAm was still significantly associated. Decreasing methylation levels at cg19693031 with increasing fasting glucose and HbA1c concentrations were observed using restricted cubic spline analysis. In diabetic patients with poorly controlled diabetes, the decrease in estimated DNAm levels was approximately 5% in comparison with participants free of diagnosed diabetes. Cg19693031, which is located within the 3′-untranslated region of TXNIP, might play a role in the pathophysiology of type 2 diabetes. This result appears biologically plausible given that thioredoxin-interacting protein is overexpressed in diabetic animals and humans and 3′-untranslated regions are known to play a regulatory role in gene expression.
Published: 2015

43. F2RL3 methylation, lung cancer incidence and mortality

Author: Yan, Zhang, Ben, Schöttker, José, Ordóñez-Mena, Bernd, Holleczek, Rongxi, Yang, Barbara, Burwinkel, Katja, Butterbach, and Hermann, Brenner
Subjects: Cohort Studies, Male, Lung Neoplasms, Germany, Smoking, Humans, Female, Receptors, Thrombin, DNA Methylation, Middle Aged, Aged
Abstract: Smoking accounts for a large share of lung cancer. F2RL3 methylation was recently identified as a biomarker closely reflecting both current and past smoking exposure. We aimed to assess the associations of F2RL3 methylation with lung cancer incidence and mortality. In a large population-based cohort study, F2RL3 methylation was measured in baseline blood samples of 4,987 participants by MassARRAY. Associations of F2RL3 methylation and smoking with lung cancer incidence/mortality during a median follow-up of 10.9 years were assessed by Cox regression, controlling for potential confounders. The ability of F2RL3 methylation to predict lung cancer was examined by Harrell's C statistics. Hypomethylation at F2RL3 was strongly associated with both lung cancer incidence and mortality, with age- and sex-adjusted hazard ratios (HR; 95% CI) of 9.99 (5.61-17.79) and 16.86 (8.53-33.34), respectively, for participants whose methylation intensity were ≤0.54 compared with whose methylation intensity were ≥0.75. Strongly elevated HRs of 2.88 (1.42-5.84) and 5.17 (2.28-11.70) persisted even after controlling for multiple covariates including smoking status and pack-years. With fully adjusted HRs of 9.92 (2.88-34.12) and 16.48 (4.10-66.15), the associations between methylation and the two outcomes were particularly strong among participants≥65 years. Combination of F2RL3 methylation and pack-years predicted lung cancer incidence with high accuracy (optimism-corrected Harrell's C statistics = 0.86 for participants≥65 years). These findings suggested that F2RL3 methylation is a very strong predictor of lung cancer risk and mortality, particularly at older age. The potential implications of F2RL3 methylation for early detection, risk stratification and prevention of lung cancer warrant further exploration.
Published: 2015

