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201. Multi-centre randomised controlled trial comparing arthroscopic hip surgery to physiotherapist-led care for femoroacetabular impingement (FAI) syndrome on hip cartilage metabolism: the Australian FASHIoN trial

Author

Hunter, David J., Eyles, Jillian, Murphy, Nicholas J., Spiers, Libby, Burns, Alexander, Davidson, Emily, Dickenson, Edward, Fary, Camdon, Foster, Nadine E., Fripp, Jurgen, Griffin, Damian R., Hall, Michelle, Kim, Young Jo, Linklater, James M., Molnar, Robert, Neubert, Ales, O’Connell, Rachel L., O’Donnell, John, O’Sullivan, Michael, Randhawa, Sunny, Reichenbach, Stephan, Schmaranzer, Florian, Singh, Parminder, Tran, Phong, Wilson, David, Zhang, Honglin, and Bennell, Kim L.

Published
2021
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204. Priorities for the effective implementation of osteoarthritis management programs: an OARSI international consensus exercise

Author

Quicke, J., Skou, S.T., Risberg, M.A.G., Roos, E.M., Thorstensson, C., Hurley, M., Nelson, A., Jinks, C., Briggs, A., Egerton, T., Allen, K., Davis, A., Dowsey, M., Holm, I., Yu, S., Dahlberg, L., Peat, G., Chan, P.K., Miller, K., Scanzello, C., Østerås, N., Schipof, D., Pais, S., Berenbaum, F., Frost, H., Walsh, N., Crossley, K., Vlieland, T.V., van den Ende, E., Slater, H., Nero, H., Jönsson, T., Woolf, A., Mills, K., O'Donnell, J., Ross, M., Hao, L.J., Eyles, Jillian P., Hunter, David J., Bennell, Kim L., Dziedzic, Krysia S., Hinman, Rana S., van der Esch, Martin, Holden, Melanie A., and Bowden, Jocelyn L.

Published
2019
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208. Lifetime Medical Costs of Knee Osteoarthritis Management in the United States: Impact of Extending Indications for Total Knee Arthroplasty

Author

Losina, Elena, Paltiel, A David, Weinstein, Alexander M, Yelin, Edward, Hunter, David J, Chen, Stephanie P, Klara, Kristina, Suter, Lisa G, Solomon, Daniel H, Burbine, Sara A, Walensky, Rochelle P, and Katz, Jeffrey N

Subjects
Osteoarthritis, Chronic Pain, Health Services, Pain Research, Arthritis, Aging, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Musculoskeletal, Good Health and Well Being, Adult, Aged, Arthroplasty, Replacement, Knee, Female, Health Care Costs, Health Services Needs and Demand, Humans, Male, Middle Aged, Models, Economic, Osteoarthritis, Knee, United States, Clinical Sciences, Public Health and Health Services, Psychology
Abstract

ObjectiveThe impact of increasing utilization of total knee arthroplasty (TKA) on lifetime costs in persons with knee osteoarthritis (OA) is understudied.MethodsWe used the Osteoarthritis Policy Model to estimate total lifetime costs and TKA utilization under a range of TKA eligibility criteria among US persons with symptomatic knee OA. Current TKA utilization was estimated from the Multicenter Osteoarthritis Study and calibrated to Health Care Cost and Utilization Project data. OA treatment efficacy and toxicity were drawn from published literature. Costs in 2013 dollars were derived from Medicare reimbursement schedules and Red Book Online. Time costs were derived from published literature and the US Bureau of Labor Statistics.ResultsEstimated average discounted (3% per year) lifetime costs for persons diagnosed with knee OA were $140,300. Direct medical costs were $129,600, with $12,400 (10%) attributable to knee OA over 28 years. OA patients spent a mean ± SD of 13 ± 10 years waiting for TKA after failing nonsurgical regimens. Under current TKA eligibility criteria, 54% of knee OA patients underwent TKA over their lifetimes. Estimated OA-related discounted lifetime direct medical costs ranged from $12,400 (54% TKA uptake) when TKA eligibility was limited to Kellgren/Lawrence grades 3 or 4 to $16,000 (70% TKA uptake) when eligibility was expanded to include symptomatic OA with a lesser degree of structural damage.ConclusionBecause of low efficacy of nonsurgical regimens, knee OA treatment-attributable costs are low, representing a small portion of all costs for OA patients. Expanding TKA eligibility increases OA-related costs substantially for the population, underscoring the need for more effective nonoperative therapies.

Published
2015

210. Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis

Author

Yarmolinsky, James, primary, Robinson, Jamie W., additional, Mariosa, Daniela, additional, Karhunen, Ville, additional, Huang, Jian, additional, Dimou, Niki, additional, Murphy, Neil, additional, Burrows, Kimberley, additional, Bouras, Emmanouil, additional, Smith-Byrne, Karl, additional, Lewis, Sarah J., additional, Galesloot, Tessel E., additional, Kiemeney, Lambertus A., additional, Vermeulen, Sita, additional, Martin, Paul, additional, Albanes, Demetrius, additional, Hou, Lifang, additional, Newcomb, Polly A., additional, White, Emily, additional, Wolk, Alicja, additional, Wu, Anna H., additional, Le Marchand, Loïc, additional, Phipps, Amanda I., additional, Buchanan, Daniel D., additional, Zhao, Sizheng Steven, additional, Gill, Dipender, additional, Chanock, Stephen J., additional, Purdue, Mark P., additional, Davey Smith, George, additional, Brennan, Paul, additional, Herzig, Karl-Heinz, additional, Järvelin, Marjo-Riitta, additional, Amos, Chris I., additional, Hung, Rayjean J., additional, Dehghan, Abbas, additional, Johansson, Mattias, additional, Gunter, Marc J., additional, Tsilidis, Kostas K., additional, Martin, Richard M., additional, Landi, Maria Teresa, additional, Stevens, Victoria, additional, Wang, Ying, additional, Albanes, Demetrios, additional, Caporaso, Neil, additional, Amos, Christopher I., additional, Shete, Sanjay, additional, Bickeböller, Heike, additional, Risch, Angela, additional, Houlston, Richard, additional, Lam, Stephen, additional, Tardon, Adonina, additional, Chen, Chu, additional, Bojesen, Stig E., additional, Wichmann, H-Erich, additional, Christiani, David, additional, Rennert, Gadi, additional, Arnold, Susanne, additional, Field, John K., additional, Le Marchand, Loic, additional, Melander, Olle, additional, Brunnström, Hans, additional, Liu, Geoffrey, additional, Andrew, Angeline, additional, Shen, Hongbing, additional, Zienolddiny, Shan, additional, Grankvist, Kjell, additional, Johansson, Mikael, additional, Teare, M. Dawn, additional, Hong, Yun-Chul, additional, Yuan, Jian-Min, additional, Lazarus, Philip, additional, Schabath, Matthew B., additional, Aldrich, Melinda C., additional, Eeles, Rosalind A., additional, Haiman, Christopher A., additional, Kote-Jarai, Zsofia, additional, Schumacher, Fredrick R., additional, Benlloch, Sara, additional, Al Olama, Ali Amin, additional, Muir, Kenneth R., additional, Berndt, Sonja I., additional, Conti, David V., additional, Wiklund, Fredrik, additional, Chanock, Stephen, additional, Tangen, Catherine M., additional, Batra, Jyotsna, additional, Clements, Judith A., additional, Grönberg, Henrik, additional, Pashayan, Nora, additional, Schleutker, Johanna, additional, Weinstein, Stephanie J., additional, West, Catharine M.L., additional, Mucci, Lorelei A., additional, Cancel-Tassin, Géraldine, additional, Koutros, Stella, additional, Sørensen, Karina Dalsgaard, additional, Grindedal, Eli Marie, additional, Neal, David E., additional, Hamdy, Freddie C., additional, Donovan, Jenny L., additional, Travis, Ruth C., additional, Hamilton, Robert J., additional, Ingles, Sue Ann, additional, Rosenstein, Barry S., additional, Lu, Yong-Jie, additional, Giles, Graham G., additional, MacInnis, Robert J., additional, Kibel, Adam S., additional, Vega, Ana, additional, Kogevinas, Manolis, additional, Penney, Kathryn L., additional, Park, Jong Y., additional, Stanfrod, Janet L., additional, Cybulski, Cezary, additional, Nordestgaard, Børge G., additional, Nielsen, Sune F., additional, Brenner, Hermann, additional, Maier, Christiane, additional, Logothetis, Christopher J., additional, John, Esther M., additional, Teixeira, Manuel R., additional, Neuhausen, Susan L., additional, De Ruyck, Kim, additional, Razack, Azad, additional, Newcomb, Lisa F., additional, Lessel, Davor, additional, Kaneva, Radka, additional, Usmani, Nawaid, additional, Claessens, Frank, additional, Townsend, Paul A., additional, Castelao, Jose Esteban, additional, Roobol, Monique J., additional, Menegaux, Florence, additional, Khaw, Kay-Tee, additional, Cannon-Albright, Lisa, additional, Pandha, Hardev, additional, Thibodeau, Stephen N., additional, Hunter, David J., additional, Kraft, Peter, additional, Blot, William J., additional, and Riboli, Elio, additional

Published
2024
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211. Risk Factors for the Development of Osteoarthritis Across the Lifespan: A Systematic Review and Meta-Analysis

Author

Duong, Vicky, primary, Abdel Shaheed, Christina, additional, Ferreira, Manuela L., additional, Narayan, Sujita W., additional, Venkatesha, Venkatesha, additional, Hunter, David. J., additional, Zhu, Jimmy, additional, Atukorala, Inoshi, additional, Kobayashi, Sarah, additional, Goh, Siew Li, additional, Brigs, Andrew, additional, Cross, Marita, additional, Espinosa-Morales, Rolando, additional, Fu, Kai, additional, Guillemin, Francis, additional, Keefe, Francis J., additional, Lohmander, L. Stefan, additional, March, Lyn, additional, Milne, George, additional, Mei, Yifang, additional, Mobasheri, Ali, additional, Namane, Mosedi, additional, Peat, George, additional, Risberg, May Arna, additional, Sharma, Saurab, additional, Sit, Regina WS, additional, Telles, Rosa Weiss, additional, Zhang, Yuqing, additional, and Cooper, Cyrus, additional

Published
2024
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214. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

