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1,207 results on '"Van Den Eeden, Stephen K"'

1. Genetically adjusted PSA levels for prostate cancer screening.

Author

Kachuri, Linda, Hoffmann, Thomas J, Jiang, Yu, Berndt, Sonja I, Shelley, John P, Schaffer, Kerry R, Machiela, Mitchell J, Freedman, Neal D, Huang, Wen-Yi, Li, Shengchao A, Easterlin, Ryder, Goodman, Phyllis J, Till, Cathee, Thompson, Ian, Lilja, Hans, Van Den Eeden, Stephen K, Chanock, Stephen J, Haiman, Christopher A, Conti, David V, Klein, Robert J, Mosley, Jonathan D, Graff, Rebecca E, and Witte, John S

Subjects
Humans, Prostatic Neoplasms, Prostate-Specific Antigen, Biopsy, Male, Early Detection of Cancer, Neoplasm Grading, Aging, Prevention, Cancer, Urologic Diseases, Prostate Cancer, Genetics, Good Health and Well Being, Medical and Health Sciences, Immunology
Abstract

Prostate-specific antigen (PSA) screening for prostate cancer remains controversial because it increases overdiagnosis and overtreatment of clinically insignificant tumors. Accounting for genetic determinants of constitutive, non-cancer-related PSA variation has potential to improve screening utility. In this study, we discovered 128 genome-wide significant associations (P

Published
2023

2. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants

Author

Wang, Anqi, Shen, Jiayi, Rodriguez, Alex A., Saunders, Edward J., Chen, Fei, Janivara, Rohini, Darst, Burcu F., Sheng, Xin, Xu, Yili, Chou, Alisha J., Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N., Plym, Anna, Sahimi, Ali, Hoffman, Thomas J., Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Laisk, Triin, Figuerêdo, Jéssica, Muir, Kenneth, Ito, Shuji, Liu, Xiaoxi, Uchio, Yuji, Kubo, Michiaki, Kamatani, Yoichiro, Lophatananon, Artitaya, Wan, Peggy, Andrews, Caroline, Lori, Adriana, Choudhury, Parichoy P., Schleutker, Johanna, Tammela, Teuvo L. J., Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G., Southey, Melissa C., MacInnis, Robert J., Cybulski, Cezary, Wokolorczyk, Dominika, Lubinski, Jan, Rentsch, Christopher T., Cho, Kelly, Mcmahon, Benjamin H., Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Martin, Richard M., Nordestgaard, Borge G., Nielsen, Sune F., Weischer, Maren, Bojesen, Stig E., Røder, Andreas, Stroomberg, Hein V., Batra, Jyotsna, Chambers, Suzanne, Horvath, Lisa, Clements, Judith A., Tilly, Wayne, Risbridger, Gail P., Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordstrom, Tobias, Pashayan, Nora, Dunning, Alison M., Ghoussaini, Maya, Travis, Ruth C., Key, Tim J., Riboli, Elio, Park, Jong Y., Sellers, Thomas A., Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie, Cook, Michael B., Mucci, Lorelei A., Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J., Penney, Kathryn L., Turman, Constance, Tangen, Catherine M., Goodman, Phyllis J., Thompson, Jr., Ian M., Hamilton, Robert J., Fleshner, Neil E., Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L., Ostrander, Elaine A., Koutros, Stella, Beane Freeman, Laura E., Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L., Hoover, Robert N., Machiela, Mitchell J., Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J., Zheng, Wei, Yeboah, Edward D., Mensah, James E., Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Wu, Yudong, Zhao, Shan-Chao, Sun, Zan, Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., West, Catharine M. L., Barnett, Gill, Maier, Christiane, Schnoeller, Thomas, Luedeke, Manuel, Kibel, Adam S., Drake, Bettina F., Cussenot, Olivier, Cancel-Tassin, Geraldine, Menegaux, Florence, Truong, Thérèse, Koudou, Yves Akoli, John, Esther M., Grindedal, Eli Marie, Maehle, Lovise, Khaw, Kay-Tee, Ingles, Sue A., Stern, Mariana C., Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Rosenstein, Barry S., Kerns, Sarah L., Ostrer, Harry, Teixeira, Manuel R., Paulo, Paula, Brandão, Andreia, Watya, Stephen, Lubwama, Alexander, Bensen, Jeannette T., Butler, Ebonee N., Mohler, James L., Taylor, Jack A., Kogevinas, Manolis, Dierssen-Sotos, Trinidad, Castaño-Vinyals, Gemma, Cannon-Albright, Lisa, Teerlink, Craig C., Huff, Chad D., Pilie, Patrick, Yu, Yao, Bohlender, Ryan J., Gu, Jian, Strom, Sara S., Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Kaneva, Radka, Slavov, Chavdar, Mitev, Vanio, Leach, Robin J., Brenner, Hermann, Chen, Xuechen, Holleczek, Bernd, Schöttker, Ben, Klein, Eric A., Hsing, Ann W., Kittles, Rick A., Murphy, Adam B., Logothetis, Christopher J., Kim, Jeri, Neuhausen, Susan L., Steele, Linda, Ding, Yuan Chun, Isaacs, William B., Nemesure, Barbara, Hennis, Anselm J. M., Carpten, John, Pandha, Hardev, Michael, Agnieszka, De Ruyck, Kim, De Meerleer, Gert, Ost, Piet, Xu, Jianfeng, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Newcomb, Lisa F., Lin, Daniel W., Fowke, Jay H., Neslund-Dudas, Christine M., Rybicki, Benjamin A., Gamulin, Marija, Lessel, Davor, Kulis, Tomislav, Usmani, Nawaid, Abraham, Aswin, Singhal, Sandeep, Parliament, Matthew, Claessens, Frank, Joniau, Steven, Van den Broeck, Thomas, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Martinez, Maria Elena, Larkin, Samantha, Townsend, Paul A., Aukim-Hastie, Claire, Bush, William S., Aldrich, Melinda C., Crawford, Dana C., Srivastava, Shiv, Cullen, Jennifer, Petrovics, Gyorgy, Casey, Graham, Wang, Ying, Tettey, Yao, Lachance, Joseph, Tang, Wei, Biritwum, Richard B., Adjei, Andrew A., Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Yamoah, Kosj, Govindasami, Koveela, Chokkalingam, Anand P., Keaton, Jacob M., Hellwege, Jacklyn N., Clark, Peter E., Jalloh, Mohamed, Gueye, Serigne M., Niang, Lamine, Ogunbiyi, Olufemi, Shittu, Olayiwola, Amodu, Olukemi, Adebiyi, Akindele O., Aisuodionoe-Shadrach, Oseremen I., Ajibola, Hafees O., Jamda, Mustapha A., Oluwole, Olabode P., Nwegbu, Maxwell, Adusei, Ben, Mante, Sunny, Darkwa-Abrahams, Afua, Diop, Halimatou, Gundell, Susan M., Roobol, Monique J., Jenster, Guido, van Schaik, Ron H. N., Hu, Jennifer J., Sanderson, Maureen, Kachuri, Linda, Varma, Rohit, McKean-Cowdin, Roberta, Torres, Mina, Preuss, Michael H., Loos, Ruth J. F., Zawistowski, Matthew, Zöllner, Sebastian, Lu, Zeyun, Van Den Eeden, Stephen K., Easton, Douglas F., Ambs, Stefan, Edwards, Todd L., Mägi, Reedik, Rebbeck, Timothy R., Fritsche, Lars, Chanock, Stephen J., Berndt, Sonja I., Wiklund, Fredrik, Nakagawa, Hidewaki, Witte, John S., Gaziano, J. Michael, Justice, Amy C., Mancuso, Nick, Terao, Chikashi, Eeles, Rosalind A., Kote-Jarai, Zsofia, Madduri, Ravi K., Conti, David V., and Haiman, Christopher A.