44. Discovery of a novel epigenetic cancer marker related to the oxidative status of human blood

Author: Ben, Schöttker, Yan, Zhang, Jonathan A, Heiss, Katja, Butterbach, Eugène H J M, Jansen, Melanie, Bewerunge-Hudler, Kai-Uwe, Saum, Bernd, Holleczek, and Hermann, Brenner
Subjects: Aged, 80 and over, DNA Replication, Male, DNA Methylation, Middle Aged, Epigenesis, Genetic, Cohort Studies, Germany, Neoplasms, Biomarkers, Tumor, Humans, CpG Islands, Female, Reactive Oxygen Species, Oxidation-Reduction, Aged, Genome-Wide Association Study
Abstract: Long-lasting oxidative stress exposure may lead to relatively stable epigenetic modifications of the DNA in order to activate anti-oxidative defence mechanisms. Oxidative stress related DNA methylation may therefore be associated (causally or as a by-product) with cancer. We measured derivatives of reactive oxygen metabolites (D-ROM), total thiol levels (TTL) and DNA methylation with the Illumina Infinium 450K BeadChip in three samples of German individuals aged ≥50 years: n = 1,000 ESTHER study baseline participants (DNA methylation only), n = 99 ESTHER eight-year follow-up participants and n = 142 participants of the BLITZ study. The correlation coefficient of methylation at cg10342304 and D-ROM in the ESTHER 8-year follow-up sample (r = -0.427; P = 1 × 10(-5)) was replicated with a P-value indicating statistical significance after correction for multiple testing in the BLITZ sample (r = -0.192; P = 0.022). The association was robust to adjusting for potential confounders. In the ESTHER baseline sample, the hazard ratio for cancer development in 11 years of follow-up comparing bottom and top quartile of DNA methylation at cg10342304 was 1.86 (95%-confidence-interval 1.01-3.43). In summary, this first epigenome-wide screening and replication study with oxidative status markers observed a negative correlation of D-ROM levels and DNA methylation at cg10342304 in two independent cohorts. This CpG site is located in the body region of the nucleoredoxin gene. The nucleoredoxin protein is a redox-dependent inhibitor of the Wnt/ß-catenin signaling pathway, a well-characterized cancer pathway. If the observed CpG-cancer association can be successfully replicated by other studies, this epigenetic marker could be an interesting biomarker of cancer risk.
Published: 2015

45. Genome-wide Association Studies Identify Genetic Loci Associated with Albuminuria in Diabetes

Author: Menno Pruijm, Thor Aspelund, Ruth J. F. Loos, Philipp S. Wild, Wolfgang Koenig, Ozren Polasek, Jacques S. Beckmann, Christa Meisinger, Aida Karina Dieffenbach, Jozef Lazar, Yi-An Ko, Lyudmyla Kedenko, Matthias Nauck, Thomas Illig, Alessandro Luciani, Christian Fuchsberger, Claudia Langenberg, Nan Cher Yeo, Bénédicte Stengel, Katalin Susztak, Karlhans Endlich, Linda T. Hiraki, Zoltán Kutalik, Nicole Endlich, Ronit Katz, Lenore J. Launer, Vladan Mijatovic, Gerjan Navis, Christian Gieger, Howard J. Jacob, Iris M. Heid, Mathias Gorski, David S. Siscovick, Bernhard K. Krämer, John Chalmers, Melanie Waldenberger, Peter