Author

Perry, John RB, Day, Felix, Elks, Cathy E, Sulem, Patrick, Thompson, Deborah J, Ferreira, Teresa, He, Chunyan, Chasman, Daniel I, Esko, Tõnu, Thorleifsson, Gudmar, Albrecht, Eva, Ang, Wei Q, Corre, Tanguy, Cousminer, Diana L, Feenstra, Bjarke, Franceschini, Nora, Ganna, Andrea, Johnson, Andrew D, Kjellqvist, Sanela, Lunetta, Kathryn L, McMahon, George, Nolte, Ilja M, Paternoster, Lavinia, Porcu, Eleonora, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Tšernikova, Natalia, Tikkanen, Emmi, Ulivi, Sheila, Wagner, Erin K, Amin, Najaf, Bierut, Laura J, Byrne, Enda M, Hottenga, Jouke-Jan, Koller, Daniel L, Mangino, Massimo, Pers, Tune H, Yerges-Armstrong, Laura M, Hua Zhao, Jing, Andrulis, Irene L, Anton-Culver, Hoda, Atsma, Femke, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Buring, Julie E, Chang-Claude, Jenny, Chanock, Stephen, Chen, Jinhui, Chenevix-Trench, Georgia, Collée, J Margriet, Couch, Fergus J, Couper, David, Coviello, Andrea D, Cox, Angela, Czene, Kamila, D’adamo, Adamo Pio, Davey Smith, George, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dieffenbach, Aida K, Dunning, Alison M, Eiriksdottir, Gudny, Eriksson, Johan G, Fasching, Peter A, Ferrucci, Luigi, Flesch-Janys, Dieter, Flyger, Henrik, Foroud, Tatiana, Franke, Lude, Garcia, Melissa E, García-Closas, Montserrat, Geller, Frank, de Geus, Eco EJ, Giles, Graham G, Gudbjartsson, Daniel F, Gudnason, Vilmundur, Guénel, Pascal, Guo, Suiqun, Hall, Per, Hamann, Ute, Haring, Robin, Hartman, Catharina A, Heath, Andrew C, Hofman, Albert, Hooning, Maartje J, Hopper, John L, Hu, Frank B, Hunter, David J, Karasik, David, and Kiel, Douglas P

Subjects
Paediatrics, Biological Sciences, Biomedical and Clinical Sciences, Genetics, Contraception/Reproduction, Pediatric, Biotechnology, Human Genome, Clinical Research, Adolescent, Age Factors, Alleles, Body Mass Index, Breast Neoplasms, Calcium-Binding Proteins, Cardiovascular Diseases, Child, Diabetes Mellitus, Type 2, Europe, Female, Genetic Loci, Genome-Wide Association Study, Genomic Imprinting, Humans, Hypothalamo-Hypophyseal System, Intercellular Signaling Peptides and Proteins, Male, Membrane Proteins, Menarche, Obesity, Ovary, Parents, Polymorphism, Single Nucleotide, Potassium Channels, Tandem Pore Domain, Proteins, Quantitative Trait Loci, Receptors, GABA-B, Receptors, Retinoic Acid, Ribonucleoproteins, Ubiquitin-Protein Ligases, Australian Ovarian Cancer Study, GENICA Network, kConFab, LifeLines Cohort Study, InterAct Consortium, Early Growth Genetics (EGG) Consortium, General Science & Technology
Abstract

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P

Published
2014

215. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer

Author

Wolpin, Brian M, Rizzato, Cosmeri, Kraft, Peter, Kooperberg, Charles, Petersen, Gloria M, Wang, Zhaoming, Arslan, Alan A, Beane-Freeman, Laura, Bracci, Paige M, Buring, Julie, Canzian, Federico, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goodman, Gary E, Goodman, Phyllis J, Jacobs, Eric J, Kamineni, Aruna, Klein, Alison P, Kolonel, Laurence N, Kulke, Matthew H, Li, Donghui, Malats, Núria, Olson, Sara H, Risch, Harvey A, Sesso, Howard D, Visvanathan, Kala, White, Emily, Zheng, Wei, Abnet, Christian C, Albanes, Demetrius, Andreotti, Gabriella, Austin, Melissa A, Barfield, Richard, Basso, Daniela, Berndt, Sonja I, Boutron-Ruault, Marie-Christine, Brotzman, Michelle, Büchler, Markus W, Bueno-de-Mesquita, H Bas, Bugert, Peter, Burdette, Laurie, Campa, Daniele, Caporaso, Neil E, Capurso, Gabriele, Chung, Charles, Cotterchio, Michelle, Costello, Eithne, Elena, Joanne, Funel, Niccola, Gaziano, J Michael, Giese, Nathalia A, Giovannucci, Edward L, Goggins, Michael, Gorman, Megan J, Gross, Myron, Haiman, Christopher A, Hassan, Manal, Helzlsouer, Kathy J, Henderson, Brian E, Holly, Elizabeth A, Hu, Nan, Hunter, David J, Innocenti, Federico, Jenab, Mazda, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay-Tee, Klein, Eric A, Kogevinas, Manolis, Krogh, Vittorio, Kupcinskas, Juozas, Kurtz, Robert C, LaCroix, Andrea, Landi, Maria T, Landi, Stefano, Le Marchand, Loic, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L, Nakamura, Yusuke, Oberg, Ann L, Owzar, Kouros, Patel, Alpa V, Peeters, Petra HM, Peters, Ulrike, Pezzilli, Raffaele, Piepoli, Ada, Porta, Miquel, Real, Francisco X, Riboli, Elio, Rothman, Nathaniel, Scarpa, Aldo, Shu, Xiao-Ou, Silverman, Debra T, Soucek, Pavel, Sund, Malin, Talar-Wojnarowska, Renata, Taylor, Philip R, and Theodoropoulos, George E

Subjects
Cancer, Aged, Case-Control Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Pancreatic Neoplasms, Polymorphism, Single Nucleotide, White People, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.

Published
2014

216. Assessing the Value of Incorporating a Polygenic Risk Score with Nongenetic Factors for Predicting Breast Cancer Diagnosis in the UK Biobank.

Author

Collister, Jennifer A., Xiaonan Liu, Littlejohns, Thomas J., Cuzick, Jack, Clifton, Lei, and Hunter, David J.

Abstract

Background: Previous studies have demonstrated that incorporating a polygenic risk score (PRS) to existing risk prediction models for breast cancer improves model fit, but to determine its clinical utility the impact on risk categorization needs to be established. We add a PRS to two well-established models and quantify the difference in classification using the net reclassification improvement (NRI). Methods: We analyzed data from 126,490 post-menopausal women of "White British" ancestry, aged 40 to 69 years at baseline from the UK Biobank prospective cohort. The breast cancer outcome was derived from linked registry data and hospital records. We combined a PRS for breast cancer with 10-year risk scores from the Tyrer-Cuzick and Gail models, and compared these to the risk scores from the models using phenotypic variables alone. We report metrics of discrimination and classification, and consider the importance of the risk threshold selected. Results: The Harrell's C statistic of the 10-year risk from the Tyrer-Cuzick and Gail models was 0.57 and 0.54, respectively, increasing to 0.67 when the PRS was included. Inclusion of the PRS gave a positive NRI for cases in both models [0.080 (95% confidence interval (CI), 0.053-0.104) and 0.051 (95% CI, 0.030-0.073), respectively], with negligible impact on controls. Conclusions: The addition of a PRS for breast cancer to the well-established Tyrer-Cuzick and Gail models provides a substantial improvement in the prediction accuracy and risk stratification. [ABSTRACT FROM AUTHOR]

Published
2024
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217. Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Author

Mavaddat, Nasim, Michailidou, Kyriaki, Dennis, Joe, Lush, Michael, Fachal, Laura, Lee, Andrew, Tyrer, Jonathan P., Chen, Ting-Huei, Wang, Qin, Bolla, Manjeet K., Yang, Xin, Adank, Muriel A., Ahearn, Thomas, Aittomäki, Kristiina, Allen, Jamie, Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Aronson, Kristan J., Auer, Paul L., Auvinen, Päivi, Barrdahl, Myrto, Beane Freeman, Laura E., Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Bogdanova, Natalia V., Bojesen, Stig E., Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Bremer, Michael, Brenner, Hermann, Brentnall, Adam, Brock, Ian W., Brooks-Wilson, Angela, Brucker, Sara Y., Brüning, Thomas, Burwinkel, Barbara, Campa, Daniele, Carter, Brian D., Castelao, Jose E., Chanock, Stephen J., Chlebowski, Rowan, Christiansen, Hans, Clarke, Christine L., Collée, J. Margriet, Cordina-Duverger, Emilie, Cornelissen, Sten, Couch, Fergus J., Cox, Angela, Cross, Simon S., Czene, Kamila, Daly, Mary B., Devilee, Peter, Dörk, Thilo, dos-Santos-Silva, Isabel, Dumont, Martine, Durcan, Lorraine, Dwek, Miriam, Eccles, Diana M., Ekici, Arif B., Eliassen, A. Heather, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Försti, Asta, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gapstur, Susan M., García-Sáenz, José A., Gaudet, Mia M., Georgoulias, Vassilios, Giles, Graham G., Gilyazova, Irina R., Glendon, Gord, Goldberg, Mark S., Goldgar, David E., González-Neira, Anna, Grenaker Alnæs, Grethe I., Grip, Mervi, Gronwald, Jacek, Grundy, Anne, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hamann, Ute, Hankinson, Susan E., Harkness, Elaine F., Hart, Steven N., He, Wei, Hein, Alexander, Heyworth, Jane, Hillemanns, Peter, Hollestelle, Antoinette, Hooning, Maartje J., Hoover, Robert N., Hopper, John L., Howell, Anthony, Huang, Guanmengqian, Humphreys, Keith, Hunter, David J., Jakimovska, Milena, Jakubowska, Anna, Janni, Wolfgang, John, Esther M., Johnson, Nichola, Jones, Michael E., Jukkola-Vuorinen, Arja, Jung, Audrey, Kaaks, Rudolf, Kaczmarek, Katarzyna, Kataja, Vesa, Keeman, Renske, Kerin, Michael J., Khusnutdinova, Elza, Kiiski, Johanna I., Knight, Julia A., Ko, Yon-Dschun, Kosma, Veli-Matti, Koutros, Stella, Kristensen, Vessela N., Krüger, Ute, Kühl, Tabea, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Lilyquist, Jenna, Lindblom, Annika, Lindström, Sara, Lissowska, Jolanta, Lo, Wing-Yee, Loibl, Sibylle, Long, Jirong, Lubiński, Jan, Lux, Michael P., MacInnis, Robert J., Maishman, Tom, Makalic, Enes, Maleva Kostovska, Ivana, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John W.M., Martinez, Maria Elena, Mavroudis, Dimitrios, McLean, Catriona, Meindl, Alfons, Menon, Usha, Middha, Pooja, Miller, Nicola, Moreno, Fernando, Mulligan, Anna Marie, Mulot, Claire, Muñoz-Garzon, Victor M., Neuhausen, Susan L., Nevanlinna, Heli, Neven, Patrick, Newman, William G., Nielsen, Sune F., Nordestgaard, Børge G., Norman, Aaron, Offit, Kenneth, Olson, Janet E., Olsson, Håkan, Orr, Nick, Pankratz, V. Shane, Park-Simon, Tjoung-Won, Perez, Jose I.A., Pérez-Barrios, Clara, Peterlongo, Paolo, Peto, Julian, Pinchev, Mila, Plaseska-Karanfilska, Dijana, Polley, Eric C., Prentice, Ross, Presneau, Nadege, Prokofyeva, Darya, Purrington, Kristen, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Rau-Murthy, Rohini, Rennert, Gad, Rennert, Hedy S., Rhenius, Valerie, Robson, Mark, Romero, Atocha, Ruddy, Kathryn J., Ruebner, Matthias, Saloustros, Emmanouil, Sandler, Dale P., Sawyer, Elinor J., Schmidt, Daniel F., Schmutzler, Rita K., Schneeweiss, Andreas, Schoemaker, Minouk J., Schumacher, Fredrick, Schürmann, Peter, Schwentner, Lukas, Scott, Christopher, Scott, Rodney J., Seynaeve, Caroline, Shah, Mitul, Sherman, Mark E., Shrubsole, Martha J., Shu, Xiao-Ou, Slager, Susan, Smeets, Ann, Sohn, Christof, Soucy, Penny, Southey, Melissa C., Spinelli, John J., Stegmaier, Christa, Stone, Jennifer, Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Terry, Mary Beth, Thöne, Kathrin, Tollenaar, Rob A.E.M., Tomlinson, Ian, Truong, Thérèse, Tzardi, Maria, Ulmer, Hans-Ulrich, Untch, Michael, Vachon, Celine M., van Veen, Elke M., Vijai, Joseph, Weinberg, Clarice R., Wendt, Camilla, Whittemore, Alice S., Wildiers, Hans, Willett, Walter, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R., Yannoukakos, Drakoulis, Zhang, Yan, Zheng, Wei, Ziogas, Argyrios, Dunning, Alison M., Thompson, Deborah J., Chenevix-Trench, Georgia, Chang-Claude, Jenny, Schmidt, Marjanka K., Hall, Per, Milne, Roger L., Pharoah, Paul D.P., Antoniou, Antonis C., Chatterjee, Nilanjan, Kraft, Peter, García-Closas, Montserrat, Simard, Jacques, and Easton, Douglas F.