Published
2023
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3. Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy

Author

Ollila, Hanna M, Sharon, Eilon, Lin, Ling, Sinnott-Armstrong, Nasa, Ambati, Aditya, Yogeshwar, Selina M, Hillary, Ryan P, Jolanki, Otto, Faraco, Juliette, Einen, Mali, Luo, Guo, Zhang, Jing, Han, Fang, Yan, Han, Dong, Xiao Song, Li, Jing, Zhang, Jun, Hong, Seung-Chul, Kim, Tae Won, Dauvilliers, Yves, Barateau, Lucie, Lammers, Gert Jan, Fronczek, Rolf, Mayer, Geert, Santamaria, Joan, Arnulf, Isabelle, Knudsen-Heier, Stine, Bredahl, May Kristin Lyamouri, Thorsby, Per Medbøe, Plazzi, Giuseppe, Pizza, Fabio, Moresco, Monica, Crowe, Catherine, Van den Eeden, Stephen K, Lecendreux, Michel, Bourgin, Patrice, Kanbayashi, Takashi, Martínez-Orozco, Francisco J, Peraita-Adrados, Rosa, Benetó, Antonio, Montplaisir, Jacques, Desautels, Alex, Huang, Yu-Shu, Jennum, Poul, Nevsimalova, Sona, Kemlink, David, Iranzo, Alex, Overeem, Sebastiaan, Wierzbicka, Aleksandra, Geisler, Peter, Sonka, Karel, Honda, Makoto, Högl, Birgit, Stefani, Ambra, Coelho, Fernando Morgadinho, Mantovani, Vilma, Feketeova, Eva, Wadelius, Mia, Eriksson, Niclas, Smedje, Hans, Hallberg, Pär, Hesla, Per Egil, Rye, David, Pelin, Zerrin, Ferini-Strambi, Luigi, Bassetti, Claudio L, Mathis, Johannes, Khatami, Ramin, Aran, Adi, Nampoothiri, Sheela, Olsson, Tomas, Kockum, Ingrid, Partinen, Markku, Perola, Markus, Kornum, Birgitte R, Rueger, Sina, Winkelmann, Juliane, Miyagawa, Taku, Toyoda, Hiromi, Khor, Seik-Soon, Shimada, Mihoko, Tokunaga, Katsushi, Rivas, Manuel, Pritchard, Jonathan K, Risch, Neil, Kutalik, Zoltan, O’Hara, Ruth, Hallmayer, Joachim, Ye, Chun Jimmie, and Mignot, Emmanuel J

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Biological Sciences, Prevention, Vaccine Related, Influenza, Autoimmune Disease, Immunization, Pneumonia & Influenza, Emerging Infectious Diseases, Infectious Diseases, 2.1 Biological and endogenous factors, Aetiology, Infection, Inflammatory and immune system, Good Health and Well Being, Humans, Autoimmunity, Influenza, Human, Influenza A Virus, H1N1 Subtype, Autoimmune Diseases, Influenza Vaccines, Narcolepsy, FinnGen
Abstract

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

Published
2023

5. Transcriptome-wide association analysis identifies candidate susceptibility genes for prostate-specific antigen levels in men without prostate cancer

Author

Chen, Dorothy M., Dong, Ruocheng, Kachuri, Linda, Hoffmann, Thomas J., Jiang, Yu, Berndt, Sonja I., Shelley, John P., Schaffer, Kerry R., Machiela, Mitchell J., Freedman, Neal D., Huang, Wen-Yi, Li, Shengchao A., Lilja, Hans, Justice, Amy C., Madduri, Ravi K., Rodriguez, Alex A., Van Den Eeden, Stephen K., Chanock, Stephen J., Haiman, Christopher A., Conti, David V., Klein, Robert J., Mosley, Jonathan D., Witte, John S., and Graff, Rebecca E.

Published
2024
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6. Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer

Author

Babic, Ana, Rosenthal, Michael H., Sundaresan, Tilak K., Khalaf, Natalia, Lee, Valerie, Brais, Lauren K., Loftus, Maureen, Caplan, Leah, Denning, Sarah, Gurung, Anamol, Harrod, Joanna, Schawkat, Khoschy, Yuan, Chen, Wang, Qiao-Li, Lee, Alice A., Biller, Leah H., Yurgelun, Matthew B., Ng, Kimmie, Nowak, Jonathan A., Aguirre, Andrew J., Bhatia, Sangeeta N., Vander Heiden, Matthew G., Van Den Eeden, Stephen K., Caan, Bette J., and Wolpin, Brian M.

Published
2023
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7. Circulating immune signatures in chronic pancreatitis with and without preceding acute pancreatitis: A pilot study

Author

Hagn-Meincke, Rasmus, Yadav, Dhiraj, Andersen, Dana K., Vege, Santhi Swaroop, Fogel, Evan L., Serrano, Jose, Bellin, Melena D., Topazian, Mark D., Conwell, Darwin L., Li, Liang, Van Den Eeden, Stephen K., Drewes, Asbjørn M., Pandol, Stephen J., Forsmark, Chris E., Fisher, William E., Hart, Phil A., Olesen, Søren S., and Park, Walter G.

Published
2024
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8. The economics of nature's healing touch: A systematic review and conceptual framework of green space, pharmaceutical prescriptions, and healthcare expenditure associations

Author

Patwary, Muhammad Mainuddin, Bardhan, Mondira, Browning, Matthew H.E.M., Astell-Burt, Thomas, van den Bosch, Matilda, Dong, Jiaying, Dzhambov, Angel M., Dadvand, Payam, Fasolino, Tracy, Markevych, Iana, McAnirlin, Olivia, Nieuwenhuijsen, Mark J., White, Mathew P., and Van Den Eeden, Stephen K.

Published
2024
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9. Interpersonal violence and painful bladder symptoms in community-dwelling midlife to older women.

Author

Raphael, Eva, Van Den Eeden, Stephen K, Gibson, Carolyn J, Tonner, Chris, Thom, David H, Subak, Leslee, and Huang, Alison J

Subjects
Humans, Cystitis, Interstitial, Prevalence, Cross-Sectional Studies, Stress Disorders, Post-Traumatic, Violence, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Patient Acuity, Intimate Partner Violence, bladder pain, interpersonal violence, posttraumatic stress disorder, urinary tract infections, Urologic Diseases, Aging, Pain Research, Chronic Pain, 2.1 Biological and endogenous factors, Aetiology, Mental Health, Clinical Research, Violence Research, Physical Injury - Accidents and Adverse Effects, Violence Against Women, Post-Traumatic Stress Disorder (PTSD), 2.3 Psychological, social and economic factors, Peace, Justice and Strong Institutions, Gender Equality, Paediatrics and Reproductive Medicine, Obstetrics & Reproductive Medicine
Abstract

BackgroundWomen are more likely to present with genitourinary complaints immediately after exposure to interpersonal violence, but little is known about the long-term effects of violence on women's urologic health, including their susceptibility to bladder pain and infections.ObjectiveTo determine whether lifetime interpersonal violence exposure and current posttraumatic stress disorder (PTSD) symptoms are associated with the prevalence or severity of painful bladder symptoms and a greater lifetime history of antibiotic-treated urinary tract infections in community-dwelling midlife and older women.Study designWe examined the cross-sectional data from a multiethnic cohort of community-dwelling women aged 40 to 80 years enrolled in a northern California integrated healthcare system. Women completed structured self-report questionnaires about their past exposure to physical and verbal/emotional intimate partner violence and sexual assault. The symptoms of PTSD were assessed using the PTSD checklist for the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition, Civilian version. Additional structured self-report measures assessed the current bladder pain, other lower urinary tract symptoms, and the history of antibiotic-treated urinary tract infections. Multivariable logistic regression models examined self-reported interpersonal violence exposure history and current PTSD symptoms in relation to current bladder pain and antibiotic-treated urinary tract infection history.ResultsAmong 1974 women (39% non-Latina White, 21% Black, 20% Latina, and 19% Asian), 22% reported lifetime interpersonal violence exposure, 22% reported bladder pain, and 60% reported a history of ever having an antibiotic-treated urinary tract infection. Lifetime experiences of sexual assault (odds ratio, 1.39; [95% confidence interval, 1.02-1.88]) and current PTSD symptoms (odds ratio, 1.96; [95% confidence interval, 1.45-2.65]) were associated with current bladder pain. A lifetime experience of physical intimate partner violence was associated with having a urinary tract infection at any time in life previously (odds ratio, 1.38; [95% confidence interval, 1.00-1.86]), as was emotional intimate partner violence (odds ratio, 1.88; [95% confidence interval, 1.43-2.48]), sexual assault (odds ratio, 1.44; [95% confidence interval, 1.09-1.91]), and current PTSD symptoms (odds ratio, 1.54; [95% confidence interval, 1.16-2.03]).ConclusionIn this ethnically diverse, community-based cohort, lifetime interpersonal violence exposures and current PTSD symptoms were independently associated with current bladder pain and the lifetime history of antibiotic-treated urinary tract infections in midlife to older women. The findings suggest that interpersonal violence and PTSD symptoms may be underrecognized markers of risk for urologic pain and infections in women, highlighting a need for trauma-informed care of these issues.

