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1. Advanced maternal age impacts physiologic adaptations to pregnancy in vervet monkeys

Author

Beth Uberseder, Matthew J. Jorgensen, Chrissy Sherrill, Alistaire Ruggiero, Kylie Kavanagh, Rachel Jeffries, Cecilia Armstrong, Matthew A. Quinn, Justin Nevarez, and Maren Plant

Subjects
Aging, Offspring, Physiology, Blood Pressure, Preeclampsia, Pregnancy, parasitic diseases, Chlorocebus aethiops, medicine, Animals, Advanced maternal age, Leukocytosis, medicine.diagnostic_test, business.industry, Complete blood count, medicine.disease, Adaptation, Physiological, Blood pressure, Phenotype, Female, Original Article, African Green Monkey, Geriatrics and Gerontology, medicine.symptom, business, Maternal Age
Abstract

The trend to delay pregnancy in the USA has resulted in the number of advanced maternal age (AMA) pregnancies to also increase. In humans, AMA is associated with a variety of pregnancy-related pathologies such as preeclampsia (PE). While AMA is known to be a factor which contributes to the development of pregnancy-induced diseases, the molecular and cellular mechanisms giving rise to this phenomenon are still very limited. This is due in part to lack of a preclinical model which has physiologic relevance to human pregnancy while also allowing control of environmental and genetic variability inherent in human studies. To determine potential physiologic relevance of the vervet/African green monkey (Chlorocebus aethiops sabaeus) as a preclinical model to study the effects of AMA on adaptations to pregnancy, thirteen age-diverse pregnant vervet monkeys (3–16 years old) were utilized to measure third trimester blood pressure (BP), complete blood count, iron measurements, and hormone levels. Significant associations were observed between third trimester diastolic BP and maternal age. Furthermore, the presence of leukocytosis with enhanced circulating neutrophils was observed in AMA mothers compared to younger mothers. Moreover, we observed a negative relationship between maternal age and estradiol, progesterone, and cortisol levels. Finally, offspring born to AMA mothers displayed a postnatal growth retardation phenotype. These studies demonstrate physiologic impairment in the adaptation to pregnancy in AMA vervet/African green monkeys. Our data indicate that the vervet/African green monkey may serve as a useful preclinical model and tool for deciphering pathological mediators of maternal disease in AMA pregnancy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11357-020-00219-8) contains supplementary material, which is available to authorized users.

Published
2020

2. Impact of Advanced Maternal Age on Physiologic Adaptations to Pregnancy in Vervet Monkeys

Author

Justin Nevarez, Cecilia Armstrong, Matthew A. Quinn, Maren Plant, Alistaire Ruggiero, Kylie Kavanagh, Rachel Jeffries, Beth Uberseder, Chrissy Sherrill, and Matthew J. Jorgensen

Subjects
Pregnancy, 030219 obstetrics & reproductive medicine, medicine.diagnostic_test, business.industry, Offspring, Complete blood count, Physiology, Context (language use), 030204 cardiovascular system & hematology, medicine.disease, Preeclampsia, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, medicine, Advanced maternal age, Leukocytosis, African Green Monkey, medicine.symptom, business
Abstract

ContextThe trend to delay pregnancy in the United States has resulted in the number of advanced maternal age (AMA) pregnancies to also increase. In humans, AMA is associated with a variety of pregnancy-related pathologies such as preeclampsia (PE). While AMA is known to be a factor which contributes to the development of pregnancy-induced diseases, the molecular and cellular mechanisms giving rise to this phenomenon are still very limited. This is due in part to lack of a pre-clinical model which has physiologic relevance to human pregnancy while also allowing control of environmental and genetic variability inherent in human studies.ObjectiveTo determine potential physiologic relevance of the vervet/African green monkey (Chlorocebus aethiops sabaeus)as a pre-clinical model to study the effects of AMA on adaptations to pregnancy.DesignThirteen age-diverse pregnant vervet monkeys (3-16 y.o.) were utilized to measure third trimester blood pressure (BP), complete blood count, iron measurements and hormone levels.ResultsSignificant associations were observed between third trimester diastolic BP and maternal age. Furthermore, the presence of leukocytosis with enhanced circulating neutrophils was observed in AMA mothers compared to younger mothers. Moreover, we observed a negative relationship between maternal age and estradiol, progesterone and cortisol levels. Finally, offspring born to AMA mothers displayed a postnatal growth retardation phenotype.ConclusionsThese studies demonstrate physiologic impairment in the adaptation to pregnancy in AMA vervet/African green monkeys. Our data indicate the vervet/African green monkey may serve as a useful pre-clinical model and tool for deciphering pathological mediators of maternal disease in AMA pregnancy.