Published
2019
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225. Alleviating the access abyss in palliative care and pain relief—an imperative of universal health coverage: the Lancet Commission report

Author

Knaul, Felicia Marie, Farmer, Paul E, Abu-Saad Huijer, Huda, Alleyne, George A O, Atun, Rifat, Binagwaho, Agnes, Bošnjak, Snežana M, Clark, David, Cleary, James F, Cossío Díaz, José R, De Lima, Liliana, Foley, Kathleen M, Frenk, Julio, Goh, Cynthia, Goldschmidt-Clermont, Pascal J, Gospodarowicz, Mary, Gwyther, Liz, Higginson, Irene J, Hughes-Hallett, Thomas, Hunter, David J, Jamison, Dean T, Krakauer, Eric L, Lohman, Diederik, Luyirika, Emmanuel B K, Medina Mora, Maria E, Mwangi-Powell, Faith N, Nishtar, Sania, O'Brien, Megan E, Radbruch, Lukas, Rajagopal, M R, Reddy, K Srinath, del Rocío Sáenz Madrigal, María, Salerno, Judith A, Bhadelia, Afsan, Allende, Silvia, Arreola-Ornelas, Héctor, Bhadelia, Nahid, Calderon, Mariana, Connor, Stephen R, Fan, Victoria Y, Gómez-Dantés, Octavio, Jiménez, Jorge, Ntizimira, Christian R, Perez-Cruz, Pedro E, Salas-Herrera, Isaias Gerardo, Spence, Dingle, Steedman, Mark R, Verguet, Stéphane, Downing, Julia D, Paudel, Bishnu D, Elsner, Maia, Gillespie, James Andrew, Hofman, Karen J, Jiang Kwete, Xiaoxiao, Khanh, Quach Thanh, Lorenz, Karl A, Méndez Carniado, Oscar, Nugent, Rachel, Rodriguez, Natalia M, Wroe, Emily B, and Zimmerman, Camilla

Published
2018
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226. International patellofemoral osteoarthritis consortium: Consensus statement on the diagnosis, burden, outcome measures, prognosis, risk factors and treatment

Author

van Middelkoop, Marienke, Bennell, Kim L., Callaghan, Michael J., Collins, Natalie J., Conaghan, Philip G., Crossley, Kay M., Eijkenboom, Joost J.F.A., van der Heijden, Rianne A., Hinman, Rana S., Hunter, David J., Meuffels, Duncan E., Mills, Kathryn, Oei, Edwin H.G., Runhaar, Jos, Schiphof, Dieuwke, Stefanik, Joshua J., and Bierma-Zeinstra, Sita M.A.

Published
2018
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227. Biomarkers for osteoarthritis: Current position and steps towards further validation

Author

Hunter, David J, Nevitt, Michael, Losina, Elena, and Kraus, Virginia

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Osteoarthritis, Prevention, Arthritis, Aging, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Musculoskeletal, Good Health and Well Being, Biomarkers, Humans, Validation Studies as Topic, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

Historically disease knowledge development and treatment innovation in osteoarthritis (OA) has been considered to be slow. One of the many reasons purported as responsible for this slow pace has been the alleged lack of valid and responsive biomarkers to ascertain efficacy, which itself has been dependent upon the slow evolution of the understanding of the complex nature of joint tissue biology. This narrative review outlines the rationale for why we need OA biomarkers with regard to biomarker validation and qualification. The main biomarkers in current development for OA are biochemical and imaging markers. We describe an approach to biomarker validation and qualification for OA clinical trials that has recently commenced with the Foundation of NIH OA Biomarkers Consortium study cosponsored by the Osteoarthritis Research Society International (OARSI). With this approach we endeavor to identify, develop, and qualify biological markers (biomarkers) to support new drug development, preventive medicine, and medical diagnostics for osteoarthritis.

Published
2014

228. Genome-wide association study of survival in patients with pancreatic adenocarcinoma

Author

Wu, Chen, Kraft, Peter, Stolzenberg-Solomon, Rachael, Steplowski, Emily, Brotzman, Michelle, Xu, Mousheng, Mudgal, Poorva, Amundadottir, Laufey, Arslan, Alan A, Bueno-de-Mesquita, H Bas, Gross, Myron, Helzlsouer, Kathy, Jacobs, Eric J, Kooperberg, Charles, Petersen, Gloria M, Zheng, Wei, Albanes, Demetrius, Boutron-Ruault, Marie-Christine, Buring, Julie E, Canzian, Federico, Cao, Guangwen, Duell, Eric J, Elena, Joanne W, Gaziano, J Michael, Giovannucci, Edward L, Hallmans, Goran, Hutchinson, Amy, Hunter, David J, Jenab, Mazda, Jiang, Guoliang, Khaw, Kay-Tee, LaCroix, Andrea, Li, Zhaoshen, Mendelsohn, Julie B, Panico, Salvatore, Patel, Alpa V, Qian, Zhi Rong, Riboli, Elio, Sesso, Howard, Shen, Hongbing, Shu, Xiao-Ou, Tjonneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrios, Virtamo, Jarmo, Visvanathan, Kala, Wactawski-Wende, Jean, Wang, Chengfeng, Yu, Kai, Zeleniuch-Jacquotte, Anne, Chanock, Stephen, Hoover, Robert, Hartge, Patricia, Fuchs, Charles S, Lin, Dongxin, and Wolpin, Brian M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Digestive Diseases, Prevention, Rare Diseases, Pancreatic Cancer, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Asian People, Biomarkers, Tumor, China, Europe, Female, Follow-Up Studies, Genome-Wide Association Study, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Models, Genetic, Pancreatic Neoplasms, Polymorphism, Single Nucleotide, Principal Component Analysis, Proportional Hazards Models, Protein Tyrosine Phosphatases, Non-Receptor, Survival Rate, White People, Cancer Genetics, Molecular Epidemiology, Clinical Sciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background and objectiveSurvival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma.MethodsWe analysed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (p≤10(-5)) were advanced to a joint analysis with 363 additional patients from China (ChinaPC).ResultsIn the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21 and 1p36.13, tagged by rs12362504 (p=1.63×10(-7)), rs981621 (p=1.65×10(-7)) and rs16861827 (p=3.75×10(-7)), respectively. 131 SNPs with p≤10(-5) were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; p=1.72×10(-7)) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The HR (95% CI) for death was 0.74 (0.66 to 0.84) in PanScan I, 0.79 (0.65 to 0.97) in ChinaPC and 0.76 (0.68 to 0.84) in the joint analysis.ConclusionsGermline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.