Published
2022

10. Systemic Neutrophil Gelatinase-Associated Lipocalin Alterations in Chronic Pancreatitis: A Multicenter, Cross-Sectional Study

Author

Gumpper-Fedus, Kristyn, Chasser, Kaylin, Pita-Grisanti, Valentina, Torok, Molly, Pfau, Timothy, Mace, Thomas A., Cole, Rachel M., Belury, Martha A., Culp, Stacey, Hart, Phil A., Krishna, Somashekar G., Lara, Luis F., Ramsey, Mitchell L., Fisher, William, Fogel, Evan L., Forsmark, Chris E., Li, Liang, Pandol, Stephen, Park, Walter G., Serrano, Jose, Van Den Eeden, Stephen K., Vege, Santhi Swaroop, Yadav, Dhiraj, Conwell, Darwin L., and Cruz-Monserrate, Zobeida

Published
2024
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11. Pancreatitis pain quality changes at year 1 follow-up, but GP130 remains a biomarker for pain

Author

Saloman, Jami L, Jennings, Kristofer, Stello, Kimberly, Li, Shuang, Evans Phillips, Anna, Hall, Kristen, Fogel, Evan L., Vege, Santhi Swaroop, Andersen, Dana K., Fisher, William E., Forsmark, Christopher E., Hart, Phil A., Pandol, Stephen J., Park, Walter G., Topazian, Mark D., Van Den Eeden, Stephen K., Serrano, Jose, Conwell, Darwin L., Li, Liang, and Yadav, Dhiraj

Published
2024
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13. Serum Biomarkers of Nociceptive and Neuropathic Pain in Chronic Pancreatitis

Author

Saloman, Jami L., Li, Yan, Stello, Kimberly, Li, Wenhao, Li, Shuang, Phillips, Anna Evans, Hall, Kristen, Fogel, Evan L., Vege, Santhi Swaroop, Li, Liang, Andersen, Dana K., Fisher, William E., Forsmark, Christopher E., Hart, Phil A., Pandol, Stephen J., Park, Walter G., Topazian, Mark D., Van Den Eeden, Stephen K., Serrano, Jose, Conwell, Darwin L., and Yadav, Dhiraj

Published
2023
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14. A Large-Scale Association Study Detects Novel Rare Variants, Risk Genes, Functional Elements, and Polygenic Architecture of Prostate Cancer Susceptibility

Author

Emami, Nima C, Cavazos, Taylor B, Rashkin, Sara R, Cario, Clinton L, Graff, Rebecca E, Tai, Caroline G, Mefford, Joel A, Kachuri, Linda, Wan, Eunice, Wong, Simon, Aaronson, David, Presti, Joseph, Habel, Laurel A, Shan, Jun, Ranatunga, Dilrini K, Chao, Chun R, Ghai, Nirupa R, Jorgenson, Eric, Sakoda, Lori C, Kvale, Mark N, Kwok, Pui-Yan, Schaefer, Catherine, Risch, Neil, Hoffmann, Thomas J, Van Den Eeden, Stephen K, and Witte, John S

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Human Genome, Cancer, Urologic Diseases, Biotechnology, Aging, Prostate Cancer, Prevention, 2.1 Biological and endogenous factors, Aetiology, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

To identify rare variants associated with prostate cancer susceptibility and better characterize the mechanisms and cumulative disease risk associated with common risk variants, we conducted an integrated study of prostate cancer genetic etiology in two cohorts using custom genotyping microarrays, large imputation reference panels, and functional annotation approaches. Specifically, 11,984 men (6,196 prostate cancer cases and 5,788 controls) of European ancestry from Northern California Kaiser Permanente were genotyped and meta-analyzed with 196,269 men of European ancestry (7,917 prostate cancer cases and 188,352 controls) from the UK Biobank. Three novel loci, including two rare variants (European ancestry minor allele frequency < 0.01, at 3p21.31 and 8p12), were significant genome wide in a meta-analysis. Gene-based rare variant tests implicated a known prostate cancer gene (HOXB13), as well as a novel candidate gene (ILDR1), which encodes a receptor highly expressed in prostate tissue and is related to the B7/CD28 family of T-cell immune checkpoint markers. Haplotypic patterns of long-range linkage disequilibrium were observed for rare genetic variants at HOXB13 and other loci, reflecting their evolutionary history. In addition, a polygenic risk score (PRS) of 188 prostate cancer variants was strongly associated with risk (90th vs. 40th-60th percentile OR = 2.62, P = 2.55 × 10-191). Many of the 188 variants exhibited functional signatures of gene expression regulation or transcription factor binding, including a 6-fold difference in log-probability of androgen receptor binding at the variant rs2680708 (17q22). Rare variant and PRS associations, with concomitant functional interpretation of risk mechanisms, can help clarify the full genetic architecture of prostate cancer and other complex traits. SIGNIFICANCE: This study maps the biological relationships between diverse risk factors for prostate cancer, integrating different functional datasets to interpret and model genome-wide data from over 200,000 men with and without prostate cancer.See related commentary by Lachance, p. 1637.

Published
2021

16. Cross-cancer evaluation of polygenic risk scores for 16 cancer types in two large cohorts.

Author

Graff, Rebecca E, Cavazos, Taylor B, Thai, Khanh K, Kachuri, Linda, Rashkin, Sara R, Hoffman, Joshua D, Alexeeff, Stacey E, Blatchins, Maruta, Meyers, Travis J, Leong, Lancelote, Tai, Caroline G, Emami, Nima C, Corley, Douglas A, Kushi, Lawrence H, Ziv, Elad, Van Den Eeden, Stephen K, Jorgenson, Eric, Hoffmann, Thomas J, Habel, Laurel A, Witte, John S, and Sakoda, Lori C

Subjects
Humans, Lung Neoplasms, Genetic Predisposition to Disease, Logistic Models, Risk Factors, Genotype, Adult, Aged, Middle Aged, Female, Male, Genome-Wide Association Study, Molecular Epidemiology, Biomarkers, Tumor, Biomarkers, Tumor
Abstract

Even distinct cancer types share biological hallmarks. Here, we investigate polygenic risk score (PRS)-specific pleiotropy across 16 cancers in European ancestry individuals from the Genetic Epidemiology Research on Adult Health and Aging cohort (16,012 cases, 50,552 controls) and UK Biobank (48,969 cases, 359,802 controls). Within cohorts, each PRS is evaluated in multivariable logistic regression models against all other cancer types. Results are then meta-analyzed across cohorts. Ten positive and one inverse cross-cancer associations are found after multiple testing correction. Two pairs show bidirectional associations; the melanoma PRS is positively associated with oral cavity/pharyngeal cancer and vice versa, whereas the lung cancer PRS is positively associated with oral cavity/pharyngeal cancer, and the oral cavity/pharyngeal cancer PRS is inversely associated with lung cancer. Overall, we validate known, and uncover previously unreported, patterns of pleiotropy that have the potential to inform investigations of risk prediction, shared etiology, and precision cancer prevention strategies.

Published
2021

17. Endogenous sex steroid hormones and risk of liver cancer among US men: Results from the Liver Cancer Pooling Project

Author

Wu, Zeni, Petrick, Jessica L., Florio, Andrea A., Guillemette, Chantal, Beane Freeman, Laura E., Buring, Julie E., Bradwin, Gary, Caron, Patrick, Chen, Yu, Eliassen, A. Heather, Engel, Lawrence S., Freedman, Neal D., Gaziano, J. Michael, Giovannuci, Edward L., Hofmann, Jonathan N., Huang, Wen-Yi, Kirsh, Victoria A., Kitahara, Cari M., Koshiol, Jill, Lee, I-Min, Liao, Linda M., Newton, Christina C., Palmer, Julie R., Purdue, Mark P., Rohan, Thomas E., Rosenberg, Lynn, Sesso, Howard D., Sinha, Rashmi, Stampfer, Meir J., Um, Caroline Y., Van Den Eeden, Stephen K., Visvanathan, Kala, Wactawski-Wende, Jean, Zeleniuch-Jacquotte, Anne, Zhang, Xuehong, Graubard, Barry I., Campbell, Peter T., and McGlynn, Katherine A.