Published
2020

3. Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types

Author

Sampson, Joshua N. Wheeler, William A. Yeager, Meredith and Panagiotou, Orestis Wang, Zhaoming Berndt, Sonja I. Lan, Qing Abnet, Christian C. Amundadottir, Laufey T. Figueroa, Jonine D. Landi, Maria Teresa Mirabello, Lisa Savage, Sharon A. Taylor, Philip R. De Vivo, Immaculata McGlynn, Katherine A. Purdue, Mark P. Rajaraman, Preetha Adami, Hans-Olov and Ahlbom, Anders Albanes, Demetrius Amary, Maria Fernanda An, She-Juan Andersson, Ulrika Andriole, Jr., Gerald Andrulis, Irene L. Angelucci, Emanuele Ansell, Stephen M. Arici, Cecilia Armstrong, Bruce K. Arslan, Alan A. Austin, Melissa A. Baris, Dalsu Barkauskas, Donald A. Bassig, Bryan A. and Becker, Nikolaus Benavente, Yolanda Benhamou, Simone Berg, Christine Van Den Berg, David Bernstein, Leslie Bertrand, Kimberly A. Birmann, Brenda M. Black, Amanda Boeing, Heiner and Boffetta, Paolo Boutron-Ruault, Marie-Christine Bracci, Paige M. Brinton, Louise Brooks-Wilson, Angela R. and Bueno-de-Mesquita, H. Bas Burdett, Laurie Buring, Julie and Butler, Mary Ann Cai, Qiuyin Cancel-Tassin, Geraldine and Canzian, Federico Carrato, Alfredo Carreon, Tania Carta, Angela Chan, John K. C. Chang, Ellen T. Chang, Gee-Chen and Chang, I-Shou Chang, Jiang Chang-Claude, Jenny Chen, Chien-Jen Chen, Chih-Yi Chen, Chu Chen, Chung-Hsing and Chen, Constance Chen, Hongyan Chen, Kexin Chen, Kuan-Yu and Chen, Kun-Chieh Chen, Ying Chen, Ying-Hsiang Chen, Yi-Song and Chen, Yuh-Min Chien, Li-Hsin Chirlaque, Maria-Dolores and Choi, Jin Eun Choi, Yi Young Chow, Wong-Ho Chung, Charles C. and Clavel, Jacqueline Clavel-Chapelon, Franoise Cocco, Pierluigi Colt, Joanne S. Comperat, Eva Conde, Lucia and Connors, Joseph M. Conti, David Cortessis, Victoria K. and Cotterchio, Michelle Cozen, Wendy Crouch, Simon Crous-Bou, Marta Cussenot, Olivier Davis, Faith G. Ding, Ti Diver, W. Ryan Dorronsoro, Miren Dossus, Laure Duell, Eric J. and Ennas, Maria Grazia Erickson, Ralph L. Feychting, Maria and Flanagan, Adrienne M. Foretova, Lenka Fraumeni, Jr., Joseph F. and Freedman, Neal D. Freeman, Laura E. Beane Fuchs, Charles and Gago-Dominguez, Manuela Gallinger, Steven Gao, Yu-Tang and Gapstur, Susan M. Garcia-Closas, Montserrat Garcia-Closas, Reina and Gascoyne, Randy D. Gastier-Foster, Julie Gaudet, Mia M. and Gaziano, J. Michael Giffen, Carol Giles, Graham G. and Giovannucci, Edward Glimelius, Bengt Goggins, Michael and Gokgoz, Nalan Goldstein, Alisa M. Gorlick, Richard Gross, Myron Grubb, III, Robert Gu, Jian Guan, Peng Gunter, Marc Guo, Huan Habermann, Thomas M. Haiman, Christopher A. and Halai, Dina Hallmans, Goran Hassan, Manal Hattinger, Claudia He, Qincheng He, Xingzhou Helzlsouer, Kathy and Henderson, Brian Henriksson, Roger Hjalgrim, Henrik and Hoffman-Bolton, Judith Hohensee, Chancellor Holford, Theodore R. and Holly, Elizabeth A. Hong, Yun-Chul Hoover, Robert N. and Horn-Ross, Pamela L. Hosain, G. M. Monawar Hosgood, III, H. Dean and Hsiao, Chin-Fu Hu, Nan Hu, Wei Hu, Zhibin Huang, Ming-Shyan Huerta, Jose-Maria Hung, Jen-Yu Hutchinson, Amy and Inskip, Peter D. Jackson, Rebecca D. Jacobs, Eric J. and Jenab, Mazda Jeon, Hyo-Sung Ji, Bu-Tian Jin, Guangfu and Jin, Li Johansen, Christoffer Johnson, Alison Jung, Yoo Jin and Kaaks, Rudolph Kamineni, Aruna Kane, Eleanor Kang, Chang Hyun Karagas, Margaret R. Kelly, Rachel S. Khaw, Kay-Tee and Kim, Christopher Kim, Hee Nam Kim, Jin Hee Kim, Jun Suk and Kim, Yeul Hong Kim, Young Tae Kim, Young-Chul Kitahara, Cari M. Klein, Alison P. Klein, Robert J. Kogevinas, Manolis and Kohno, Takashi Kolonel, Laurence