Vollenweider, Nicole Soranzo, Igor Rudan, Ron T. Gansevoort, Jeffrey R. O'Connell, Christian Müller, Margot Haun, Joshua C. Denny, Olivier Devuyst, Rainer Rettig, Holly Kramer, Jian'an Luan, Tamara B. Harris, Marie Metzger, Christian M. Shaffer, Ming-Huei Chen, Giovanni Malerba, Reiner Biffar, Man Li, Josef Coresh, Harald Grallert, Belen Ponte, Ian H. de Boer, Barbara Kollerits, Myriam Rheinberger, Vincent Chouraki, Jean-Charles Lambert, Katja Butterbach, Albert V. Smith, Georg Ehret, Audrey Y. Chu, Antonio Lupo, Caroline S. Fox, Alan R. Shuldiner, Pavel Hamet, Shih-Jen Hwang, Yong Li, Sylvia E. Rosas, Daniel Taliun, Niek Verweij, Luigi Ferrucci, Uwe Völker, Braxton D. Mitchell, H Brenner, Sven Bergmann, Bernhard Paulweber, Matthew Hoffman, Sylvia Stracke, Rossella Sorice, Robert J. Carroll, Florian Kronenberg, Jing Hua Zhao, Qiong Yang, Johanne Tremblay, Peter P. Pramstaller, Vilmundur Gudnason, Murielle Bochud, Daniel Ackermann, Hans L. Hillege, Nicholas J. Wareham, Mark Woodward, Eric Boerwinkle, Uwe Lendeckel, Guo Li, Georg Homuth, I. Mateo Leach, Gudny Eiriksdottir, Cristian Pattaro, Andrew D. Paterson, Henry Völzke, Gérard Waeber, Carsten A. Böger, Giovanni Gambaro, Meredith C. Foster, Henri Wallaschofski, Adrienne Tin, Catherine Helmer, Bamidele O. Tayo, Matthias Olden, Anna Köttgen, Toshiko Tanaka, Caroline Hayward, Tanguy Corre, Stefan Coassin, Alexander Teumer, Tanja Zeller, H.-Erich Wichmann, Afshin Parsa, Allison Zappa, Pim van der Harst, Ponte, Belen, Ehret, Georg Benedikt, Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Life Course Epidemiology (LCE), Cardiovascular Centre (CVC), and Value, Affordability and Sustainability (VALUE)
Subjects: Male, 0301 basic medicine, diabetes, gene, Endocrinology, Diabetes and Metabolism, Genome-wide association study, Kidney, GLOMERULAR-FILTRATION-RATE, Cathepsin C, Gene Knockout Techniques, cubilin, Settore MED/14 - NEFROLOGIA, Diabetic Nephropathies, MODULATES PROTEINURIA, ddc:616, HERITABILITY, Diabetes, Genetics/Genomes/Proteomics/Metabolomics, Middle Aged, RISK POPULATION COHORTS, 3. Good health, INSIGHTS, Kidney Tubules, Female, Sulfotransferases, medicine.symptom, RAB38, Adult, EXPRESSION, medicine.medical_specialty, Renal function, Receptors, Cell Surface, 610 Medicine & health, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, albuminuria, Diabetes Mellitus, Experimental, 03 medical and health sciences, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Animals, Humans, Genetic Predisposition to Disease, Aged, MORTALITY, KIDNEY-DISEASE, medicine.disease, Cubilin, Rats, Minor allele frequency, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, rab GTP-Binding Proteins, COLLABORATIVE METAANALYSIS, Albuminuria, 570 Life sciences, biology, albuminuria, diabetes, cubilin, Genome-Wide Association Study, Kidney disease
Abstract: Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10−10). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10–7) and 13% for RAB38/CTSC (P = 5.8 × 10−7). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.
Published: 2015