Published
2023
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19. Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry

Author

Chen, Fei, Madduri, Ravi K., Rodriguez, Alex A., Darst, Burcu F., Chou, Alisha, Sheng, Xin, Wang, Anqi, Shen, Jiayi, Saunders, Edward J., Rhie, Suhn K., Bensen, Jeannette T., Ingles, Sue A., Kittles, Rick A., Strom, Sara S., Rybicki, Benjamin A., Nemesure, Barbara, Isaacs, William B., Stanford, Janet L., Zheng, Wei, Sanderson, Maureen, John, Esther M., Park, Jong Y., Xu, Jianfeng, Wang, Ying, Berndt, Sonja I., Huff, Chad D., Yeboah, Edward D., Tettey, Yao, Lachance, Joseph, Tang, Wei, Rentsch, Christopher T., Cho, Kelly, Mcmahon, Benjamin H., Biritwum, Richard B., Adjei, Andrew A., Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Sellers, Thomas A., Yamoah, Kosj, Murphy, Adam B., Crawford, Dana C., Patel, Alpa V., Bush, William S., Aldrich, Melinda C., Cussenot, Olivier, Petrovics, Gyorgy, Cullen, Jennifer, Neslund-Dudas, Christine M., Stern, Mariana C., Kote-Jarai, Zsofia, Govindasami, Koveela, Cook, Michael B., Chokkalingam, Anand P., Hsing, Ann W., Goodman, Phyllis J., Hoffmann, Thomas J., Drake, Bettina F., Hu, Jennifer J., Keaton, Jacob M., Hellwege, Jacklyn N., Clark, Peter E., Jalloh, Mohamed, Gueye, Serigne M., Niang, Lamine, Ogunbiyi, Olufemi, Idowu, Michael O., Popoola, Olufemi, Adebiyi, Akindele O., Aisuodionoe-Shadrach, Oseremen I., Ajibola, Hafees O., Jamda, Mustapha A., Oluwole, Olabode P., Nwegbu, Maxwell, Adusei, Ben, Mante, Sunny, Darkwa-Abrahams, Afua, Mensah, James E., Diop, Halimatou, Van Den Eeden, Stephen K., Blanchet, Pascal, Fowke, Jay H., Casey, Graham, Hennis, Anselm J., Lubwama, Alexander, Thompson, Ian M., Jr., Leach, Robin, Easton, Douglas F., Preuss, Michael H., Loos, Ruth J., Gundell, Susan M., Wan, Peggy, Mohler, James L., Fontham, Elizabeth T., Smith, Gary J., Taylor, Jack A., Srivastava, Shiv, Eeles, Rosaline A., Carpten, John D., Kibel, Adam S., Multigner, Luc, Parent, Marie-Élise, Menegaux, Florence, Cancel-Tassin, Geraldine, Klein, Eric A., Andrews, Caroline, Rebbeck, Timothy R., Brureau, Laurent, Ambs, Stefan, Edwards, Todd L., Watya, Stephen, Chanock, Stephen J., Witte, John S., Blot, William J., Michael Gaziano, J., Justice, Amy C., Conti, David V., and Haiman, Christopher A.

Published
2023
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20. Distinct Serum Immune Profiles Define the Spectrum of Acute and Chronic Pancreatitis From the Multicenter Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) Study

Author

Li, Liang, Yadav, Dhiraj, Conwell, Darwin L., Hart, Phil A., Vege, Santhi Swaroop, Fogel, Evan L., Serrano, Jose, Andersen, Dana, Bellin, Melena D., Topazian, Mark, Van Den Eeden, Stephen K., Pandol, Stephen J., Forsmark, Chris, Fisher, William E., Park, Walter G., Lee, Bomi, Jones, Elaina K., Manohar, Murli, Topazian, Mark D., Forsmark, Chris E., Husain, Sohail Z., and Habtezion, Aida

Published
2023
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21. Pan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts.

Author

Rashkin, Sara R, Graff, Rebecca E, Kachuri, Linda, Thai, Khanh K, Alexeeff, Stacey E, Blatchins, Maruta A, Cavazos, Taylor B, Corley, Douglas A, Emami, Nima C, Hoffman, Joshua D, Jorgenson, Eric, Kushi, Lawrence H, Meyers, Travis J, Van Den Eeden, Stephen K, Ziv, Elad, Habel, Laurel A, Hoffmann, Thomas J, Sakoda, Lori C, and Witte, John S

Subjects
Humans, Neoplasms, Genetic Predisposition to Disease, Risk Assessment, Risk Factors, Case-Control Studies, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, European Continental Ancestry Group, Female, Male, Genome-Wide Association Study, Genetic Pleiotropy, Carcinogenesis, Polymorphism, Single Nucleotide
Abstract

Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. Here, we undertake genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (408,786 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detect 21 genome-wide significant associations independent of previously reported results. Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.

Published
2020

22. A genome‐wide association study of prostate cancer in Latinos

Author

Du, Zhaohui, Hopp, Hannah, Ingles, Sue A, Huff, Chad, Sheng, Xin, Weaver, Brandi, Stern, Mariana, Hoffmann, Thomas J, John, Esther M, Van Den Eeden, Stephen K, Strom, Sara, Leach, Robin J, Thompson, Ian M, Witte, John S, Conti, David V, and Haiman, Christopher A

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prevention, Urologic Diseases, Human Genome, Prostate Cancer, Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Aged, Alleles, Biomarkers, Tumor, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Hispanic or Latino, Humans, Male, Middle Aged, Multifactorial Inheritance, Odds Ratio, Polymorphism, Single Nucleotide, Prostatic Neoplasms, prostate cancer, Latino men, GWAS, admixture mapping, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Latinos represent

Published
2020

23. Cervical dystonia incidence and diagnostic delay in a multiethnic population.

Author

LaHue, Sara C, Albers, Kathleen, Goldman, Samuel, Lo, Raymond Y, Gu, Zhuqin, Leimpeter, Amethyst, Fross, Robin, Comyns, Kathleen, Marras, Connie, de Kleijn, Annelie, Smit, Robin, Katz, Maya, Ozelius, Laurie J, Bressman, Susan, Saunders-Pullman, Rachel, Comella, Cynthia, Klingman, Jeffrey, Nelson, Lorene M, Van Den Eeden, Stephen K, and Tanner, Caroline M

Subjects
Humans, Torticollis, Incidence, Logistic Models, Odds Ratio, Female, Male, Delayed Diagnosis, cervical dystonia, diagnostic delay, incidence, Clinical Research, Neurosciences, Digestive Diseases, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Clinical Sciences, Human Movement and Sports Sciences, Neurology & Neurosurgery
Abstract

BackgroundCurrent cervical dystonia (CD) incidence estimates are based on small numbers in relatively ethnically homogenous populations. The frequency and consequences of delayed CD diagnosis is poorly characterized.ObjectivesTo determine CD incidence and characterize CD diagnostic delay within a large, multiethnic integrated health maintenance organization.MethodsWe identified incident CD cases using electronic medical records and multistage screening of more than 3 million Kaiser Permanente Northern California members from January 1, 2003, to December 31, 2007. A final diagnosis was made by movement disorders specialist consensus. Diagnostic delay was measured by questionnaire and health utilization data. Incidence rates were estimated assuming a Poisson distribution of cases and directly standardized to the 2000 U.S. census. Multivariate logistic regression models were employed to assess diagnoses and behaviors preceding CD compared with matched controls, adjusting for age, sex, and membership duration.ResultsCD incidence was 1.18/100,000 person-years (95% confidence interval [CI], 0.35-2.0; women, 1.81; men, 0.52) based on 200 cases over 15.4 million person-years. Incidence increased with age. Half of the CD patients interviewed reported diagnostic delay. Diagnoses more common in CD patients before the index date included essential tremor (odds ratio [OR] 68.1; 95% CI, 28.2-164.5), cervical disc disease (OR 3.83; 95% CI, 2.8-5.2), neck sprain/strain (OR 2.77; 95% CI, 1.99-3.62), anxiety (OR 2.24; 95% CI, 1.63-3.11) and depression (OR 1.94; 95% CI, 1.4-2.68).ConclusionsCD incidence is greater in women and increases with age. Diagnostic delay is common and associated with adverse effects. © 2019 International Parkinson and Movement Disorder Society.

Published
2020

24. The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 in a pooled analysis of 16,024 men from 22 studies

Author

Watts, Eleanor L, Perez‐Cornago, Aurora, Appleby, Paul N, Albanes, Demetrius, Ardanaz, Eva, Black, Amanda, Bueno‐de‐Mesquita, H Bas, Chan, June M, Chen, Chu, Chubb, SA Paul, Cook, Michael B, Deschasaux, Mélanie, Donovan, Jenny L, English, Dallas R, Flicker, Leon, Freedman, Neal D, Galan, Pilar, Giles, Graham G, Giovannucci, Edward L, Gunter, Marc J, Habel, Laurel A, Häggström, Christel, Haiman, Christopher, Hamdy, Freddie C, Hercberg, Serge, Holly, Jeff M, Huang, Jiaqi, Huang, Wen‐Yi, Johansson, Mattias, Kaaks, Rudolf, Kubo, Tatsuhiko, Lane, J Athene, Layne, Tracy M, Le Marchand, Loic, Martin, Richard M, Metter, E Jeffrey, Mikami, Kazuya, Milne, Roger L, Morris, Howard A, Mucci, Lorelei A, Neal, David E, Neuhouser, Marian L, Oliver, Steven E, Overvad, Kim, Ozasa, Kotaro, Pala, Valeria, Pernar, Claire H, Pollak, Michael, Rowlands, Mari‐Anne, Schaefer, Catherine A, Schenk, Jeannette M, Stattin, Pär, Tamakoshi, Akiko, Thysell, Elin, Touvier, Mathilde, Trichopoulou, Antonia, Tsilidis, Konstantinos K, Van Den Eeden, Stephen K, Weinstein, Stephanie J, Wilkens, Lynne, Yeap, Bu B, Key, Timothy J, Allen, Naomi E, and Travis, Ruth C

Subjects
Cancer, Aging, Urologic Diseases, Adult, Aged, Aged, 80 and over, Anthropometry, Biomarkers, Tumor, Cross-Sectional Studies, Humans, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Male, Middle Aged, Neoplasms, Prospective Studies, Young Adult, IGFs, IGFBPs, pooled analysis, correlates, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP-1, IGFBP-2 and IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.

