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Gaziano, John

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Gaziano, John
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    Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer
    (2014) Wolpin, Brian M.; Rizzato, Cosmeri; Kraft, Phillip; 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; 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, John; Giese, Nathalia A.; Giovannucci, Edward; 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; 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 H. M.; 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.; Theodoropoulos, George E.; Thornquist, Mark; Tjønneland, Anne; Tobias, Geoffrey S.; Trichopoulos, Dimitrios; Vodicka, Pavel; Wactawski-Wende, Jean; Wentzensen, Nicolas; Wu, Chen; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Hoover, Robert; Hartge, Patricia; Fuchs, Charles; Chanock, Stephen J.; Stolzenberg-Solomon, Rachael S.; Amundadottir, Laufey T.
    We performed a multistage genome-wide association study (GWAS) 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). An independent signal was identified 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 has identified multiple new susceptibility alleles for pancreatic cancer worthy of follow-up studies.
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    Television Viewing Time, Physical Activity, and Mortality Among African Americans
    (Centers for Disease Control and Prevention, 2018) Imran, Tasnim F.; Ommerborn, Mark; Clark, Cheryl; Correa, Adolfo; Dubbert, Patricia; Gaziano, John; Djousse, Luc
    Background: Prolonged television viewing time, a marker of sedentary activity, is independently associated with increased all-cause mortality; however, this association has rarely been studied in African Americans. The objective of our study was to examine the association between television viewing time and mortality among African Americans by using data from the Jackson Heart Study (JHS). Methods: We studied 5,289 participants from the JHS study who reported television viewing time (h/day) in the JHS baseline questionnaire from 2000 through 2004. Using multivariable Cox regression models adjusted for age, sex, smoking, alcohol use, physical activity, nutrition, prevalent coronary heart disease, chronic kidney disease, diabetes, and hypertension, we computed hazard ratios to examine the association between television viewing time (≤2 h/day, 2–4 h/day, and ≥4 h/day) and mortality. Results: Participants had a mean age of 55 years, and 64% were women. After a median follow-up of 9.9 years (interquartile range, 9.0–10.7), 615 deaths occurred (data analysis conducted in 2017). Hazard ratios for mortality were 1.08 (0.86–1.37) for television time of 2 to 4 hours per day and 1.48 (95% CI: 1.19–1.83) for television time of greater than or equal to 4 hours per day when compared with those who watched television less than 2 hours per day (P trend = .002). When we restricted analyses to those who performed leisure-time activities, the hazard ratios for mortality were 1.10 (95% CI, 0.84–1.45) for television viewing of 2 to 4 hours per day and 1.45 (95% CI, 1.13–1.86) for more than 4 hours per day compared with the less than 2 hours per day. Conclusion: Our findings suggest that greater television viewing time, even among those who perform leisure-time physical activities, is associated with increased all-cause mortality among African Americans. Thus, it may serve as an indicator of a sedentary lifestyle with potential for intervention.
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    Association between Class III Obesity (BMI of 40–59 kg/m2) and Mortality: A Pooled Analysis of 20 Prospective Studies
    (Public Library of Science, 2014) Kitahara, Cari M.; Flint, Alan; Berrington de Gonzalez, Amy; Bernstein, Leslie; Brotzman, Michelle; MacInnis, Robert J.; Moore, Steven C.; Robien, Kim; Rosenberg, Philip S.; Singh, Pramil N.; Weiderpass, Elisabete; Adami, Hans Olov; Anton-Culver, Hoda; Ballard-Barbash, Rachel; Buring, Julie; Freedman, D. Michal; Fraser, Gary E.; Beane Freeman, Laura E.; Gapstur, Susan M.; Gaziano, John; Giles, Graham G.; Håkansson, Niclas; Hoppin, Jane A.; Hu, Frank; Koenig, Karen; Linet, Martha S.; Park, Yikyung; Patel, Alpa V.; Purdue, Mark P.; Schairer, Catherine; Sesso, Howard; Visvanathan, Kala; White, Emily; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Hartge, Patricia
    Background: The prevalence of class III obesity (body mass index [BMI]≥40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity. Methods and Findings: In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19–83 y at baseline, classified as obese class III (BMI 40.0–59.9 kg/m2) compared with those classified as normal weight (BMI 18.5–24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976–2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40–44.9, 45–49.9, 50–54.9, and 55–59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7–7.3), 8.9 (95% CI: 7.4–10.4), 9.8 (95% CI: 7.4–12.2), and 13.7 (95% CI: 10.5–16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report. Conclusions: Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight. Please see later in the article for the Editors' Summary
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    Aspirin Use and Risk of Atrial Fibrillation in the Physicians' Health Study
    (Blackwell Publishing Ltd, 2014) Ofman, Peter; Petrone, Andrew B.; Peralta, Adelqui; Hoffmeister, Peter; Albert, Christine; Djousse, Luc; Gaziano, John; Rahilly‐Tierney, Catherine R.