N. Kooperberg, Charles and Kricker, Anne Krogh, Vittorio Kunitoh, Hideo Kurtz, Robert C. Kweon, Sun-Seog LaCroix, Andrea Lawrence, Charles and Lecanda, Fernando Lee, Victor Ho Fun Li, Donghui Li, Haixin and Li, Jihua Li, Yao-Jen Li, Yuqing Liao, Linda M. and Liebow, Mark Lightfoot, Tracy Lim, Wei-Yen Lin, Chien-Chung and Lin, Dongxin Lindstrom, Sara Linet, Martha S. Link, Brian K. Liu, Chenwei Liu, Jianjun Liu, Li Ljungberg, Boerje Lloreta, Josep Di Lollo, Simonetta Lu, Daru Lund, Eiluv Malats, Nuria Mannisto, Satu Le Marchand, Loic and Marina, Neyssa Masala, Giovanna Mastrangelo, Giuseppe and Matsuo, Keitaro Maynadie, Marc Mckay, James McKean-Cowdin, Roberta Melbye, Mads Melin, Beatrice S. Michaud, Dominique S. Mitsudomi, Tetsuya Monnereau, Alain Montalvan, Rebecca and Moore, Lee E. Mortensen, Lotte Maxild Nieters, Alexandra and North, Kari E. Novak, Anne J. Oberg, Ann L. Offit, Kenneth and Oh, In-Jae Olson, Sara H. Palli, Domenico Pao, William and Park, In Kyu Park, Jae Yong Park, Kyong Hwa and Patino-Garcia, Ana Pavanello, Sofia Peeters, Petra H. M. and Perng, Reury-Perng Peters, Ulrike Petersen, Gloria M. Picci, Piero Pike, Malcolm C. Porru, Stefano Prescott, Jennifer and Prokunina-Olsson, Ludmila Qian, Biyun Qiao, You-Lin Rais, Marco Riboli, Elio Riby, Jacques Risch, Harvey A. and Rizzato, Cosmeri Rodabough, Rebecca Roman, Eve Roupret, Morgan Ruder, Avima M. de Sanjose, Silvia Scelo, Ghislaine and Schned, Alan Schumacher, Fredrick Schwartz, Kendra and Schwenn, Molly Scotlandi, Katia Seow, Adeline Serra, Consol and Serra, Massimo Sesso, Howard D. Setiawan, Veronica Wendy and Severi, Gianluca Severson, Richard K. Shanafelt, Tait D. and Shen, Hongbing Shen, Wei Shin, Min-Ho Shiraishi, Kouya and Shu, Xiao-Ou Siddiq, Afshan Sierrasesumaga, Luis Sihoe, Alan Dart Loon Skibola, Christine F. Smith, Alex Smith, Martyn T. and Southey, Melissa C. Spinelli, John J. Staines, Anthony and Stampfer, Meir Stern, Marianna C. Stevens, Victoria L. and Stolzenberg-Solomon, Rachael S. Su, Jian Su, Wu-Chou Sund, Malin Sung, Jae Sook Sung, Sook Whan Tan, Wen Tang, Wei and Tardon, Adonina Thomas, David Thompson, Carrie A. and Tinker, Lesley F. Tirabosco, Roberto Tjonneland, Anne and Travis, Ruth C. Trichopoulos, Dimitrios Tsai, Fang-Yu Tsai, Ying-Huang Tucker, Margaret Turner, Jenny Vajdic, Claire M. and Vermeulen, Roel C. H. Villano, Danylo J. Vineis, Paolo and Virtamo, Jarmo Visvanathan, Kala Wactawski-Wende, Jean Wang, Chaoyu Wang, Chih-Liang Wang, Jiu-Cun Wang, Junwen Wei, Fusheng Weiderpass, Elisabete Weiner, George J. Weinstein, Stephanie Wentzensen, Nicolas White, Emily Witzig, Thomas E. and Wolpin, Brian M. Wong, Maria Pik Wu, Chen Wu, Guoping and Wu, Junjie Wu, Tangchun Wu, Wei Wu, Xifeng Wu, Yi-Long Wunder, Jay S. Xiang, Yong-Bing Xu, Jun Xu, Ping and Yang, Pan-Chyr Yang, Tsung-Ying Ye, Yuanqing Yin, Zhihua and Yokota, Jun Yoon, Ho-Il Yu, Chong-Jen Yu, Herbert and Yu, Kai Yuan, Jian-Min Zelenetz, Andrew Zeleniuch-Jacquotte, Anne Zhang, Xu-Chao Zhang, Yawei Zhao, Xueying Zhao, Zhenhong Zheng, Hong Zheng, Tongzhang Zheng, Wei Zhou, Baosen Zhu, Meng Zucca, Mariagrazia Boca, Simina M. and Cerhan, James R. Ferri, Giovanni M. Hartge, Patricia Hsiung, Chao Agnes Magnani, Corrado Miligi, Lucia Morton, Lindsay M. and Smedby, Karin E. Teras, Lauren R. Vijai, Joseph Wang, Sophia S. Brennan, Paul Caporaso, Neil E. Hunter, David J. and Kraft, Peter Rothman, Nathaniel Silverman, Debra T. and Slager, Susan L. Chanock, Stephen J. Chatterjee, Nilanjan

Abstract

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

Published
2015

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