Published
2019

25. The association between genetically elevated polyunsaturated fatty acids and risk of cancer

Author

Tintle, Nathan, Rice, Terri, Cheng, Iona, Jenkins, Mark, Gallinger, Steve, Cornish, Alex J., Sud, Amit, Vijayakrishnan, Jayaram, Wrensch, Margaret, Johansson, Mattias, Norman, Aaron D., Klein, Alison, Clay-Gilmour, Alyssa, Franke, Andre, Ardisson Korat, Andres V., Wheeler, Bill, Nilsson, Björn, Smith, Caren, Heng, Chew-Kiat, Song, Ci, Riadi, David, Claus, Elizabeth B., Ellinghaus, Eva, Ostroumova, Evgenia, Hosnijeh, de Vathaire, Florent, Cugliari, Giovanni, Matullo, Giuseppe, Oi-Lin Ng, Irene, Passow, Jeanette E., Foo, Jia Nee, Han, Jiali, Liu, Jianjun, Barnholtz-Sloan, Jill, Schildkraut, Joellen M., Maris, John, Wiemels, Joseph L., Hemminki, Kari, Yang, Keming, Kiemeney, Lambertus A., Wu, Lang, Amundadottir, Laufey, Stern, Marc-Henri, Boutron, Marie-Christine, Iles, Mark Martin, Purdue, Mark P., Stanulla, Martin, Bondy, Melissa, Gaudet, Mia, Mobuchon, Lenha, Camp, Nicola J., Sham, Pak Chung, Guénel, Pascal, Brennan, Paul, Taylor, Philip R., Ostrom, Quinn, Stolzenberg-Solomon, Rachael, Dorajoo, Rajkumar, Houlston, Richard, Jenkins, Robert B., Diskin, Sharon, Berndt, Sonja I., Tsavachidis, Spiridon, Channock, Stephen J., Harrison, Tabitha, Galesloot, Tessel, Gyllensten, Ulf, Joseph, Vijai, Shi, Y., Yang, Wenjian, Lin, Yi, Van Den Eeden, Stephen K., Haycock, Philip C., Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N., Burgess, Stephen, Khankari, Nikhil K., Tsilidis, Konstantinos K., Gaunt, Tom R., Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M., OMara, Tracy, Spurdle, Amanda B., Iles, Mark M., Law, Matthew H., Slager, Susan L., Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R., Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C., Block, Robert C., Amos, Christopher I., Hung, Rayjean J., Zheng, Wei, Gunter, Marc J., Smith, George Davey, Relton, Caroline, and Martin, Richard M.

Published
2023
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26. T1 signal intensity ratio of the pancreas as an imaging biomarker for the staging of chronic pancreatitis

Author

Tirkes, Temel, Dasyam, Anil K., Shah, Zarine K., Fogel, Evan L., Vege, Santhi Swaroop, Li, Liang, Li, Shuang, Chang, Stephanie T., Farinas, Carlos A., Grajo, Joseph R., Mawad, Kareem, Takahashi, Naoki, Venkatesh, Sudhakar K., Wachsman, Ashley, Fisher, William E., Forsmark, Christopher E., Hart, Phil A., Pandol, Stephen J., Park, Walter G., Van Den Eeden, Stephen K., Yang, Yunlong, Topazian, Mark, Andersen, Dana K., Serrano, Jose, Conwell, Darwin L., and Yadav, Dhiraj

Published
2022
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29. Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms.

Author

Emami, Nima C, Kachuri, Linda, Meyers, Travis J, Das, Rajdeep, Hoffman, Joshua D, Hoffmann, Thomas J, Hu, Donglei, Shan, Jun, Feng, Felix Y, Ziv, Elad, Van Den Eeden, Stephen K, and Witte, John S

Subjects
Prostate, Humans, Prostatic Neoplasms, Serine Endopeptidases, Cohort Studies, Gene Expression Profiling, Models, Genetic, European Continental Ancestry Group, Male, Transcriptome
Abstract

Here we train cis-regulatory models of prostate tissue gene expression and impute expression transcriptome-wide for 233,955 European ancestry men (14,616 prostate cancer (PrCa) cases, 219,339 controls) from two large cohorts. Among 12,014 genes evaluated in the UK Biobank, we identify 38 associated with PrCa, many replicating in the Kaiser Permanente RPGEH. We report the association of elevated TMPRSS2 expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the TMPRSS2:ERG fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism. Three novel genes, HOXA4, KLK1, and TIMM23, additionally replicate in the RPGEH cohort. Furthermore, 4 genes, MSMB, NCOA4, PCAT1, and PPP1R14A, are associated with PrCa in a trans-ethnic meta-analysis (N = 9117). Many genes exhibit evidence for allele-specific transcriptional activation by PrCa master-regulators (including androgen receptor) in Position Weight Matrix, Chip-Seq, and Hi-C experimental data, suggesting common regulatory mechanisms for the associated genes.

Published
2019

31. The Kaiser Permanente Research Bank Cancer Cohort: a collaborative resource to improve cancer care and survivorship

Author

Feigelson, Heather Spencer, Clarke, Christina L., Van Den Eeden, Stephen K., Weinmann, Sheila, Burnett-Hartman, Andrea N., Rowell, Sarah, Scott, Shauna Goldberg, White, Larissa L., Ter-Minassian, Monica, Honda, Stacey A. A., Young, Deborah R., Kamineni, Aruna, Chinn, Terrence, Lituev, Alexander, Bauck, Alan, and McGlynn, Elizabeth A.

Published
2022
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33. A Prospective Study to Establish a New-Onset Diabetes Cohort

Author

Maitra, Anirban, Sharma, Ayush, Brand, Randall E, Van Den Eeden, Stephen K, Fisher, William E, Hart, Phil A, Hughes, Steven J, Mather, Kieren J, Pandol, Stephen J, Park, Walter G, Feng, Ziding, Serrano, Jose, Rinaudo, Jo Ann S, Srivastava, Sudhir, and Chari, Suresh T

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Diabetes, Prevention, Cancer, Rare Diseases, Pancreatic Cancer, Digestive Diseases, Clinical Research, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Metabolic and endocrine, Good Health and Well Being, Biomedical Research, Blood Specimen Collection, Carcinoma, Pancreatic Ductal, Diabetes Mellitus, Type 2, Early Diagnosis, Humans, Middle Aged, Pancreatic Neoplasms, Pancreatitis, Chronic, Prospective Studies, Research Design, Young Adult, screening, sporadic pancreatic cancer, diabetes, high-risk group, biomarker, Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer, Gastroenterology & Hepatology, Clinical sciences
Abstract

The National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC's origin, structure, governance, and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects 50 years or older with new-onset diabetes, called the NOD cohort. Using a define, enrich, and find early detection approach, the aims of the NOD study are to (a) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD (define), (b) establish a biobank of clinically annotated biospecimens from presymptomatic PDAC and control new-onset type 2 diabetes mellitus subjects, (c) conduct phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients (enrich), and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms (find). It is expected that 85 to 100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients.