    Background: Inflammatory processes have been associated with an increased risk of atrial fibrillation (AF), potentially allowing for preventive therapy by anti‐inflammatory agents such as aspirin. However, the effect of chronic aspirin on the incidence of AF has not been evaluated in a prospective cohort followed for an extended period. Methods and Results: This study was comprised of a prospective cohort of 23 480 male participants of the Physicians' Health Study. Aspirin intake and covariates were estimated using self‐reported questionnaires. Incident AF was ascertained through yearly follow‐up questionnaires. Cox's regression, with adjustment for multiple covariates, was used to estimate relative risk of AF. Average age at baseline was 65.1±8.9 years. During a mean follow‐up of 10.0 years, 2820 cases of AF were reported. Age‐standardized incidence rates were 12.6, 11.1, 12.7, 11.3, 15.8, and 13.8/1000 person‐years for people reporting baseline aspirin intake of 0, <14 days per year, 14 to 30 days per year, 30 to 120 days per year, 121 to 180 days per year, and >180 days per year, respectively. Multivariable adjusted hazard ratios (95% confidence interval) for incident AF were 1.00 (reference), 0.88 (0.76 to 1.02), 0.93 (0.76 to 1.14), 0.96 (0.80 to 1.14), 1.07 (0.80 to 1.14), and 1.04 (0.94 to 1.15) across consecutive categories of aspirin intake. Analysis of the data using time‐varying Cox's regression model to update aspirin intake over time showed similar results. Conclusions: In a large cohort of males followed for a long period, we did not find any association between aspirin use and incident AF.
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    Fried Food Consumption and Cardiovascular Health: A Review of Current Evidence
    (MDPI, 2015) Gadiraju, Taraka V.; Patel, Yash; Gaziano, John; Djousse, Luc
    Fried food consumption and its effects on cardiovascular disease are still subjects of debate. The objective of this review was to summarize current evidence on the association between fried food consumption and cardiovascular disease, diabetes, hypertension and obesity and to recommend directions for future research. We used PubMed, Google Scholar and Medline searches to retrieve pertinent publications. Most available data were based on questionnaires as a tool to capture fried food intakes, and study design was limited to case-control and cohort studies. While few studies have reported a positive association between frequencies of fried food intake and risk of coronary artery disease, heart failure, diabetes or hypertension, other investigators have failed to confirm such an association. There is strong evidence suggesting a higher risk of developing chronic disease when fried foods are consumed more frequently (i.e., four or more times per week). Major gaps in the current literature include a lack of detailed information on the type of oils used for frying foods, stratification of the different types of fried food, frying procedure (deep and pan frying), temperature and duration of frying, how often oils were reused and a lack of consideration of overall dietary patterns. Besides addressing these gaps, future research should also develop tools to better define fried food consumption at home versus away from home and to assess their effects on chronic diseases. In summary, the current review provides enough evidence to suggest adverse health effects with higher frequency of fried food consumption. While awaiting confirmation from future studies, it may be advisable to the public to consume fried foods in moderation while emphasizing an overall healthy diet.