Published
2014

229. Bone marrow lesion volume reduction is not associated with improvement of other periarticular bone measures: data from the Osteoarthritis Initiative

Author

Driban, Jeffrey B, Lo, Grace H, Price, Lori, Pang, Jincheng, Miller, Eric, Ward, Robert J, Hunter, David J, Eaton, Charles B, Lynch, John A, and McAlindon, Timothy E

Abstract

Abstract Introduction We evaluated the associations between bone marrow lesion (BML) volume change and changes in periarticular bone mineral density (paBMD) as well as subchondral sclerosis to determine whether BML change is associated with other local bone changes. Methods The convenience sample comprised participants in the Osteoarthritis Initiative (OAI) with weight-bearing posterior-anterior knee radiographs and magnetic resonance images (MRIs) at the 24- and 48-month visits and dual-energy x-ray absorptiometry (DXA) at the 30-/36-month and 48-month visits. The right knee was assessed unless contraindicated for MRI. We used knee DXA scans to measure medial tibia paBMD and medial/lateral paBMD ratio (M:L paBMD). Knee radiographs were scored for sclerosis (grades 0 to 3) in the medial tibia. Two raters determined BML volume on sagittal fat-suppressed MRI by using a semiautomated segmentation method. To focus on knees with only medial tibia BML changes, knees with lateral tibial BMLs were excluded. Medial tibial BML volume change was classified into three groups: BML regression (lowest quartile of medial tibial BML volume change), no-to-minimal change (middle two quartiles), and BML progression (highest quartile). We used proportional odds logistic regression models to evaluate the association between quartiles of changes in medial paBMD or M:L paBMD ratio, as outcomes, and BML volume change. Results The sample (n = 308) included 163 (53%) female subjects, 212 (69%) knees with radiographic osteoarthritis, and participants with a mean age of 63.8 ± 9.3 years and mean body mass index of 29.8 ± 4.7 kg/m2. We found an association between greater increases in medial tibia paBMD and BML regression (OR = 1.7 (95% confidence interval (CI) = 1.1 to 2.8)) and a similar trend for BML progression (OR = 1.6 (95% CI = 1.0 to 2.6]). We also detected associations between greater increase in M:L paBMD and BML regression (OR = 1.6 (95% CI = 1.0 to 2.7]) and BML progression (OR = 1.8 (95% CI = 1.1 to 3.0)), although BML regression had borderline statistical significance. The frequency of sclerosis progression in the medial tibia (n = 14) was greater among knees with BML progression or regression compared with knees without BML change (P = 0.01 and P = 0.04, respectively). Conclusion BML regression and BML progression are characterized by concurrent increases in paBMD and sclerosis, which are characteristic of increased radiographic osteoarthritis severity. At least during 24 months, BML regression is not representative of improvement in other periarticular bone measures.

Published
2013

230. Evaluation of bone marrow lesion volume as a knee osteoarthritis biomarker - longitudinal relationships with pain and structural changes: data from the osteoarthritis initiative

Author

Driban, Jeffrey B, Price, Lori, Lo, Grace H, Pang, Jincheng, Hunter, David J, Miller, Eric, Ward, Robert J, Eaton, Charles B, Lynch, John A, and McAlindon, Timothy E

Abstract

Abstract Introduction Bone marrow lesion (BML) size may be an important imaging biomarker for osteoarthritis-related clinical trials and reducing BML size may be an important therapeutic goal. However, data on the interrelationships between BML size, pain, and structural progression are inconsistent and rarely examined in the same cohort. Therefore, we evaluated the cross-sectional and longitudinal associations of BML volume with knee pain and joint space narrowing (JSN). Methods A BML volume assessment was performed on magnetic resonance images of the knee collected at the 24- and 48-month Osteoarthritis Initiative visits from a convenience sample of 404 participants in the progression cohort. During the same visits, knee pain was assessed with WOMAC pain scores and knee radiographs were acquired and scored for JSN. BML volume was summed to generate a total knee volume and an index tibiofemoral compartment volume (compartment with greater baseline JSN). Primary analyses included multiple linear regressions (outcome = pain, predictor = total knee BML volume) and logistic regressions (outcome = JSN, predictor = index tibiofemoral compartment BML volume). Results This sample was 49% female with a mean age of 63 (9.2 standard deviation (SD)) years, and 71% had radiographic osteoarthritis in the study knee. Larger baseline BMLs were associated with greater baseline knee pain (P = 0.01), the presence of JSN at baseline (odds ratio (OR) = 1.50, 95% confidence interval (CI) = 1.23 to 1.83), and JSN progression (OR = 1.27, 95%CI = 1.11 to 1.46). Changes in total knee BML volume had a positive association with changes in knee pain severity (P = 0.004) and this association may be driven by knees that were progressing from no or small baseline BMLs to larger BMLs. In contrast, we found no linear positive relationship between BML volume change and JSN progression. Instead, regression of medial tibiofemoral BML volume was associated with JSN progression compared to knees with no or minimal changes in BML volume (OR = 3.36, 95%CI = 1.55 to 7.28). However, follow-up analyses indicated that the association between JSN progression and BML volume change may primarily be influenced by baseline BML volume. Conclusion Large baseline BMLs are associated with greater baseline knee pain, the presence of JSN at baseline, and disease progression. Additionally, BML regression is associated with decreased knee pain but not a reduced risk of concurrent JSN progression.

Published
2013

231. A Genome-Wide Association Study of Depressive Symptoms

Author

Hek, Karin, Demirkan, Ayse, Lahti, Jari, Terracciano, Antonio, Teumer, Alexander, Cornelis, Marilyn C, Amin, Najaf, Bakshis, Erin, Baumert, Jens, Ding, Jingzhong, Liu, Yongmei, Marciante, Kristin, Meirelles, Osorio, Nalls, Michael A, Sun, Yan V, Vogelzangs, Nicole, Yu, Lei, Bandinelli, Stefania, Benjamin, Emelia J, Bennett, David A, Boomsma, Dorret, Cannas, Alessandra, Coker, Laura H, de Geus, Eco, De Jager, Philip L, Diez-Roux, Ana V, Purcell, Shaun, Hu, Frank B, Rimm, Eric B, Hunter, David J, Jensen, Majken K, Curhan, Gary, Rice, Kenneth, Penman, Alan D, Rotter, Jerome I, Sotoodehnia, Nona, Emeny, Rebecca, Eriksson, Johan G, Evans, Denis A, Ferrucci, Luigi, Fornage, Myriam, Gudnason, Vilmundur, Hofman, Albert, Illig, Thomas, Kardia, Sharon, Kelly-Hayes, Margaret, Koenen, Karestan, Kraft, Peter, Kuningas, Maris, Massaro, Joseph M, Melzer, David, Mulas, Antonella, Mulder, Cornelis L, Murray, Anna, Oostra, Ben A, Palotie, Aarno, Penninx, Brenda, Petersmann, Astrid, Pilling, Luke C, Psaty, Bruce, Rawal, Rajesh, Reiman, Eric M, Schulz, Andrea, Shulman, Joshua M, Singleton, Andrew B, Smith, Albert V, Sutin, Angelina R, Uitterlinden, André G, Völzke, Henry, Widen, Elisabeth, Yaffe, Kristine, Zonderman, Alan B, Cucca, Francesco, Harris, Tamara, Ladwig, Karl-Heinz, Llewellyn, David J, Räikkönen, Katri, Tanaka, Toshiko, van Duijn, Cornelia M, Grabe, Hans J, Launer, Lenore J, Lunetta, Kathryn L, Mosley, Thomas H, Newman, Anne B, Tiemeier, Henning, and Murabito, Joanne

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Mental Health, Clinical Research, Depression, Brain Disorders, Human Genome, Mental Illness, 2.1 Biological and endogenous factors, Aged, Aged, 80 and over, Chromosomes, Human, Pair 5, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Center for Epidemiologic Studies Depression Scale, CHARGE consortium, depression, depressive symptoms, genetics, genome-wide association study, meta-analysis, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry, Biological sciences, Biomedical and clinical sciences, Psychology
Abstract

BackgroundDepression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms.MethodsIn this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p

Published
2013

232. Transforming Epidemiology for 21st Century Medicine and Public Health

Author

Khoury, Muin J, Lam, Tram Kim, Ioannidis, John PA, Hartge, Patricia, Spitz, Margaret R, Buring, Julie E, Chanock, Stephen J, Croyle, Robert T, Goddard, Katrina A, Ginsburg, Geoffrey S, Herceg, Zdenko, Hiatt, Robert A, Hoover, Robert N, Hunter, David J, Kramer, Barnet S, Lauer, Michael S, Meyerhardt, Jeffrey A, Olopade, Olufunmilayo I, Palmer, Julie R, Sellers, Thomas A, Seminara, Daniela, Ransohoff, David F, Rebbeck, Timothy R, Tourassi, Georgia, Winn, Deborah M, Zauber, Ann, and Schully, Sheri D

Subjects
Epidemiology, Public Health, Health Sciences, Cancer, 2.6 Resources and infrastructure (aetiology), Good Health and Well Being, Biomedical Research, Epidemiologic Studies, Guidelines as Topic, History, 21st Century, Humans, Medical Oncology, National Cancer Institute (U.S.), Neoplasms, United States, National Cancer Institute, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

In 2012, the National Cancer Institute (NCI) engaged the scientific community to provide a vision for cancer epidemiology in the 21st century. Eight overarching thematic recommendations, with proposed corresponding actions for consideration by funding agencies, professional societies, and the research community emerged from the collective intellectual discourse. The themes are (i) extending the reach of epidemiology beyond discovery and etiologic research to include multilevel analysis, intervention evaluation, implementation, and outcomes research; (ii) transforming the practice of epidemiology by moving toward more access and sharing of protocols, data, metadata, and specimens to foster collaboration, to ensure reproducibility and replication, and accelerate translation; (iii) expanding cohort studies to collect exposure, clinical, and other information across the life course and examining multiple health-related endpoints; (iv) developing and validating reliable methods and technologies to quantify exposures and outcomes on a massive scale, and to assess concomitantly the role of multiple factors in complex diseases; (v) integrating "big data" science into the practice of epidemiology; (vi) expanding knowledge integration to drive research, policy, and practice; (vii) transforming training of 21st century epidemiologists to address interdisciplinary and translational research; and (viii) optimizing the use of resources and infrastructure for epidemiologic studies. These recommendations can transform cancer epidemiology and the field of epidemiology, in general, by enhancing transparency, interdisciplinary collaboration, and strategic applications of new technologies. They should lay a strong scientific foundation for accelerated translation of scientific discoveries into individual and population health benefits.