Published
2018

34. PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies

Author

Yadav, Dhiraj, Park, Walter G, Fogel, Evan L, Li, Liang, Chari, Suresh T, Feng, Ziding, Fisher, William E, Forsmark, Christopher E, Jeon, Christie Y, Habtezion, Aida, Hart, Phil A, Hughes, Steven J, Othman, Mohamed O, Rinaudo, Jo Ann S, Pandol, Stephen J, Tirkes, Temel, Serrano, Jose, Srivastava, Sudhir, Van Den Eeden, Stephen K, Whitcomb, David C, Topazian, Mark, and Conwell, Darwin L

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Pancreatic Cancer, Prevention, Digestive Diseases, Rare Diseases, Cancer, Clinical Research, 2.1 Biological and endogenous factors, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Aetiology, Oral and gastrointestinal, Adult, Biomarkers, Blood Specimen Collection, Diabetes Mellitus, Disease Progression, Humans, Longitudinal Studies, Observational Studies as Topic, Outcome Assessment, Health Care, Pancreatic Neoplasms, Pancreatitis, Chronic, Prospective Studies, Research Design, Specimen Handling, Translational Research, Biomedical, United States, pancreas, alcohol, tobacco, genetic, biorepository, cohort, Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer, Gastroenterology & Hepatology, Clinical sciences
Abstract

Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) is the first prospective, observational cohort study of chronic pancreatitis (CP) in the United States. The primary goals of PROCEED are to define disease progression, test the predictive capability of candidate biomarkers, and develop a platform to conduct translational and mechanistic studies in CP. Using objective and consensus-driven criteria, PROCEED will enroll adults at different stages of CP-controls, suspected CP, and definite CP. In addition to collecting detailed information using structured case report forms and protocol-mandated evaluations at baseline and during follow-up, PROCEED will establish a linked biorepository of blood, urine, saliva, stool, pancreatic fluid, and pancreatic tissue. Enrollment for PROCEED began in June 2017. As of July 1, 2018, nine clinical centers of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer are enrolling, and 350 subjects have completed baseline evaluation. In conclusion, PROCEED will provide the most accurate and reliable estimates to date on progression of CP. The established cohort and biorepository will facilitate numerous analyses, leading to new strategies for diagnosis, methods to monitor disease progression, and treatment of CP.

Published
2018

35. Genetic variation in the SIM1 locus is associated with erectile dysfunction

Author

Jorgenson, Eric, Matharu, Navneet, Palmer, Melody R, Yin, Jie, Shan, Jun, Hoffmann, Thomas J, Thai, Khanh K, Zhou, Xujia, Hotaling, James M, Jarvik, Gail P, Ahituv, Nadav, Wessells, Hunter, and Van Den Eeden, Stephen K

Subjects
Contraception/Reproduction, Genetics, Human Genome, Urologic Diseases, Biotechnology, Clinical Research, Prevention, 2.1 Biological and endogenous factors, Aetiology, Aged, Alleles, Body Mass Index, Case-Control Studies, Chromosomes, Human, Pair 6, Cohort Studies, Erectile Dysfunction, Genetic Predisposition to Disease, Genetic Variation, Humans, Leptin, Male, Melanocortins, Middle Aged, Promoter Regions, Genetic, genome-wide association, erectile dysfunction, SIM1, genetic, melanocortin
Abstract

Erectile dysfunction affects millions of men worldwide. Twin studies support the role of genetic risk factors underlying erectile dysfunction, but no specific genetic variants have been identified. We conducted a large-scale genome-wide association study of erectile dysfunction in 36,649 men in the multiethnic Kaiser Permanente Northern California Genetic Epidemiology Research in Adult Health and Aging cohort. We also undertook replication analyses in 222,358 men from the UK Biobank. In the discovery cohort, we identified a single locus (rs17185536-T) on chromosome 6 near the single-minded family basic helix-loop-helix transcription factor 1 (SIM1) gene that was significantly associated with the risk of erectile dysfunction (odds ratio = 1.26, P = 3.4 × 10-25). The association replicated in the UK Biobank sample (odds ratio = 1.25, P = 6.8 × 10-14), and the effect is independent of known erectile dysfunction risk factors, including body mass index (BMI). The risk locus resides on the same topologically associating domain as SIM1 and interacts with the SIM1 promoter, and the rs17185536-T risk allele showed differential enhancer activity. SIM1 is part of the leptin-melanocortin system, which has an established role in body weight homeostasis and sexual function. Because the variants associated with erectile dysfunction are not associated with differences in BMI, our findings suggest a mechanism that is specific to sexual function.

Published
2018

36. High-resolution mapping of traffic related air pollution with Google street view cars and incidence of cardiovascular events within neighborhoods in Oakland, CA.

Author

Alexeeff, Stacey E, Roy, Ananya, Shan, Jun, Liu, Xi, Messier, Kyle, Apte, Joshua S, Portier, Christopher, Sidney, Stephen, and Van Den Eeden, Stephen K

Subjects
Humans, Cardiovascular Diseases, Air Pollutants, Incidence, Retrospective Studies, Cohort Studies, Cities, Air Pollution, Vehicle Emissions, Residence Characteristics, Adult, Aged, Middle Aged, California, Female, Male, Young Adult, Geographic Mapping, Traffic-Related Pollution, Air pollution, Cardiovascular disease, Coronary heart disease, Mobile monitoring, Mortality, Public Health and Health Services, Toxicology
Abstract

BACKGROUND:Some studies have linked long-term exposure to traffic related air pollutants (TRAP) with adverse cardiovascular health outcomes; however, previous studies have not linked highly variable concentrations of TRAP measured at street-level within neighborhoods to cardiovascular health outcomes. METHODS:Long-term pollutant concentrations for nitrogen dioxide [NO2], nitric oxide [NO], and black carbon [BC] were obtained by street-level mobile monitoring on 30 m road segments and linked to residential addresses of 41,869 adults living in Oakland during 2010 to 2015. We fit Cox proportional hazard models to estimate the relationship between air pollution exposures and time to first cardiovascular event. Secondary analyses examined effect modification by diabetes and age. RESULTS:Long-term pollutant concentrations [mean, (standard deviation; SD)] for NO2, NO and BC were 9.9 ppb (SD 3.8), 4.9 ppb (SD 3.8), and 0.36 μg/m3 (0.17) respectively. A one SD increase in NO2, NO and BC, was associated with a change in risk of a cardiovascular event of 3% (95% confidence interval [CI] -6% to 12%), 3% (95% CI -5% to 12%), and - 1% (95% CI -8% to 7%), respectively. Among the elderly (≥65 yrs), we found an increased risk of a cardiovascular event of 12% for NO2 (95% CI: 2%, 24%), 12% for NO (95% CI: 3%, 22%), and 7% for BC (95% CI: -3%, 17%) per one SD increase. We found no effect modification by diabetes. CONCLUSIONS:Street-level differences in long-term exposure to TRAP were associated with higher risk of cardiovascular events among the elderly, indicating that within-neighborhood differences in TRAP are important to cardiovascular health. Associations among the general population were consistent with results found in previous studies, though not statistically significant.

Published
2018

39. Characterizing mechanism-based pain phenotypes in patients with chronic pancreatitis: a cross-sectional analysis of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies

Author

Saloman, Jami L., Conwell, Darwin L., Fogel, Evan, Vege, Santhi Swaroop, Li, Liang, Li, Shuang, Andersen, Dana K., Fisher, William E., Forsmark, Christopher E., Hart, Phil A., Pandol, Stephen J., Park, Walter G., Phillips, Anna Evans, Topazian, Mark, Van Den Eeden, Stephen K., Serrano, Jose, and Yadav, Dhiraj

Published
2023
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40. Characterizing mechanism-based pain phenotypes in patients with chronic pancreatitis: a cross-sectional analysis of the PROCEED study.

Author

Saloman, Jami L., Conwell, Darwin L., Fogel, Evan, Vege, Santhi Swaroop, Li, Liang, Li, Shuang, Andersen, Dana K., Fisher, William E., Forsmark, Christopher E., Hart, Phil A., Pandol, Stephen J., Park, Walter G., Phillips, Anna Evans, Topazian, Mark, Van Den Eeden, Stephen K., Serrano, Jose, and Yadav, Dhiraj

Published
2022
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41. Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry

Author

Conti, David V, Wang, Kan, Sheng, Xin, Bensen, Jeannette T, Hazelett, Dennis J, Cook, Michael B, Ingles, Sue A, Kittles, Rick A, Strom, Sara S, Rybicki, Benjamin A, Nemesure, Barbara, Isaacs, William B, Stanford, Janet L, Zheng, Wei, Sanderson, Maureen, John, Esther M, Park, Jong Y, Xu, Jianfeng, Stevens, Victoria L, Berndt, Sonja I, Huff, Chad D, Wang, Zhaoming, Yeboah, Edward D, Tettey, Yao, Biritwum, Richard B, Adjei, Andrew A, Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Sellers, Thomas A, Yamoah, Kosj, Murphy, Adam B, Crawford, Dana C, Gapstur, Susan M, Bush, William S, Aldrich, Melinda C, Cussenot, Olivier, Petrovics, Gyorgy, Cullen, Jennifer, Neslund-Dudas, Christine, Stern, Mariana C, Jarai, Zsofia-Kote, Govindasami, Koveela, Chokkalingam, Anand P, Hsing, Ann W, Goodman, Phyllis J, Hoffmann, Thomas, Drake, Bettina F, Hu, Jennifer J, Clark, Peter E, Van Den Eeden, Stephen K, Blanchet, Pascal, Fowke, Jay H, Casey, Graham, Hennis, Anselm JM, Han, Ying, Lubwama, Alexander, Thompson, Ian M, Leach, Robin, Easton, Douglas F, Schumacher, Fredrick, Van den Berg, David J, Gundell, Susan M, Stram, Alex, Wan, Peggy, Xia, Lucy, Pooler, Loreall C, Mohler, James L, Fontham, Elizabeth TH, Smith, Gary J, Taylor, Jack A, Srivastava, Shiv, Eeles, Rosalind A, Carpten, John, Kibel, Adam S, Multigner, Luc, Parent, Marie-Elise, Menegaux, Florence, Cancel-Tassin, Geraldine, Klein, Eric A, Brureau, Laurent, Stram, Daniel O, Watya, Stephen, Chanock, Stephen J, Witte, John S, Blot, William J, Henderson, Brian E, and Haiman, Christopher A