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    Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
    (Nature Publishing Group, 2016) Machiela, Mitchell J.; Zhou, Weiyin; Karlins, Eric; Sampson, Joshua N.; Freedman, Neal D.; Yang, Qi; Hicks, Belynda; Dagnall, Casey; Hautman, Christopher; Jacobs, Kevin B.; Abnet, Christian C.; Aldrich, Melinda C.; Amos, Christopher; Amundadottir, Laufey T.; Arslan, Alan A.; Beane-Freeman, Laura E.; Berndt, Sonja I.; Black, Amanda; Blot, William J.; Bock, Cathryn H.; Bracci, Paige M.; Brinton, Louise A.; Bueno-de-Mesquita, H Bas; Burdett, Laurie; Buring, Julie E.; Butler, Mary A.; Canzian, Federico; Carreón, Tania; Chaffee, Kari G.; Chang, I-Shou; Chatterjee, Nilanjan; Chen, Chu; Chen, Constance; Chen, Kexin; Chung, Charles C.; Cook, Linda S.; Crous Bou, Marta; Cullen, Michael; Davis, Faith G.; De Vivo, Immaculata; Ding, Ti; Doherty, Jennifer; Duell, Eric J.; Epstein, Caroline G.; Fan, Jin-Hu; Figueroa, Jonine D.; Fraumeni, Joseph F.; Friedenreich, Christine M.; Fuchs, Charles; Gallinger, Steven; Gao, Yu-Tang; Gapstur, Susan M.; Garcia-Closas, Montserrat; Gaudet, Mia M.; Gaziano, John; Giles, Graham G.; Gillanders, Elizabeth M.; Giovannucci, Edward; Goldin, Lynn; Goldstein, Alisa M.; Haiman, Christopher A.; Hallmans, Goran; Hankinson, Susan; Harris, Curtis C.; Henriksson, Roger; Holly, Elizabeth A.; Hong, Yun-Chul; Hoover, Robert N.; Hsiung, Chao A.; Hu, Nan; Hu, Wei; Hunter, David; Hutchinson, Amy; Jenab, Mazda; Johansen, Christoffer; Khaw, Kay-Tee; Kim, Hee Nam; Kim, Yeul Hong; Kim, Young Tae; Klein, Alison P.; Klein, Robert; Koh, Woon-Puay; Kolonel, Laurence N.; Kooperberg, Charles; Kraft, Phillip; Krogh, Vittorio; Kurtz, Robert C.; LaCroix, Andrea; Lan, Qing; Landi, Maria Teresa; Marchand, Loic Le; Li, Donghui; Liang, Xiaolin; Liao, Linda M.; Lin, Dongxin; Liu, Jianjun; Lissowska, Jolanta; Lu, Lingeng; Magliocco, Anthony M.; Malats, Nuria; Matsuo, Keitaro; McNeill, Lorna H.; McWilliams, Robert R.; Melin, Beatrice S.; Mirabello, Lisa; Moore, Lee; Olson, Sara H.; Orlow, Irene; Park, Jae Yong; Patiño-Garcia, Ana; Peplonska, Beata; Peters, Ulrike; Petersen, Gloria M.; Pooler, Loreall; Prescott, Jennifer; Prokunina-Olsson, Ludmila; Purdue, Mark P.; Qiao, You-Lin; Rajaraman, Preetha; Real, Francisco X.; Riboli, Elio; Risch, Harvey A.; Rodriguez-Santiago, Benjamin; Ruder, Avima M.; Savage, Sharon A.; Schumacher, Fredrick; Schwartz, Ann G.; Schwartz, Kendra L.; Seow, Adeline; Wendy Setiawan, Veronica; Severi, Gianluca; Shen, Hongbing; Sheng, Xin; Shin, Min-Ho; Shu, Xiao-Ou; Silverman, Debra T.; Spitz, Margaret R.; Stevens, Victoria L.; Stolzenberg-Solomon, Rachael; Stram, Daniel; Tang, Ze-Zhong; Taylor, Philip R.; Teras, Lauren R.; Tobias, Geoffrey S.; Van Den Berg, David; Visvanathan, Kala; Wacholder, Sholom; Wang, Jiu-Cun; Wang, Zhaoming; Wentzensen, Nicolas; Wheeler, William; White, Emily; Wiencke, John K.; Wolpin, Brian M.; Wong, Maria Pik; Wu, Chen; Wu, Tangchun; Wu, Xifeng; Wu, Yi-Long; Wunder, Jay S.; Xia, Lucy; Yang, Hannah P.; Yang, Pan-Chyr; Yu, Kai; Zanetti, Krista A.; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Zhou, Baosen; Ziegler, Regina G.; Perez-Jurado, Luis A.; Caporaso, Neil E.; Rothman, Nathaniel; Tucker, Margaret; Dean, Michael C.; Yeager, Meredith; Chanock, Stephen J.