Published
2013

233. A genome-wide association study of early menopause and the combined impact of identified variants

Author

Perry, John RB, Corre, Tanguy, Esko, Tõnu, Chasman, Daniel I, Fischer, Krista, Franceschini, Nora, He, Chunyan, Kutalik, Zoltan, Mangino, Massimo, Rose, Lynda M, Smith, Albert Vernon, Stolk, Lisette, Sulem, Patrick, Weedon, Michael N, Zhuang, Wei V, Arnold, Alice, Ashworth, Alan, Bergmann, Sven, Buring, Julie E, Burri, Andrea, Chen, Constance, Cornelis, Marilyn C, Couper, David J, Goodarzi, Mark O, Gudnason, Vilmundur, Harris, Tamara, Hofman, Albert, Jones, Michael, Kraft, Peter, Launer, Lenore, Laven, Joop SE, Li, Guo, McKnight, Barbara, Masciullo, Corrado, Milani, Lili, Orr, Nicholas, Psaty, Bruce M, Ridker, Paul M, Rivadeneira, Fernando, Sala, Cinzia, Salumets, Andres, Schoemaker, Minouk, Traglia, Michela, Waeber, Gérard, Chanock, Stephen J, Demerath, Ellen W, Garcia, Melissa, Hankinson, Susan E, Hu, Frank B, Hunter, David J, Lunetta, Kathryn L, Metspalu, Andres, Montgomery, Grant W, Murabito, Joanne M, Newman, Anne B, Ong, Ken K, Spector, Tim D, Stefansson, Kari, Swerdlow, Anthony J, Thorsteinsdottir, Unnur, Van Dam, Rob M, Uitterlinden, André G, Visser, Jenny A, Vollenweider, Peter, Toniolo, Daniela, and Murray, Anna

Subjects
Biological Sciences, Genetics, Human Genome, Contraception/Reproduction, Infertility, Prevention, Aging, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Reproductive health and childbirth, Good Health and Well Being, Case-Control Studies, Female, Gene Frequency, Genome-Wide Association Study, Humans, Menopause, Premature, Polymorphism, Single Nucleotide, Primary Ovarian Insufficiency, Quantitative Trait Loci, Risk, ReproGen Consortium, Medical and Health Sciences, Genetics & Heredity
Abstract

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

Published
2013

234. Large-scale genotyping identifies 41 new loci associated with breast cancer risk

Author

Michailidou, Kyriaki, Hall, Per, Gonzalez-Neira, Anna, Ghoussaini, Maya, Dennis, Joe, Milne, Roger L, Schmidt, Marjanka K, Chang-Claude, Jenny, Bojesen, Stig E, Bolla, Manjeet K, Wang, Qin, Dicks, Ed, Lee, Andrew, Turnbull, Clare, Rahman, Nazneen, Fletcher, Olivia, Peto, Julian, Gibson, Lorna, dos Santos Silva, Isabel, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Czene, Kamila, Irwanto, Astrid, Liu, Jianjun, Waisfisz, Quinten, Meijers-Heijboer, Hanne, Adank, Muriel, van der Luijt, Rob B, Hein, Rebecca, Dahmen, Norbert, Beckman, Lars, Meindl, Alfons, Schmutzler, Rita K, Müller-Myhsok, Bertram, Lichtner, Peter, Hopper, John L, Southey, Melissa C, Makalic, Enes, Schmidt, Daniel F, Uitterlinden, Andre G, Hofman, Albert, Hunter, David J, Chanock, Stephen J, Vincent, Daniel, Bacot, François, Tessier, Daniel C, Canisius, Sander, Wessels, Lodewyk FA, Haiman, Christopher A, Shah, Mitul, Luben, Robert, Brown, Judith, Luccarini, Craig, Schoof, Nils, Humphreys, Keith, Li, Jingmei, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Couch, Fergus J, Wang, Xianshu, Vachon, Celine, Stevens, Kristen N, Lambrechts, Diether, Moisse, Matthieu, Paridaens, Robert, Christiaens, Marie-Rose, Rudolph, Anja, Nickels, Stefan, Flesch-Janys, Dieter, Johnson, Nichola, Aitken, Zoe, Aaltonen, Kirsimari, Heikkinen, Tuomas, Broeks, Annegien, Veer, Laura J Van't, van der Schoot, C Ellen, Guénel, Pascal, Truong, Thérèse, Laurent-Puig, Pierre, Menegaux, Florence, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Zamora, M Pilar, Perez, Jose Ignacio Arias, Pita, Guillermo, Alonso, M Rosario, Cox, Angela, Brock, Ian W, Cross, Simon S, Reed, Malcolm WR, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, and Henderson, Brian E

Subjects
Biological Sciences, Genetics, Human Genome, Prevention, Breast Cancer, Cancer, Breast Neoplasms, Case-Control Studies, Cooperative Behavior, Female, Gene-Environment Interaction, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Risk Factors, Breast and Ovarian Cancer Susceptibility Collaboration, Hereditary Breast and Ovarian Cancer Research Group Netherlands, kConFab Investigators, Australian Ovarian Cancer Study Group, GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.

Published
2013

235. Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis

Author

Peters, Ulrike, Jiao, Shuo, Schumacher, Fredrick R, Hutter, Carolyn M, Aragaki, Aaron K, Baron, John A, Berndt, Sonja I, Bézieau, Stéphane, Brenner, Hermann, Butterbach, Katja, Caan, Bette J, Campbell, Peter T, Carlson, Christopher S, Casey, Graham, Chan, Andrew T, Chang–Claude, Jenny, Chanock, Stephen J, Chen, Lin S, Coetzee, Gerhard A, Coetzee, Simon G, Conti, David V, Curtis, Keith R, Duggan, David, Edwards, Todd, Fuchs, Charles S, Gallinger, Steven, Giovannucci, Edward L, Gogarten, Stephanie M, Gruber, Stephen B, Haile, Robert W, Harrison, Tabitha A, Hayes, Richard B, Henderson, Brian E, Hoffmeister, Michael, Hopper, John L, Hudson, Thomas J, Hunter, David J, Jackson, Rebecca D, Jee, Sun Ha, Jenkins, Mark A, Jia, Wei–Hua, Kolonel, Laurence N, Kooperberg, Charles, Küry, Sébastien, LaCroix, Andrea Z, Laurie, Cathy C, Laurie, Cecelia A, Le Marchand, Loic, Lemire, Mathieu, Levine, David, Lindor, Noralane M, Liu, Yan, Ma, Jing, Makar, Karen W, Matsuo, Keitaro, Newcomb, Polly A, Potter, John D, Prentice, Ross L, Qu, Conghui, Rohan, Thomas, Rosse, Stephanie A, Schoen, Robert E, Seminara, Daniela, Shrubsole, Martha, Shu, Xiao–Ou, Slattery, Martha L, Taverna, Darin, Thibodeau, Stephen N, Ulrich, Cornelia M, White, Emily, Xiang, Yongbing, Zanke, Brent W, Zeng, Yi–Xin, Zhang, Ben, Zheng, Wei, Hsu, Li, and Registry, Genetics and Epidemiology of Colorectal Cancer Consortium Colon Cancer Family

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Nutrition and Dietetics, Digestive Diseases, Prevention, Genetics, Cancer, Colo-Rectal Cancer, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Age Distribution, Aged, Aged, 80 and over, Colorectal Neoplasms, Cyclin D2, DNA-Binding Proteins, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Incidence, Laminin, Male, Middle Aged, Polymorphism, Single Nucleotide, Prognosis, Risk Assessment, Sex Distribution, T-Box Domain Proteins, Colon Cancer Family Registry and the Genetics and Epidemiology of Colorectal Cancer Consortium, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsHeritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.MethodsWe 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.ResultsBased 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)).ConclusionsIn 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
2013

236. Polymorphisms in genes related to one-carbon metabolism are not related to pancreatic cancer in PanScan and PanC4

Author

Leenders, Max, Bhattacharjee, Samsiddhi, Vineis, Paolo, Stevens, Victoria, Bueno-de-Mesquita, H Bas, Shu, Xiao-Ou, Amundadottir, Laufey, Gross, Myron, Tobias, Geoffrey S, Wactawski-Wende, Jean, Arslan, Alan A, Duell, Eric J, Fuchs, Charles S, Gallinger, Steven, Hartge, Patricia, Hoover, Robert N, Holly, Elizabeth A, Jacobs, Eric J, Klein, Alison P, Kooperberg, Charles, LaCroix, Andrea, Li, Donghui, Mandelson, Margaret T, Olson, Sara H, Petersen, Gloria, Risch, Harvey A, Yu, Kai, Wolpin, Brian M, Zheng, Wei, Agalliu, Ilir, Albanes, Demetrius, Boutron-Ruault, Marie-Christine, Bracci, Paige M, Buring, Julie E, Canzian, Federico, Chang, Kenneth, Chanock, Stephen J, Cotterchio, Michelle, Gaziano, J Michael, Giovanucci, Edward L, Goggins, Michael, Hallmans, Göran, Hankinson, Susan E, Hoffman-Bolton, Judith A, Hunter, David J, Hutchinson, Amy, Jacobs, Kevin B, Jenab, Mazda, Khaw, Kay-Tee, Kraft, Peter, Krogh, Vittorio, Kurtz, Robert C, McWilliams, Robert R, Mendelsohn, Julie B, Patel, Alpa V, Rabe, Kari G, Riboli, Elio, Tjønneland, Anne, Trichopoulos, Dimitrios, Virtamo, Jarmo, Visvanathan, Kala, Elena, Joanne W, Yu, Herbert, Zeleniuch-Jacquotte, Anne, and Stolzenberg-Solomon, Rachael Z

Subjects
Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Cancer, Digestive Diseases, Genetics, Pancreatic Cancer, Prevention, Rare Diseases, Aetiology, 2.1 Biological and endogenous factors, Carbon, Case-Control Studies, Cohort Studies, Germ-Line Mutation, Humans, Pancreatic Neoplasms, Polymorphism, Single Nucleotide, United States, Pancreatic cancer, One-carbon metabolism, Polymorphisms, Biomarkers, Public Health and Health Services, Oncology and carcinogenesis
Abstract

PurposeThe evidence of a relation between folate intake and one-carbon metabolism (OCM) with pancreatic cancer (PanCa) is inconsistent. In this study, the association between genes and single-nucleotide polymorphisms (SNPs) related to OCM and PanCa was assessed.MethodsUsing biochemical knowledge of the OCM pathway, we identified thirty-seven genes and 834 SNPs to examine in association with PanCa. Our study included 1,408 cases and 1,463 controls nested within twelve cohorts (PanScan). The ten SNPs and five genes with lowest p values (

Published
2013

237. Volumetric flow prediction using multiple plane particle image velocimetry

Author

Hunter, David J.

Subjects
620.106, QA Mathematics, TA Engineering (General). Civil engineering (General)
Abstract

This thesis presents an approach to predicting a 3-dimensional, 3-component velocity field of a fluid ow that possesses a homogeneous dimension. At the core of this approach is the technique of stochastic estimation, which is commonly used to combine a small number of instantaneous measurements with previously acquired statistical data, to produce a prediction of the flow over a large number of locations. In the proposed technique, particle image velocimetry (PIV) is used to provide measurements for the stochastic estimation procedure, and the statistical stationarity along the homogeneous dimension of the flow is exploited to extend the use of stochastic estimation to provide a full volumetric prediction. The first section concerns the prediction performance of stochastic estimation. It is shown how the traditional approach to stochastic estimation is equivalent to ordinary least squares (OLS) regression. The properties of OLS, previously unconsidered in stochastic estimation literature, are presented, and shown to have a number of practical uses in the design and implementation of stochastic estimation procedures. Several alternative approaches to flow prediction are selected for further study, and their performance is compared in a series of trials, based on data from a numerically simulated channel flow. The newly-introduced biased techniques are shown to outperform or equal the accuracy of the stochastic estimation techniques across the entire range of parameters under investigation. The second section introduces the proposed volumetric prediction technique. A proof of concept is obtained using volumetric data from the simulated channel flow, and the resulting predictions show excellent quantitative and qualitative agreement with the original data. The predicted vortex ring data compares favourably with previous theoretical and experimental studies, and visualisation of the volumetric data appears to show the existence of secondary vortical structures around the outside of the ring core, which have previously only been observed in numerical simulations.