Subjects
Aging, Human Genome, Cancer, Prevention, Prostate Cancer, Biotechnology, Clinical Research, Genetics, Urologic Diseases, 2.1 Biological and endogenous factors, Aetiology, Blacks, Case-Control Studies, Checkpoint Kinase 2, Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 22, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Insulin Receptor Substrate Proteins, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms, PRACTICAL/ELLIPSE Consortium, Black People, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10 × 10-12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 × 10-10). At 13q34, the signal is located 5' of the gene IRS2 and 3' of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk.

Published
2017

42. Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer.

Author

Hoffmann, Thomas J, Passarelli, Michael N, Graff, Rebecca E, Emami, Nima C, Sakoda, Lori C, Jorgenson, Eric, Habel, Laurel A, Shan, Jun, Ranatunga, Dilrini K, Quesenberry, Charles P, Chao, Chun R, Ghai, Nirupa R, Aaronson, David, Presti, Joseph, Nordström, Tobias, Wang, Zhaoming, Berndt, Sonja I, Chanock, Stephen J, Mosley, Jonathan D, Klein, Robert J, Middha, Mridu, Lilja, Hans, Melander, Olle, Kvale, Mark N, Kwok, Pui-Yan, Schaefer, Catherine, Risch, Neil, Van Den Eeden, Stephen K, and Witte, John S

Subjects
Prostate, Humans, Prostatic Neoplasms, Prostate-Specific Antigen, Gene Expression, Gene Frequency, Polymorphism, Single Nucleotide, Alleles, Adult, Aged, Aged, 80 and over, Middle Aged, African Continental Ancestry Group, Asian Continental Ancestry Group, European Continental Ancestry Group, Male, Genome-Wide Association Study, Genetic Loci, Biomarkers, Tumor
Abstract

Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa-such as genetics-can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P

Published
2017

43. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Conti, David V., Darst, Burcu F., Moss, Lilit C., Saunders, Edward J., Sheng, Xin, Chou, Alisha, Schumacher, Fredrick R., Olama, Ali Amin Al, Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N., Sahimi, Ali, Hoffmann, Thomas J., Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Muir, Kenneth, Lophatananon, Artitaya, Wan, Peggy, Le Marchand, Loic, Wilkens, Lynne R., Stevens, Victoria L., Gapstur, Susan M., Carter, Brian D., Schleutker, Johanna, Tammela, Teuvo L. J., Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G., Southey, Melissa C., MacInnis, Robert J., Cybulski, Cezary, Wokołorczyk, Dominika, Lubiński, Jan, Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Martin, Richard M., Nordestgaard, Børge G., Nielsen, Sune F., Weischer, Maren, Bojesen, Stig E., Røder, Martin Andreas, Iversen, Peter, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Horvath, Lisa, Clements, Judith A., Tilley, Wayne, Risbridger, Gail P., Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordström, Tobias, Pashayan, Nora, Dunning, Alison M., Ghoussaini, Maya, Travis, Ruth C., Key, Tim J., Riboli, Elio, Park, Jong Y., Sellers, Thomas A., Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie J., Mucci, Lorelei A., Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J., Penney, Kathryn L., Turman, Constance, Tangen, Catherine M., Goodman, Phyllis J., Thompson, Jr., Ian M., Hamilton, Robert J., Fleshner, Neil E., Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L., Ostrander, Elaine A., Geybels, Milan S., Koutros, Stella, Freeman, Laura E. Beane, Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L., Hoover, Robert N., Machiela, Mitchell J., Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J., Zheng, Wei, Yeboah, Edward D., Mensah, James E., Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Wu, Yudong, Zhao, Shan-Chao, Sun, Zan, Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., West, Catharine M. L., Burnet, Neil, Barnett, Gill, Maier, Christiane, Schnoeller, Thomas, Luedeke, Manuel, Kibel, Adam S., Drake, Bettina F., Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Koudou, Yves Akoli, John, Esther M., Grindedal, Eli Marie, Maehle, Lovise, Khaw, Kay-Tee, Ingles, Sue A., Stern, Mariana C., Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Rosenstein, Barry S., Kerns, Sarah L., Ostrer, Harry, Teixeira, Manuel R., Paulo, Paula, Brandão, Andreia, Watya, Stephen, Lubwama, Alexander, Bensen, Jeannette T., Fontham, Elizabeth T. H., Mohler, James, Taylor, Jack A., Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Cannon-Albright, Lisa, Teerlink, Craig C., Huff, Chad D., Strom, Sara S., Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Kaneva, Radka, Slavov, Chavdar, Mitev, Vanio, Leach, Robin J., Weaver, Brandi, Brenner, Hermann, Cuk, Katarina, Holleczek, Bernd, Saum, Kai-Uwe, Klein, Eric A., Hsing, Ann W., Kittles, Rick A., Murphy, Adam B., Logothetis, Christopher J., Kim, Jeri, Neuhausen, Susan L., Steele, Linda, Ding, Yuan Chun, Isaacs, William B., Nemesure, Barbara, Hennis, Anselm J. M., Carpten, John, Pandha, Hardev, Michael, Agnieszka, De Ruyck, Kim, De Meerleer, Gert, Ost, Piet, Xu, Jianfeng, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Newcomb, Lisa F., Lin, Daniel W., Fowke, Jay H., Neslund-Dudas, Christine, Rybicki, Benjamin A., Gamulin, Marija, Lessel, Davor, Kulis, Tomislav, Usmani, Nawaid, Singhal, Sandeep, Parliament, Matthew, Claessens, Frank, Joniau, Steven, Van den Broeck, Thomas, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Martinez, Maria Elena, Larkin, Samantha, Townsend, Paul A., Aukim-Hastie, Claire, Bush, William S., Aldrich, Melinda C., Crawford, Dana C., Srivastava, Shiv, Cullen, Jennifer C., Petrovics, Gyorgy, Casey, Graham, Roobol, Monique J., Jenster, Guido, van Schaik, Ron H. N., Hu, Jennifer J., Sanderson, Maureen, Varma, Rohit, McKean-Cowdin, Roberta, Torres, Mina, Mancuso, Nicholas, Berndt, Sonja I., Van Den Eeden, Stephen K., Easton, Douglas F., Chanock, Stephen J., Cook, Michael B., Wiklund, Fredrik, Nakagawa, Hidewaki, Witte, John S., Eeles, Rosalind A., Kote-Jarai, Zsofia, and Haiman, Christopher A.