    To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
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    Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure
    (Public Library of Science, 2016) Smith, J. Gustav; Felix, Janine F.; Morrison, Alanna C.; Kalogeropoulos, Andreas; Trompet, Stella; Wilk, Jemma B.; Gidlöf, Olof; Wang, Xinchen; Morley, Michael; Mendelson, Michael; Joehanes, Roby; Ligthart, Symen; Shan, Xiaoyin; Bis, Joshua C.; Wang, Ying A.; Sjögren, Marketa; Ngwa, Julius; Brandimarto, Jeffrey; Stott, David J.; Aguilar, David; Rice, Kenneth M.; Sesso, Howard; Demissie, Serkalem; Buckley, Brendan M.; Taylor, Kent D.; Ford, Ian; Yao, Chen; Liu, Chunyu; Sotoodehnia, Nona; van der Harst, Pim; Stricker, Bruno H. Ch.; Kritchevsky, Stephen B.; Liu, Yongmei; Gaziano, John; Hofman, Albert; Moravec, Christine S.; Uitterlinden, André G.; Kellis, Manolis; van Meurs, Joyce B.; Margulies, Kenneth B.; Dehghan, Abbas; Levy, Daniel; Olde, Björn; Psaty, Bruce M.; Cupples, L. Adrienne; Jukema, J. Wouter; Djousse, Luc; Franco, Oscar H.; Boerwinkle, Eric; Boyer, Laurie A.; Newton-Cheh, Christopher; Butler, Javed; Vasan, Ramachandran S.; Cappola, Thomas P.; Smith, Nicholas L.
    Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.
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    Consumption of Fried Foods and Risk of Heart Failure in the Physicians' Health Study
    (Blackwell Publishing Ltd, 2015) Djousse, Luc; Petrone, Andrew B.; Gaziano, John
    Background: Consumption of fried foods is highly prevalent in the Western dietary pattern. Though limited studies have reported a positive association between frequency of fried food intake and risk of coronary artery disease, diabetes, or hypertension, other investigators failed to report such an association. It is unclear whether intake of fried foods is associated with a higher risk of heart failure (HF). Hence, we sought to examine the association between the frequency of fried food consumption and the risk of HF. Methods and Results: This was a prospective cohort study of 15 362 participants from the Physicians' Health Study. Fried food intake frequency was assessed by a food frequency questionnaire (1997–2001), and incident HF was captured by annual questionnaires. We used Cox regression to calculate hazard ratios (HRs) of HF. After an average follow‐up of 9.6±2.4 years, a total of 632 new HF cases occurred in this cohort. Compared to subjects who reported fried food consumption of <1 per week, HRs (95% CI) for HF were 1.24 (1.04 to 1.48), 1.28 (1.00 to 1.63), and 2.03 (1.37 to 3.02) for fried food intake of 1 to 3/week, 4 to 6/week, and 7+/week, respectively, after adjustment for age, energy intake, alcohol use, exercise, smoking, and overall diet score (P linear trend, 0.0002). Similar results were obtained for intake of fried foods at home or away from home and among subjects with higher dietary score or HF without antecedent myocardial infarction. Conclusions: Our data are consistent with a positive association of fried food intake frequency with incident HF in male physicians.
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    Elevated circulating branched chain amino acids are an early event in pancreatic adenocarcinoma development
    (2014) Mayers, Jared R.; Wu, Chen; Clish, Clary B.; Kraft, Phillip; Torrence, Margaret E.; Fiske, Brian P.; Yuan, Chen; Bao, Ying; Townsend, Mary K.; Tworoger, Shelley; Davidson, Shawn M.; Papagiannakopoulos, Thales; Yang, Annan; Dayton, Talya L.; Ogino, Shuji; Stampfer, Meir; Giovannucci, Edward; Qian, Zhi Rong; Rubinson, Douglas; Ma, Jing; Sesso, Howard; Gaziano, John; Cochrane, Barbara B.; Liu, Simin; Wactawski–Wende, Jean; Manson, JoAnn; Pollak, Michael N.; Kimmelman, Alec C.; Souza, Amanda; Pierce, Kerry; Wang, Thomas J.; Gerszten, Robert; Fuchs, Charles; Heiden, Matthew G. Vander; Wolpin, Brian M.
    Most patients with pancreatic ductal adenocarcinoma (PDAC) are diagnosed with advanced disease and survive less than 12 months1. PDAC has been linked with obesity and glucose intolerance2-4, but whether changes in circulating metabolites are associated with early cancer progression is unknown. To better understand metabolic derangements associated with early disease, we profiled metabolites in prediagnostic plasma from pancreatic cancer cases and matched controls from four prospective cohort studies. We find that elevated plasma levels of branched chain amino acids (BCAAs) are associated with a greater than 2–fold increased risk of future pancreatic cancer diagnosis. This elevated risk was independent of known predisposing factors, with the strongest association observed among subjects with samples collected 2 to 5 years prior to diagnosis when occult disease is likely present. We show that plasma BCAAs are also elevated in mice with early stage pancreatic cancers driven by mutant Kras expression, and that breakdown of tissue protein accounts for the increase in plasma BCAAs that accompanies early stage disease. Together, these findings suggest that increased whole–body protein breakdown is an early event in development of PDAC.