Published
2010

238. Establishing outcome measures in early knee osteoarthritis

Author

Emery, Carolyn A., Whittaker, Jackie L., Mahmoudian, Armaghan, Lohmander, L. Stefan, Roos, Ewa M., Bennell, Kim L., Toomey, Clodagh M., Reimer, Raylene A., Thompson, Dylan, Ronsky, Janet L., Kuntze, Gregor, Lloyd, David G., Andriacchi, Thomas, Englund, Martin, Kraus, Virginia B., Losina, Elena, Bierma-Zeinstra, Sita, Runhaar, Jos, Peat, George, Luyten, Frank P., Snyder-Mackler, Lynn, Risberg, May Arna, Mobasheri, Ali, Guermazi, Ali, Hunter, David J., and Arden, Nigel K.

Published
2019
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239. Genome-wide association study of germline variants and breast cancer-specific mortality

Author

Escala-Garcia, Maria, Guo, Qi, Dörk, Thilo, Canisius, Sander, Keeman, Renske, Dennis, Joe, Beesley, Jonathan, Lecarpentier, Julie, Bolla, Manjeet K., Wang, Qin, Abraham, Jean, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L., Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Boeckx, Bram, Bojesen, Stig E., Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brentnall, Adam, Brinton, Louise, Broberg, Per, Brock, Ian W., Brucker, Sara Y., Burwinkel, Barbara, Caldas, Carlos, Caldés, Trinidad, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D., Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chenevix-Trench, Georgia, Cheng, Ting-Yuan David, Chin, Suet-Feung, Clarke, Christine L., NBCS Collaborators, Cordina-Duverger, Emilie, Couch, Fergus J., Cox, David G., Cox, Angela, Cross, Simon S., Czene, Kamila, Daly, Mary B., Devilee, Peter, Dunn, Janet A., Dunning, Alison M., Durcan, Lorraine, Dwek, Miriam, Earl, Helena M., Ekici, Arif B., Eliassen, A. Heather, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Evans, D. Gareth, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, Galle, Eva, Gapstur, Susan M., García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., George, Angela, Georgoulias, Vassilios, Giles, Graham G., Glendon, Gord, Goldgar, David E., González-Neira, Anna, Alnæs, Grethe I. Grenaker, Grip, Mervi, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan, Harkness, Elaine F., Harrington, Patricia A., Hart, Steven N., Hartikainen, Jaana M., Hein, Alexander, Hillemanns, Peter, Hiller, Louise, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J., Hoover, Robert N., Hopper, John L., Howell, Anthony, Huang, Guanmengqian, Humphreys, Keith, Hunter, David J., Janni, Wolfgang, John, Esther M., Jones, Michael E., Jukkola-Vuorinen, Arja, Jung, Audrey, Kaaks, Rudolf, Kabisch, Maria, Kaczmarek, Katarzyna, Kerin, Michael J., Khan, Sofia, Khusnutdinova, Elza, Kiiski, Johanna I., Kitahara, Cari M., Knight, Julia A., Ko, Yon-Dschun, Koppert, Linetta B., Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N., Krüger, Ute, Kühl, Tabea, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Li, Lian, Lindblom, Annika, Lindström, Sara, Linet, Martha, Lissowska, Jolanta, Lo, Wing-Yee, Loibl, Sibylle, Lubiński, Jan, Lux, Michael P., MacInnis, Robert J., Maierthaler, Melanie, Maishman, Tom, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Mavroudis, Dimitrios, McLean, Catriona, Meindl, Alfons, Middha, Pooja, Miller, Nicola, Milne, Roger L., Moreno, Fernando, Mulligan, Anna Marie, Mulot, Claire, Nassir, Rami, Neuhausen, Susan L., Newman, William T., Nielsen, Sune F., Nordestgaard, Børge G., Norman, Aaron, Olsson, Håkan, Orr, Nick, Pankratz, V. Shane, Park-Simon, Tjoung-Won, Perez, Jose I. A., Pérez-Barrios, Clara, Peterlongo, Paolo, Petridis, Christos, Pinchev, Mila, Prajzendanc, Karoliona, Prentice, Ross, Presneau, Nadege, Prokofieva, Darya, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Ramachandran, Dhanya, Rennert, Gadi, Rennert, Hedy S., Rhenius, Valerie, Romero, Atocha, Roylance, Rebecca, Saloustros, Emmanouil, Sawyer, Elinor J., Schmidt, Daniel F., Schmutzler, Rita K., Schneeweiss, Andreas, Schoemaker, Minouk J., Schumacher, Fredrick, Schwentner, Lukas, Scott, Rodney J., Scott, Christopher, Seynaeve, Caroline, Shah, Mitul, Simard, Jacques, Smeets, Ann, Sohn, Christof, Southey, Melissa C., Swerdlow, Anthony J., Talhouk, Aline, Tamimi, Rulla M., Tapper, William J., Teixeira, Manuel R., Tengström, Maria, Terry, Mary Beth, Thöne, Kathrin, Tollenaar, Rob A. E. M., Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Turman, Constance, Turnbull, Clare, Ulmer, Hans-Ulrich, Untch, Michael, Vachon, Celine, van Asperen, Christi J., van den Ouweland, Ans M. W., van Veen, Elke M., Wendt, Camilla, Whittemore, Alice S., Willett, Walter, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R., Zhang, Yan, Easton, Douglas F., Fasching, Peter A., Nevanlinna, Heli, Eccles, Diana M., Pharoah, Paul D. P., and Schmidt, Marjanka K.

Published
2019
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240. Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium

Author

Elena, Joanne W, Steplowski, Emily, Yu, Kai, Hartge, Patricia, Tobias, Geoffrey S, Brotzman, Michelle J, Chanock, Stephen J, Stolzenberg-Solomon, Rachael Z, Arslan, Alan A, Bueno-de-Mesquita, H Bas, Helzlsouer, Kathy, Jacobs, Eric J, LaCroix, Andrea, Petersen, Gloria, Zheng, Wei, Albanes, Demetrius, Allen, Naomi E, Amundadottir, Laufey, Bao, Ying, Boeing, Heiner, Boutron-Ruault, Marie-Christine, Buring, Julie E, Gaziano, J Michael, Giovannucci, Edward L, Duell, Eric J, Hallmans, Göran, Howard, Barbara V, Hunter, David J, Hutchinson, Amy, Jacobs, Kevin B, Kooperberg, Charles, Kraft, Peter, Mendelsohn, Julie B, Michaud, Dominique S, Palli, Domenico, Phillips, Lawrence S, Overvad, Kim, Patel, Alpa V, Sansbury, Leah, Shu, Xiao-Ou, Simon, Michael S, Slimani, Nadia, Trichopoulos, Dimitrios, Visvanathan, Kala, Virtamo, Jarmo, Wolpin, Brian M, Zeleniuch-Jacquotte, Anne, Fuchs, Charles S, Hoover, Robert N, and Gross, Myron

Subjects
Biomedical and Clinical Sciences, Epidemiology, Health Services and Systems, Health Sciences, Oncology and Carcinogenesis, Obesity, Rare Diseases, Digestive Diseases, Pancreatic Cancer, Prevention, Cancer, Diabetes, 2.1 Biological and endogenous factors, Good Health and Well Being, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Case-Control Studies, Cohort Studies, Diabetes Complications, Diabetes Mellitus, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms, Risk Factors, Public Health and Health Services, Oncology and carcinogenesis
Abstract

PurposeDiabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan).MethodsThe pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case-control study design. Subjects who were diagnosed with diabetes near the time (

Published
2013

243. Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer.

Author

Li, Donghui, Duell, Eric J, Yu, Kai, Risch, Harvey A, Olson, Sara H, Kooperberg, Charles, Wolpin, Brian M, Jiao, Li, Dong, Xiaoqun, Wheeler, Bill, Arslan, Alan A, Bueno-de-Mesquita, H Bas, Fuchs, Charles S, Gallinger, Steven, Gross, Myron, Hartge, Patricia, Hoover, Robert N, Holly, Elizabeth A, Jacobs, Eric J, Klein, Alison P, LaCroix, Andrea, Mandelson, Margaret T, Petersen, Gloria, Zheng, Wei, Agalliu, Ilir, Albanes, Demetrius, Boutron-Ruault, Marie-Christine, Bracci, Paige M, Buring, Julie E, Canzian, Federico, Chang, Kenneth, Chanock, Stephen J, Cotterchio, Michelle, Gaziano, J Michael, Giovannucci, Edward L, Goggins, Michael, Hallmans, Göran, Hankinson, Susan E, Hoffman Bolton, Judith A, Hunter, David J, Hutchinson, Amy, Jacobs, Kevin B, Jenab, Mazda, Khaw, Kay-Tee, Kraft, Peter, Krogh, Vittorio, Kurtz, Robert C, McWilliams, Robert R, Mendelsohn, Julie B, Patel, Alpa V, Rabe, Kari G, Riboli, Elio, Shu, Xiao-Ou, Tjønneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrios, Virtamo, Jarmo, Visvanathan, Kala, Watters, Joanne, Yu, Herbert, Zeleniuch-Jacquotte, Anne, Amundadottir, Laufey, and Stolzenberg-Solomon, Rachael Z

Subjects
Humans, Pancreatic Neoplasms, Genetic Predisposition to Disease, Case-Control Studies, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10(-6), 1.6 × 10(-5), 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10(-5)), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.