Published
2021
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44. Predictors of impact of vaginal symptoms in postmenopausal women

Author

Hunter, Mary M, Nakagawa, Sanae, Van Den Eeden, Stephen K, Kuppermann, Miriam, and Huang, Alison J

Subjects
Biomedical and Clinical Sciences, Clinical and Health Psychology, Health Services and Systems, Health Sciences, Psychology, Reproductive Medicine, Mental Health, Mind and Body, Clinical Research, Depression, Aging, Behavioral and Social Science, Management of diseases and conditions, 7.1 Individual care needs, Reproductive health and childbirth, Activities of Daily Living, Age Factors, Aged, Body Image, Body Mass Index, Emotions, Ethnicity, Female, Humans, Middle Aged, Postmenopause, Quality of Life, Self Concept, Sexual Behavior, Sexual Dysfunctions, Psychological, Surveys and Questionnaires, Urinary Incontinence, Vaginal Diseases, Vaginal dryness, Vulvovaginal atrophy, Urinary incontinence, Menopausal symptoms, Medical and Health Sciences, Obstetrics & Reproductive Medicine, Biomedical and clinical sciences, Health sciences
Abstract

ObjectiveThis study aims to identify factors associated with greater impact of vaginal symptoms on the functioning and well-being of postmenopausal women.MethodsPostmenopausal women who reported vaginal dryness, itching, irritation, or pain with sexual activity completed the multidimensional Day-to-day Impact of Vaginal Aging (DIVA) questionnaire and underwent assessment of multiple sociodemographic and clinical factors that have the potential to influence the impact of vaginal symptoms. Multivariable linear regression analyses examined relationships between selected participant characteristics and DIVA scale scores assessing symptom impact on activities of daily living, emotional well-being, self-concept and body image, and sexual functioning.ResultsAmong 745 symptomatic participants, the mean (SD) age was 56 (9) years, and 66% were racial/ethnic minorities. Women with comorbid depression reported greater impact of vaginal symptoms on all dimensions of functioning and well-being measured by the DIVA questionnaire (11%-22% estimated increase in impact scores associated with every three-point increase in Hospital and Anxiety Depression Scale scores). Women with urinary incontinence also reported greater impact of vaginal symptoms on activities of daily living, emotional well-being, and self-concept and body image (27%-37% estimated increase in impact scores). Age, partner status, frequency of sexual activity, general health, and body mass index also predicted greater impact on at least one domain.ConclusionsFindings suggest that special efforts should be made to identify and treat vaginal symptoms in postmenopausal women known to have depression or urinary incontinence, as these women may experience greater impact of vaginal symptoms on multiple domains of functioning and quality of life.

Published
2016

48. A Large Multiethnic Genome-Wide Association Study of Prostate Cancer Identifies Novel Risk Variants and Substantial Ethnic Differences

Author

Hoffmann, Thomas J, Van Den Eeden, Stephen K, Sakoda, Lori C, Jorgenson, Eric, Habel, Laurel A, Graff, Rebecca E, Passarelli, Michael N, Cario, Clinton L, Emami, Nima C, Chao, Chun R, Ghai, Nirupa R, Shan, Jun, Ranatunga, Dilrini K, Quesenberry, Charles P, Aaronson, David, Presti, Joseph, Wang, Zhaoming, Berndt, Sonja I, Chanock, Stephen J, McDonnell, Shannon K, French, Amy J, Schaid, Daniel J, Thibodeau, Stephen N, Li, Qiyuan, Freedman, Matthew L, Penney, Kathryn L, Mucci, Lorelei A, Haiman, Christopher A, Henderson, Brian E, Seminara, Daniela, Kvale, Mark N, Kwok, Pui-Yan, Schaefer, Catherine, Risch, Neil, and Witte, John S

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Cancer, Minority Health, Urologic Diseases, Prevention, Prostate Cancer, Aging, Clinical Research, Human Genome, Health Disparities, Adult, Aged, Alleles, Biomarkers, Tumor, Case-Control Studies, Ethnicity, Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, INDEL Mutation, Male, Middle Aged, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, Reproducibility of Results, Risk, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

UnlabelledA genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10(-19) (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10(-23)) and SLC22A3 (P = 3.2 × 10(-52)). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10(-13); OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004).SignificanceTaken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations.

Published
2015

49. Genotyping Informatics and Quality Control for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort.

Author

Kvale, Mark N, Hesselson, Stephanie, Hoffmann, Thomas J, Cao, Yang, Chan, David, Connell, Sheryl, Croen, Lisa A, Dispensa, Brad P, Eshragh, Jasmin, Finn, Andrea, Gollub, Jeremy, Iribarren, Carlos, Jorgenson, Eric, Kushi, Lawrence H, Lao, Richard, Lu, Yontao, Ludwig, Dana, Mathauda, Gurpreet K, McGuire, William B, Mei, Gangwu, Miles, Sunita, Mittman, Michael, Patil, Mohini, Quesenberry, Charles P, Ranatunga, Dilrini, Rowell, Sarah, Sadler, Marianne, Sakoda, Lori C, Shapero, Michael, Shen, Ling, Shenoy, Tanu, Smethurst, David, Somkin, Carol P, Van Den Eeden, Stephen K, Walter, Lawrence, Wan, Eunice, Webster, Teresa, Whitmer, Rachel A, Wong, Simon, Zau, Chia, Zhan, Yiping, Schaefer, Catherine, Kwok, Pui-Yan, and Risch, Neil

Subjects
Humans, Oligonucleotide Array Sequence Analysis, Cohort Studies, Computational Biology, Aging, Polymorphism, Single Nucleotide, Quality Control, Adult, Health, Female, Male, Molecular Epidemiology, Genotyping Techniques, Affymetrix Axiom, GERA cohort, genome-wide genotyping, quality control, saliva DNA, Genetics, Human Genome, Generic health relevance, Developmental Biology
Abstract

The Kaiser Permanente (KP) Research Program on Genes, Environment and Health (RPGEH), in collaboration with the University of California-San Francisco, undertook genome-wide genotyping of >100,000 subjects that constitute the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. The project, which generated >70 billion genotypes, represents the first large-scale use of the Affymetrix Axiom Genotyping Solution. Because genotyping took place over a short 14-month period, creating a near-real-time analysis pipeline for experimental assay quality control and final optimized analyses was critical. Because of the multi-ethnic nature of the cohort, four different ethnic-specific arrays were employed to enhance genome-wide coverage. All assays were performed on DNA extracted from saliva samples. To improve sample call rates and significantly increase genotype concordance, we partitioned the cohort into disjoint packages of plates with similar assay contexts. Using strict QC criteria, the overall genotyping success rate was 103,067 of 109,837 samples assayed (93.8%), with a range of 92.1-95.4% for the four different arrays. Similarly, the SNP genotyping success rate ranged from 98.1 to 99.4% across the four arrays, the variation depending mostly on how many SNPs were included as single copy vs. double copy on a particular array. The high quality and large scale of genotype data created on this cohort, in conjunction with comprehensive longitudinal data from the KP electronic health records of participants, will enable a broad range of highly powered genome-wide association studies on a diversity of traits and conditions.

Published
2015

50. Characterizing Race/Ethnicity and Genetic Ancestry for 100,000 Subjects in the Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort.

Author

Banda, Yambazi, Kvale, Mark N, Hoffmann, Thomas J, Hesselson, Stephanie E, Ranatunga, Dilrini, Tang, Hua, Sabatti, Chiara, Croen, Lisa A, Dispensa, Brad P, Henderson, Mary, Iribarren, Carlos, Jorgenson, Eric, Kushi, Lawrence H, Ludwig, Dana, Olberg, Diane, Quesenberry, Charles P, Rowell, Sarah, Sadler, Marianne, Sakoda, Lori C, Sciortino, Stanley, Shen, Ling, Smethurst, David, Somkin, Carol P, Van Den Eeden, Stephen K, Walter, Lawrence, Whitmer, Rachel A, Kwok, Pui-Yan, Schaefer, Catherine, and Risch, Neil

Subjects
Humans, Cohort Studies, Pedigree, Genomics, Aging, Principal Component Analysis, Adult, Middle Aged, Health, Female, Male, Molecular Epidemiology, Ethnicity, Racial Groups, RPGEH GERA, admixture, population structure, principal components, race/ethnicity, Clinical Research, Genetics, Developmental Biology
Abstract

Using genome-wide genotypes, we characterized the genetic structure of 103,006 participants in the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging Cohort and analyzed the relationship to self-reported race/ethnicity. Participants endorsed any of 23 race/ethnicity/nationality categories, which were collapsed into seven major race/ethnicity groups. By self-report the cohort is 80.8% white and 19.2% minority; 93.8% endorsed a single race/ethnicity group, while 6.2% endorsed two or more. Principal component (PC) and admixture analyses were generally consistent with prior studies. Approximately 17% of subjects had genetic ancestry from more than one continent, and 12% were genetically admixed, considering only nonadjacent geographical origins. Self-reported whites were spread on a continuum along the first two PCs, indicating extensive mixing among European nationalities. Self-identified East Asian nationalities correlated with genetic clustering, consistent with extensive endogamy. Individuals of mixed East Asian-European genetic ancestry were easily identified; we also observed a modest amount of European genetic ancestry in individuals self-identified as Filipinos. Self-reported African Americans and Latinos showed extensive European and African genetic ancestry, and Native American genetic ancestry for the latter. Among 3741 genetically identified parent-child pairs, 93% were concordant for self-reported race/ethnicity; among 2018 genetically identified full-sib pairs, 96% were concordant; the lower rate for parent-child pairs was largely due to intermarriage. The parent-child pairs revealed a trend toward increasing exogamy over time; the presence in the cohort of individuals endorsing multiple race/ethnicity categories creates interesting challenges and future opportunities for genetic epidemiologic studies.

Published
2015

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