46. Genome-wide association study of colorectal cancer identifies six new susceptibility loci

Author: Katja Butterbach, Christopher K. Edlund, Duncan C. Thomas, Gianluca Severi, Motoki Iwasaki, Keith R. Curtis, Emily White, Fredrick R. Schumacher, Wei Shi, Sun Ha Jee, W. James Gauderman, Dee W. West, Robert W. Haile, Wei Hua Jia, Jing Ma, Graham Casey, Mark A. Jenkins, Wei Zheng, Stéphane Bézieau, Mathiew Lemire, Andrea Z. LaCroix, Charles S. Fuchs, David Van Den Berg, Cecelia A. Laurie, Yong-Bing Xiang, Gad Rennert, Tabitha A. Harrison, Karen W. Makar, Marilena Melas, Hermann Brenner, Laurence N. Kolonel, Christopher S. Carlson, Cathy C. Laurie, Barbara K. Fortini, Shoichiro Tsugane, John F. Harju, Bhramar Mukherjee, Steven Gallinger, Darin Taverna, John L. Hopper, John D. Potter, Polly A. Newcomb, Aaron K. Aragaki, Sonja I. Berndt, Keitaro Matsuo, Cornelia M. Ulrich, Stephanie L. Schmit, Jane C. Figueiredo, Li Li, Victor Moreno, Eric J. Jacobs, Gregory Idos, Kana Wu, Stephen B. Gruber, Stephen J. Chanock, Kevin McDonnell, David K. Levine, Amit Joshi, Shuo Jiao, Brian E. Henderson, Thomas J. Hudson, Andrew T. Chan, Daniela Seminara, Stephanie M. Gogarten, Christopher P. Fischer, Roger C. Green, David Duggan, Bette J. Caan, Ulrike Peters, Richard B. Hayes, N. M. Lindor, Rebecca D. Jackson, David J. Hunter, Martha L. Slattery, Loic Le Marchand, Ben Zhang, Edward L. Giocannucci, Brent W. Zanke, Stephanie A. Rosse, David V. Conti, Sebastian Kury, Leon Raskin, Manish Gala, Shu Chen Huang, Frank J. Manion, Hansong Wang, Hedy S. Rennert, Gerhard A. Coetzee, Carolyn M. Hutter, Suminori Kono, Jenny Chang-Claude, Graham G. Giles, Michael Hoffmeister, Xiao-Ou Shu, Caroline McNeil, Flavio Lejbkowicz, Robert E. Schoen, Li Hsu, Conghui Qu, Peter T. Campbell, and Charles Kooperberg
Subjects: Colorectal cancer, General Physics and Astronomy, Genome-wide association study, Biology, Bioinformatics, Genoma humà, Polymorphism, Single Nucleotide, Article, General Biochemistry, Genetics and Molecular Biology, Polymorphism (computer science), Càncer colorectal, Odds Ratio, medicine, Genetic predisposition, Genetics, Humans, Genetic Predisposition to Disease, Multidisciplinary, Human genome, Case-control study, Cancer, General Chemistry, medicine.disease, Genetic epidemiology, Case-Control Studies, Colorectal Neoplasms, Genètica, Genome-Wide Association Study
Abstract: El document inclou una pàgina final amb una correcció (corrigendum). Aquesta, per si sola, té el següent DOI: 10.1038/ncomms9739 i es va publicar al mateix vol. 6., Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P
Published: 2015

47. Smoking habits and leukocyte telomere length dynamics among older adults: Results from the ESTHER cohort

Author: Petra Boukamp, Hermann Brenner, Ute Mons, Aysel Müezzinler, Katja Butterbach, Matthias Schick, Bernd Holleczek, Christa Stegmaier, Aida Karina Dieffenbach, Hermann Stammer, and Kai Uwe Saum
Subjects: Male, Aging, Smoking habit, Cross-sectional study, Population, Biochemistry, Endocrinology, Bayesian multivariate linear regression, Genetics, Leukocytes, Medicine, Humans, education, Molecular Biology, Telomere Shortening, Aged, education.field_of_study, business.industry, Smoking, Follow up studies, Telomere Homeostasis, Cell Biology, Middle Aged, Telomere, Increased risk, Cross-Sectional Studies, Cohort, Female, business, Cohort study, Demography, Follow-Up Studies
Abstract: Leukocyte telomere length (LTL) shortens with age and short LTL has been associated with increased mortality and increased risk for some age-related outcomes. This study aims to analyse the associations of smoking habits with LTL and rate of LTL change per year in older adults.LTL was measured by quantitative PCR at baseline in 3600 older adults, who were enrolled in a population-based cohort study in Germany. For longitudinal analyses, measurements were repeated in blood samples obtained at 8-year follow-up from 1000 participants. Terminal Restriction Fragment analysis was additionally performed in a sub-sample to obtain absolute LTL in base pairs. Multivariate linear regression models were used to estimate associations of smoking habits with baseline LTL and changes in LTL over time.LTL was inversely associated with age (r=-0.090, p0.0001). Women had longer LTL than men (p0.0001). Smoking was inversely associated with LTL. On average, current smokers had 73 base pairs (BP) shorter LTL compared to never smokers. Smoking intensity and pack-years of smoking were also inversely associated with LTL, and a positive association was observed with years since smoking cessation. Slower LTL attrition rates were observed in ever smokers over 8years of follow-up.Our cross-sectional analysis supports suggestions that smoking might contribute to shortening of LTL but this relationship could not be shown longitudinally. The overall rather small effect sizes observed for smoking-related variables suggest that LTL reflects smoking-related health hazards only to a very limited extent.
Published: 2014