Published
2012

244. Characterization of Gene–Environment Interactions for Colorectal Cancer Susceptibility Loci

Author

Hutter, Carolyn M, Chang-Claude, Jenny, Slattery, Martha L, Pflugeisen, Bethann M, Lin, Yi, Duggan, David, Nan, Hongmei, Lemire, Mathieu, Rangrej, Jagadish, Figueiredo, Jane C, Jiao, Shuo, Harrison, Tabitha A, Liu, Yan, Chen, Lin S, Stelling, Deanna L, Warnick, Greg S, Hoffmeister, Michael, Küry, Sébastien, Fuchs, Charles S, Giovannucci, Edward, Hazra, Aditi, Kraft, Peter, Hunter, David J, Gallinger, Steven, Zanke, Brent W, Brenner, Hermann, Frank, Bernd, Ma, Jing, Ulrich, Cornelia M, White, Emily, Newcomb, Polly A, Kooperberg, Charles, LaCroix, Andrea Z, Prentice, Ross L, Jackson, Rebecca D, Schoen, Robert E, Chanock, Stephen J, Berndt, Sonja I, Hayes, Richard B, Caan, Bette J, Potter, John D, Hsu, Li, Bézieau, Stéphane, Chan, Andrew T, Hudson, Thomas J, and Peters, Ulrike

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Digestive Diseases, Nutrition, Prevention, Cancer, Colo-Rectal Cancer, Human Genome, Colorectal Neoplasms, Diet, Gene-Environment Interaction, Genetic Predisposition to Disease, Genotype, Humans, Polymorphism, Single Nucleotide, Oncology and Carcinogenesis, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Genome-wide association studies (GWAS) have identified more than a dozen loci associated with colorectal cancer (CRC) risk. Here, we examined potential effect-modification between single-nucleotide polymorphisms (SNP) at 10 of these loci and probable or established environmental risk factors for CRC in 7,016 CRC cases and 9,723 controls from nine cohort and case-control studies. We used meta-analysis of an efficient empirical-Bayes estimator to detect potential multiplicative interactions between each of the SNPs [rs16892766 at 8q23.3 (EIF3H/UTP23), rs6983267 at 8q24 (MYC), rs10795668 at 10p14 (FLJ3802842), rs3802842 at 11q23 (LOC120376), rs4444235 at 14q22.2 (BMP4), rs4779584 at 15q13 (GREM1), rs9929218 at 16q22.1 (CDH1), rs4939827 at 18q21 (SMAD7), rs10411210 at 19q13.1 (RHPN2), and rs961253 at 20p12.3 (BMP2)] and select major CRC risk factors (sex, body mass index, height, smoking status, aspirin/nonsteroidal anti-inflammatory drug use, alcohol use, and dietary intake of calcium, folate, red meat, processed meat, vegetables, fruit, and fiber). The strongest statistical evidence for a gene-environment interaction across studies was for vegetable consumption and rs16892766, located on chromosome 8q23.3, near the EIF3H and UTP23 genes (nominal P(interaction) = 1.3 × 10(-4); adjusted P = 0.02). The magnitude of the main effect of the SNP increased with increasing levels of vegetable consumption. No other interactions were statistically significant after adjusting for multiple comparisons. Overall, the association of most CRC susceptibility loci identified in initial GWAS seems to be invariant to the other risk factors considered; however, our results suggest potential modification of the rs16892766 effect by vegetable consumption.

Published
2012

245. Genome-wide association analysis identifies three new breast cancer susceptibility loci

Author

Ghoussaini, Maya, Fletcher, Olivia, Michailidou, Kyriaki, Turnbull, Clare, Schmidt, Marjanka K, Dicks, Ed, Dennis, Joe, Wang, Qin, Humphreys, Manjeet K, Luccarini, Craig, Baynes, Caroline, Conroy, Don, Maranian, Melanie, Ahmed, Shahana, Driver, Kristy, Johnson, Nichola, Orr, Nicholas, dos Santos Silva, Isabel, Waisfisz, Quinten, Meijers-Heijboer, Hanne, Uitterlinden, Andre G, Rivadeneira, Fernando, Hall, Per, Czene, Kamila, Irwanto, Astrid, Liu, Jianjun, Nevanlinna, Heli, Aittomäki, Kristiina, Blomqvist, Carl, Meindl, Alfons, Schmutzler, Rita K, Müller-Myhsok, Bertram, Lichtner, Peter, Chang-Claude, Jenny, Hein, Rebecca, Nickels, Stefan, Flesch-Janys, Dieter, Tsimiklis, Helen, Makalic, Enes, Schmidt, Daniel, Bui, Minh, Hopper, John L, Apicella, Carmel, Park, Daniel J, Southey, Melissa, Hunter, David J, Chanock, Stephen J, Broeks, Annegien, Verhoef, Senno, Hogervorst, Frans BL, Fasching, Peter A, Lux, Michael P, Beckmann, Matthias W, Ekici, Arif B, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guénel, Pascal, Truong, Thérèse, Cordina-Duverger, Emilie, Menegaux, Florence, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Milne, Roger L, Alonso, M Rosario, González-Neira, Anna, Benítez, Javier, Anton-Culver, Hoda, Ziogas, Argyrios, Bernstein, Leslie, Dur, Christina Clarke, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Stegmaier, Christa, Justenhoven, Christina, Brauch, Hiltrud, Brüning, Thomas, Wang-Gohrke, Shan, Eilber, Ursula, Dörk, Thilo, Schürmann, Peter, Bremer, Michael, Hillemanns, Peter, Bogdanova, Natalia V, Antonenkova, Natalia N, Rogov, Yuri I, Karstens, Johann H, Bermisheva, Marina, Prokofieva, Darya, Khusnutdinova, Elza, Lindblom, Annika, Margolin, Sara, and Mannermaa, Arto

Subjects
Biological Sciences, Genetics, Estrogen, Human Genome, Prevention, Cancer, Breast Cancer, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 21, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Logistic Models, Polymorphism, Single Nucleotide, Principal Component Analysis, White People, Netherlands Collaborative Group on Hereditary Breast and Ovarian Cancer, Familial Breast Cancer Study, Gene Environment Interaction of Breast Cancer in Germany (GENICA) Network, kConFab Investigators, Australian Ovarian Cancer Study Group, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.

Published
2012

246. Meta-analysis of new genome-wide association studies of colorectal cancer risk

Author

Peters, Ulrike, Hutter, Carolyn M, Hsu, Li, Schumacher, Fredrick R, Conti, David V, Carlson, Christopher S, Edlund, Christopher K, Haile, Robert W, Gallinger, Steven, Zanke, Brent W, Lemire, Mathieu, Rangrej, Jagadish, Vijayaraghavan, Raakhee, Chan, Andrew T, Hazra, Aditi, Hunter, David J, Ma, Jing, Fuchs, Charles S, Giovannucci, Edward L, Kraft, Peter, Liu, Yan, Chen, Lin, Jiao, Shuo, Makar, Karen W, Taverna, Darin, Gruber, Stephen B, Rennert, Gad, Moreno, Victor, Ulrich, Cornelia M, Woods, Michael O, Green, Roger C, Parfrey, Patrick S, Prentice, Ross L, Kooperberg, Charles, Jackson, Rebecca D, LaCroix, Andrea Z, Caan, Bette J, Hayes, Richard B, Berndt, Sonja I, Chanock, Stephen J, Schoen, Robert E, Chang-Claude, Jenny, Hoffmeister, Michael, Brenner, Hermann, Frank, Bernd, Bézieau, Stéphane, Küry, Sébastien, Slattery, Martha L, Hopper, John L, Jenkins, Mark A, Le Marchand, Loic, Lindor, Noralane M, Newcomb, Polly A, Seminara, Daniela, Hudson, Thomas J, Duggan, David J, Potter, John D, and Casey, Graham

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Prevention, Cancer Genomics, Human Genome, Cancer, Colo-Rectal Cancer, Digestive Diseases, 2.1 Biological and endogenous factors, Colorectal Neoplasms, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Odds Ratio, Polymorphism, Single Nucleotide, Risk Factors, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity, Reproductive medicine
Abstract

Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p

Published
2012

247. A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation

Author

Coviello, Andrea D, Haring, Robin, Wellons, Melissa, Vaidya, Dhananjay, Lehtimäki, Terho, Keildson, Sarah, Lunetta, Kathryn L, He, Chunyan, Fornage, Myriam, Lagou, Vasiliki, Mangino, Massimo, Onland-Moret, N Charlotte, Chen, Brian, Eriksson, Joel, Garcia, Melissa, Liu, Yong Mei, Koster, Annemarie, Lohman, Kurt, Lyytikäinen, Leo-Pekka, Petersen, Ann-Kristin, Prescott, Jennifer, Stolk, Lisette, Vandenput, Liesbeth, Wood, Andrew R, Zhuang, Wei Vivian, Ruokonen, Aimo, Hartikainen, Anna-Liisa, Pouta, Anneli, Bandinelli, Stefania, Biffar, Reiner, Brabant, Georg, Cox, David G, Chen, Yuhui, Cummings, Steven, Ferrucci, Luigi, Gunter, Marc J, Hankinson, Susan E, Martikainen, Hannu, Hofman, Albert, Homuth, Georg, Illig, Thomas, Jansson, John-Olov, Johnson, Andrew D, Karasik, David, Karlsson, Magnus, Kettunen, Johannes, Kiel, Douglas P, Kraft, Peter, Liu, Jingmin, Ljunggren, Östen, Lorentzon, Mattias, Maggio, Marcello, Markus, Marcello RP, Mellström, Dan, Miljkovic, Iva, Mirel, Daniel, Nelson, Sarah, Papunen, Laure Morin, Peeters, Petra HM, Prokopenko, Inga, Raffel, Leslie, Reincke, Martin, Reiner, Alex P, Rexrode, Kathryn, Rivadeneira, Fernando, Schwartz, Stephen M, Siscovick, David, Soranzo, Nicole, Stöckl, Doris, Tworoger, Shelley, Uitterlinden, André G, van Gils, Carla H, Vasan, Ramachandran S, Wichmann, H-Erich, Zhai, Guangju, Bhasin, Shalender, Bidlingmaier, Martin, Chanock, Stephen J, De Vivo, Immaculata, Harris, Tamara B, Hunter, David J, Kähönen, Mika, Liu, Simin, Ouyang, Pamela, Spector, Tim D, van der Schouw, Yvonne T, Viikari, Jorma, Wallaschofski, Henri, McCarthy, Mark I, Frayling, Timothy M, Murray, Anna, Franks, Steve, Järvelin, Marjo-Riitta, de Jong, Frank H, Raitakari, Olli, Teumer, Alexander, Ohlsson, Claes, Murabito, Joanne M, and Perry, John RB

Subjects
Biological Sciences, Genetics, Cancer, Estrogen, Women's Health, Aging, Prostate Cancer, Urologic Diseases, Human Genome, Cancer Genomics, Breast Cancer, 2.1 Biological and endogenous factors, Metabolic and endocrine, Alleles, Female, Genetic Heterogeneity, Genome-Wide Association Study, Gonadal Steroid Hormones, Humans, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Sex Characteristics, Sex Hormone-Binding Globulin, Developmental Biology
Abstract