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    Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
    (Nature Publishing Group, 2016) Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry; Ingles, Sue A.; Kittles, Rick A.; Strom, Sara S.; Rybicki, Benjamin A.; Nemesure, Barbara; Isaacs, William B.; Zheng, Wei; Pettaway, Curtis A.; Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P.; John, Esther M.; Murphy, Adam B.; Signorello, Lisa B; Carpten, John; Leske, M. Cristina; Wu, Suh-Yuh; Hennis, Anslem J. M.; Neslund-Dudas, Christine; Hsing, Ann W.; Chu, Lisa; Goodman, Phyllis J.; Klein, Eric A.; Witte, John S.; Casey, Graham; Kaggwa, Sam; Cook, Michael B.; Stram, Daniel O.; Blot, William J.; Eeles, Rosalind A.; Easton, Douglas; Kote-Jarai, ZSofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G.; Southey, Melissa C.; Fitzgerald, Liesel M.; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E.; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L. J.; Nordestgaard, Børge G.; Key, Tim J.; Travis, Ruth C.; Neal, David E.; Donovan, Jenny L.; Hamdy, Freddie C.; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L.; Thibodeau, Stephen N.; McDonnell, Shannon K.; Schaid, Daniel J.; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S.; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Teerlink, Craig; Brenner, Hermann; Dieffenbach, Aida K.; Arndt, Volker; Park, Jong Y.; Sellers, Thomas A.; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A.; Teixeira, Manuel R.; Pandha, Hardev; Michael, Agnieszka; Paulo, Paula; Maia, Sofia; Kierzek, Andrzej; Cook, Margaret; Guy, Michelle; Govindasami, Koveela; Leongamornlert, Daniel; Sawyer, Emma J.; Wilkinson, Rosemary; Saunders, Edward J.; Tymrakiewicz, Malgorzata; Dadaev, Tokhir; Morgan, Angela; Fisher, Cyril; Hazel, Steve; Livni, Naomi; Lophatananon, Artitaya; Pedersen, John; Hopper, John L.; Adolfson, Jan; Stattin, Paer; Johansson, Jan-Erik; Cavalli-Bjoerkman, Carin; Karlsson, Ami; Broms, Michael; Auvinen, Anssi; Kujala, Paula; Maeaettaenen, Liisa; Murtola, Teemu; Taari, Kimmo; Weischer, Maren; Nielsen, Sune F.; Klarskov, Peter; Roder, Andreas; Iversen, Peter; Wallinder, Hans; Gustafsson, Sven; Cox, Angela; Brown, Paul; George, Anne; Marsden, Gemma; Lane, Athene; Davis, Michael; Tillmans, Lori; Riska, Shaun; Wang, Liang; Rinckleb, Antje; Lubiski, Jan; Stegmaier, Christa; Pow-Sang, Julio; Park, Hyun; Radlein, Selina; Rincon, Maria; Haley, James; Zachariah, Babu; Kachakova, Darina; Popov, Elenko; Mitkova, Atanaska; Vlahova, Aleksandrina; Dikov, Tihomir; Christova, Svetlana; Heathcote, Peter; Wood, Glenn; Malone, Greg; Saunders, Pamela; Eckert, Allison; Yeadon, Trina; Kerr, Kris; Collins, Angus; Turner, Megan; Srinivasan, Srilakshmi; Kedda, Mary-Anne; Alexander, Kimberly; Omara, Tracy; Wu, Huihai; Henrique, Rui; Pinto, Pedro; Santos, Joana; Barros-Silva, Joao; Conti, David V.; Albanes, Demetrius; Berg, Christine; Berndt, Sonja I.; Campa, Daniele; Crawford, E. David; Diver, W. Ryan; Gapstur, Susan M.; Gaziano, John; Giovannucci, Edward; Hoover, Robert; Hunter, David; Johansson, Mattias; Kraft, Phillip; Le Marchand, Loic; Lindström, Sara; Navarro, Carmen; Overvad, Kim; Riboli, Elio; Siddiq, Afshan; Stevens, Victoria L.; Trichopoulos, Dimitrios; Vineis, Paolo; Yeager, Meredith; Trynka, Gosia; Raychaudhuri, Soumya; Schumacher, Frederick R.; Price, Alkes; Freedman, Matthew; Haiman, Christopher A.; Pasaniuc, Bogdan
    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.