48. Estimating the heritability of colorectal cancer

Author: Katja Butterbach, John D. Potter, Hermann Brenner, Shuo Jiao, Jenny Chang-Claude, Emily White, Bette J. Caan, Tabitha A. Harrison, Li Hsu, Christopher S. Carlson, Jian Gong, Keith R. Curtis, Daniela Seminara, Robert E. Schoen, Michael Hoffmeister, Anja Rudolph, Sonja I. Berndt, Andrew T. Chan, Stephen J. Chanock, Richard B. Hayes, Martha L. Slattery, Brian E. Henderson, Laurence N. Kolonel, Loic Le Marchand, David J. Duggan, and Ulrike Peters
Subjects: Genetics, Models, Statistical, Association Studies Articles, Quantitative Trait Loci, Smoking, Case-control study, Genetic Variation, Genome-wide association study, Single-nucleotide polymorphism, General Medicine, Biology, Heritability, Quantitative trait locus, Polymorphism, Single Nucleotide, Polymorphism (computer science), Case-Control Studies, Genetic variation, Humans, Genetic Predisposition to Disease, Colorectal Neoplasms, Molecular Biology, Genetics (clinical), Genetic association, Genome-Wide Association Study
Abstract: A sizable fraction of colorectal cancer (CRC) is expected to be explained by heritable factors, with heritability estimates ranging from 12 to 35% twin and family studies. Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) associated with CRC risk. Although it has been shown that these CRC susceptibility SNPs only explain a small proportion of the genetic risk, it is not clear how much of the heritability these SNPs explain and how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we estimated the heritability of CRC under different scenarios using Genome-Wide Complex Trait Analysis in the Genetics and Epidemiology of Colorectal Cancer Consortium including 8025 cases and 10 814 controls. We estimated that the heritability explained by known common CRC SNPs identified in GWAS was 0.65% (95% CI:0.3-1%; P = 1.11 × 10-16), whereas the heritability explained by all common SNPs was at least 7.42% (95% CI: 4.71-10.12%; P = 8.13 × 10(-8)), suggesting that many common variants associated with CRC risk remain to be detected. Comparing the heritability explained by the common variants with that from twin and family studies, a fraction of the heritability may be explained by other genetic variants, such as rare variants. In addition, our analysis showed that the gene × smoking interaction explained a significant proportion of the CRC variance (P = 1.26 × 10(-2)). In summary, our results suggest that known CRC SNPs only explain a small proportion of the heritability and more common SNPs have yet to be identified.
Published: 2014

49. Cross-sectional and longitudinal changes in DNA methylation with age: an epigenome-wide analysis revealing over 60 novel age-associated CpG sites

Author: Katja Butterbach, Ines Florath, Melanie Bewerunge-Hudler, Hermann Brenner, and Heiko Müller
Subjects: Oncology, Epigenomics, medicine.medical_specialty, Aging, Cross-sectional study, Population, Biology, Polymorphism, Single Nucleotide, Epigenesis, Genetic, Internal medicine, Genetics, medicine, Humans, Longitudinal Studies, education, Molecular Biology, Genetics (clinical), Aged, Aged, 80 and over, education.field_of_study, Age Factors, Infant, Newborn, Molecular Sequence Annotation, General Medicine, Methylation, Articles, DNA Methylation, Middle Aged, Cross-Sectional Studies, CpG site, DNA methylation, Cohort, CpG Islands, Cohort study, Genome-Wide Association Study
Abstract: Understanding the role of epigenetic modifications, e.g. DNA methylation, in the process of aging requires the characterization of methylation patterns in large cohorts. We analysed >480 000 CpG sites using Infinium HumanMethylation450 BeadChip (Illumina) in whole blood DNA of 965 participants of a population-based cohort study aged between 50 and 75 years. In an exploratory analysis in 400 individuals, 200 CpG sites with the highest Spearman correlation coefficients for the association between methylation and age were identified. Of these 200 CpGs, 162 were significantly associated with age, which was verified in an independent cohort of 498 individuals using mixed linear regression models adjusted for gender, smoking behaviour, age-related diseases and random batch effect and corrected for multiple testing by Bonferroni. In another independent cohort of 67 individuals without history of major age-related diseases and with a follow-up of 8 years, we observed a gain in methylation at 96% (52%, significant) of the positively age-associated CpGs and a loss at all (89%, significant) of the negatively age-associated CpGs in each individual while getting 8 years older. A regression model for age prediction based on 17 CpGs as predicting variables explained 71% of the variance in age with an average accuracy of 2.6 years. In comparison with cord blood samples obtained from the Ulm Birth Cohort Study, we observed a more than 2-fold change in mean methylation levels from birth to older age at 86 CpGs. We were able to identify 65 novel CpG sites with significant association of methylation with age.
Published: 2013

50. Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-wide Meta-analysis

Author: Stéphane Bézieau, Ross L. Prentice, John D. Potter, Bette J. Caan, John L. Hopper, Steven Gallinger, Wei Zheng, Mathieu Lemire, Hermann Brenner, Tabitha A. Harrison, Laurence N. Kolonel, Simon G. Coetzee, Karen W. Makar, Thomas J. Hudson, Fredrick R. Schumacher, Noralane M. Lindor, Todd L. Edwards, Jenny Chang-Claude, Jing Ma, David V. Conti, Stephanie A. Rosse, Yan Liu, Sonja I. Berndt, Darin Taverna, Gerhard A. Coetzee, Carolyn M. Hutter, Cornelia M. Ulrich, Edward Giovannucci, Sébastien Küry, Stephen J. Chanock, Cecelia A. Laurie, Lin Chen, David Duggan, Aaron K. Aragaki, Keitaro Matsuo, Charles Kooperberg, David J. Hunter, Brent W. Zanke, Martha L. Slattery, Cathy C. Laurie, Christopher S. Carlson, Loic Le Marchand, Polly A. Newcomb, Katja Butterbach, Martha J. Shrubsole, Xiao-Ou Shu, Li Hsu, Emily White, Conghui Qu, Peter T. Campbell, John A. Baron, Sun Ha Jee, Michael Hoffmeister, Mark A. Jenkins, Ulrike Peters, Wei Hua Jia, Keith R. Curtis, Yong-Bing Xiang, Andrea Z. LaCroix, Andrew T. Chan, Robert E. Schoen, Charles S. Fuchs, David K. Levine, Shuo Jiao, Thomas E. Rohan, Richard B. Hayes, Robert W. Haile, Rebecca D. Jackson, Brian E. Henderson, Ben Zhang, Daniela Seminara, Stephanie M. Gogarten, Yi Xin Zeng, Stephen B. Gruber, Stephen N. Thibodeau, and Graham Casey
Subjects: Male, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Biology, Laminin, gamma 1, Polymorphism, Single Nucleotide, Risk Assessment, Article, Age Distribution, Cyclin D2, Humans, Genetic Predisposition to Disease, Sex Distribution, Gene, Aged, Genetics, Aged, 80 and over, Nucleic acid binding protein 1, Hepatology, Incidence, Gastroenterology, Middle Aged, Prognosis, Minor allele frequency, DNA-Binding Proteins, Genetic Loci, Female, Laminin, Colorectal Neoplasms, T-Box Domain Proteins, Genome-Wide Association Study
Abstract: Background & Aims Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. Methods We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. Results Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10 −8 : an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10 −8 ). We also found evidence for 3 additional loci with P values less than 5.0 × 10 −7 : a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10 −8 ), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10 −8 ), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10 −7 ). Conclusions In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
Published: 2012

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