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

Published
2012

248. Design, Delivery, Maintenance, and Outcomes of Peer-to-Peer Online Support Groups for People With Chronic Musculoskeletal Disorders: Systematic Review

Author

Maclachlan, Liam R, Mills, Kathryn, Lawford, Belinda J, Egerton, Thorlene, Setchell, Jenny, Hall, Leanne M, Plinsinga, Melanie L, Besomi, Manuela, Teo, Pek Ling, Eyles, Jillian P, Mellor, Rebecca, Melo, Luciano, Robbins, Sarah, Hodges, Paul W, Hunter, David J, Vicenzino, Bill, and Bennell, Kim L

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Public aspects of medicine, RA1-1270
Abstract

BackgroundOnline support groups (OSGs) are one way for people with chronic diseases, their family or friends, and health professionals to communicate, gain information, and provide social support. As the number of peer-to-peer OSGs for chronic musculoskeletal conditions grows, it is important to gain insight into the different designs of groups available, who is accessing them, if and how they may be effective, and what strategies are being used to implement or increase consumer engagement. ObjectiveThe objectives of this systematic review of people with musculoskeletal conditions were to (1) describe the design features (functions, usage options, moderation, and expert input) of peer-to-peer OSGs, (2) describe the characteristics of the individuals using peer-to-peer OSGs, (3) synthesize the evidence on outcomes of participation, and (4) identify strategies used in the delivery and maintenance of OSGs. MethodsA search comprising terms related to the population (people with musculoskeletal disorders) and the intervention (peer-to-peer OSGs) was conducted in 6 databases. Results were filtered from 1990 (internet inception) to February 2019. Studies identified in the search were screened according to predefined eligibility criteria using a 2-step process. Quantitative studies were appraised by 2 reviewers using the Risk Of Bias In Non-Randomized Studies of Interventions tool. Qualitative studies were appraised by 2 different reviewers using the Critical Appraisal Skills Programme checklist. Extracted data were synthesized narratively. ResultsWe examined 21 studies with low to moderate risk of bias. Of these studies, 13 studies included OSGs hosted on public platforms, 11 studies examined OSGs that were conducted in English, and 6 studies used moderators or peer leaders to facilitate engagement. Studies either reported the number of OSG members (n=1985 across all studies) or the number of posts (range: 223-200,000). The majority of OSG members were females who were not full-time employees and with varied levels of education. There were no randomized controlled trials measuring the efficacy of OSGs. Qualitative and quantitative studies identified empowerment, social support, self-management behavior, and health literacy as primary constructs to measure OSG efficacy. Neutral or marginal improvement was reported in these constructs. Sharing experiences and a greater level of engagement appeared to have an important influence on OSGs efficacy. The extent to which members posted on the website influenced engagement. ConclusionsAcross a diverse range of designs, languages, included features, and delivery platforms, peer-to-peer OSGs for chronic musculoskeletal conditions attract predominantly female participants of all ages and education levels. The level of participation of a member appears to be related to their perceived benefit, health literacy, and empowerment. Future studies are needed to identify which design and maintenance strategies have superior efficacy and whether there are concomitant improvements in health outcomes for people with chronic musculoskeletal conditions resulting from participation in OSGs. Trial RegistrationPROSPERO International Prospective Register of Systematic Reviews CRD42018090326; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42018090326

Published
2020
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249. Variant ABO Blood Group Alleles, Secretor Status, and Risk of Pancreatic Cancer: Results from the Pancreatic Cancer Cohort Consortium

Author

Wolpin, Brian M, Kraft, Peter, Xu, Mousheng, Steplowski, Emily, Olsson, Martin L, Arslan, Alan A, Bueno-de-Mesquita, H Bas, Gross, Myron, Helzlsouer, Kathy, Jacobs, Eric J, LaCroix, Andrea, Petersen, Gloria, Stolzenberg-Solomon, Rachael Z, Zheng, Wei, Albanes, Demetrius, Allen, Naomi E, Amundadottir, Laufey, Austin, Melissa A, Boutron-Ruault, Marie-Christine, Buring, Julie E, Canzian, Federico, Chanock, Stephen J, Gaziano, J Michael, Giovannucci, Edward L, Hallmans, Göran, Hankinson, Susan E, Hoover, Robert N, Hunter, David J, Hutchinson, Amy, Jacobs, Kevin B, Kooperberg, Charles, Mendelsohn, Julie B, Michaud, Dominique S, Overvad, Kim, Patel, Alpa V, Sanchéz, Maria-José, Sansbury, Leah, Shu, Xiao-Ou, Slimani, Nadia, Tobias, Geoffrey S, Trichopoulos, Dimitrios, Vineis, Paolo, Visvanathan, Kala, Virtamo, Jarmo, Wactawski-Wende, Jean, Watters, Joanne, Yu, Kai, Zeleniuch-Jacquotte, Anne, Hartge, Patricia, and Fuchs, Charles S

Subjects
Digestive Diseases, Cancer, Clinical Research, Genetics, Rare Diseases, Pancreatic Cancer, Prevention, Human Genome, Aetiology, 2.1 Biological and endogenous factors, ABO Blood-Group System, Alleles, Cohort Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glycosyltransferases, Humans, Odds Ratio, Pancreatic Neoplasms, Phenotype, Polymorphism, Single Nucleotide, Medical and Health Sciences, Epidemiology
Abstract

BackgroundSubjects with non-O ABO blood group alleles have increased risk of pancreatic cancer. Glycosyltransferase activity is greater for the A(1) versus A(2) variant, whereas O01 and O02 variants are nonfunctioning. We hypothesized: 1) A(1) allele would confer greater risk than A(2) allele, 2) protective effect of the O allele would be equivalent for O01 and O02 variants, 3) secretor phenotype would modify the association with risk.MethodsWe determined ABO variants and secretor phenotype from single nucleotide polymorphisms in ABO and FUT2 genes in 1,533 cases and 1,582 controls from 12 prospective cohort studies. Adjusted odds ratios (OR) for pancreatic cancer were calculated using logistic regression.ResultsAn increased risk was observed in participants with A(1) but not A(2) alleles. Compared with subjects with genotype O/O, genotypes A(2)/O, A(2)/A(1), A(1)/O, and A(1)/A(1) had ORs of 0.96 (95% CI, 0.72-1.26), 1.46 (95% CI, 0.98-2.17), 1.48 (95% CI, 1.23-1.78), and 1.71 (95% CI, 1.18-2.47). Risk was similar for O01 and O02 variant O alleles. Compared with O01/O01, the ORs for each additional allele of O02, A(1), and A(2) were 1.00 (95% CI, 0.87-1.14), 1.38 (95% CI, 1.20-1.58), and 0.96 (95% CI, 0.77-1.20); P, O01 versus O02 = 0.94, A(1) versus A(2) = 0.004. Secretor phenotype was not an effect modifier (P-interaction = 0.63).ConclusionsAmong participants in a large prospective cohort consortium, ABO allele subtypes corresponding to increased glycosyltransferase activity were associated with increased pancreatic cancer risk.ImpactThese data support the hypothesis that ABO glycosyltransferase activity influences pancreatic cancer risk rather than actions of other nearby genes on chromosome 9q34.

Published
2010

250. Family history of cancer and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan).

Author

Jacobs, Eric J, Chanock, Stephen J, Fuchs, Charles S, Lacroix, Andrea, McWilliams, Robert R, Steplowski, Emily, Stolzenberg-Solomon, Rachael Z, Arslan, Alan A, Bueno-de-Mesquita, H Bas, Gross, Myron, Helzlsouer, Kathy, Petersen, Gloria, Zheng, Wei, Agalliu, Ilir, Allen, Naomi E, Amundadottir, Laufey, Boutron-Ruault, Marie-Christine, Buring, Julie E, Canzian, Federico, Clipp, Sandra, Dorronsoro, Miren, Gaziano, J Michael, Giovannucci, Edward L, Hankinson, Susan E, Hartge, Patricia, Hoover, Robert N, Hunter, David J, Jacobs, Kevin B, Jenab, Mazda, Kraft, Peter, Kooperberg, Charles, Lynch, Shannon M, Sund, Malin, Mendelsohn, Julie B, Mouw, Tracy, Newton, Christina C, Overvad, Kim, Palli, Domenico, Peeters, Petra HM, Rajkovic, Aleksandar, Shu, Xiao-Ou, Thomas, Gilles, Tobias, Geoffrey S, Trichopoulos, Dimitrios, Virtamo, Jarmo, Wactawski-Wende, Jean, Wolpin, Brian M, Yu, Kai, and Zeleniuch-Jacquotte, Anne

Subjects
Humans, Pancreatic Neoplasms, Genetic Predisposition to Disease, Case-Control Studies, Cohort Studies, Genome-Wide Association Study, Colo-Rectal Cancer, Clinical Research, Rare Diseases, Aging, Cancer, Digestive Diseases, Prostate Cancer, Ovarian Cancer, Pancreatic Cancer, Breast Cancer, Prevention, Urologic Diseases, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

A family history of pancreatic cancer has consistently been associated with increased risk of pancreatic cancer. However, uncertainty remains about the strength of this association. Results from previous studies suggest a family history of select cancers (i.e., ovarian, breast and colorectal) could also be associated, although not as strongly, with increased risk of pancreatic cancer. We examined the association between a family history of 5 types of cancer (pancreas, prostate, ovarian, breast and colorectal) and risk of pancreatic cancer using data from a collaborative nested case-control study conducted by the Pancreatic Cancer Cohort Consortium. Cases and controls were from cohort studies from the United States, Europe and China, and a case-control study from the Mayo Clinic. Analyses of family history of pancreatic cancer included 1,183 cases and 1,205 controls. A family history of pancreatic cancer in a parent, sibling or child was associated with increased risk of pancreatic cancer [multivariate-adjusted odds ratios (ORs) = 1.76, 95% confidence interval (CI) = 1.19-2.61]. A family history of prostate cancer was also associated with increased risk (OR = 1.45, 95% CI = 1.12-1.89). There were no statistically significant associations with a family history of ovarian cancer (OR = 0.82, 95% CI = 0.52-1.31), breast cancer (OR = 1.21, 95% CI = 0.97-1.51) or colorectal cancer (OR = 1.17, 95% CI = 0.93-1.47). Our results confirm a moderate sized association between a family history of pancreatic cancer and risk of pancreatic cancer and also provide evidence for an association with a family history of prostate cancer worth further study.

Published
2010

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