Dehydroepiandrosterone and its sulfate predict the 5-year risk of coronary heart disease events in elderly men

Journal article

Tivesten, Åsa, Vandenput, Liesbeth, Carlzon, Daniel, Nilsson, Maria, Karlsson, Magnus K., Ljunggren, Östen, Barrett-Connor, Elizabeth, Mellström, Dan and Ohlsson, Claes. (2014). Dehydroepiandrosterone and its sulfate predict the 5-year risk of coronary heart disease events in elderly men. Journal of the American College of Cardiology. 64(17), pp. 1801 - 1810. https://doi.org/10.1016/j.jacc.2014.05.076
AuthorsTivesten, Åsa, Vandenput, Liesbeth, Carlzon, Daniel, Nilsson, Maria, Karlsson, Magnus K., Ljunggren, Östen, Barrett-Connor, Elizabeth, Mellström, Dan and Ohlsson, Claes
Abstract

Background: The adrenal sex hormone dehydroepiandrosterone (DHEA), which is present in serum mainly as the sulfate DHEA-S, is the most abundant steroid hormone in human blood. Its levels decline dramatically with age. Despite the great amount of literature on vascular and metabolic actions of DHEA/-S, evidence for an association between DHEA/-S levels and cardiovascular events is contradictory. Objectives: This study tested the hypothesis that serum DHEA and DHEA-S are predictors of major coronary heart disease (CHD) and/or cerebrovascular disease (CBD) events in a large cohort of elderly men. Methods: We used gas and liquid chromatography-mass spectrometry to analyze baseline levels of DHEA and DHEA-S in the prospective population-based Osteoporotic Fractures in Men study in Sweden (2,416 men, ages 69 to 81 years). Complete cardiovascular clinical outcomes were available from national Swedish registers. Results: During the 5-year follow-up, 302 participants experienced a CHD event, and 225 had a CBD event. Both DHEA and DHEA-S levels were inversely associated with the age-adjusted risk of a CHD event; the hazard ratios and 95% confidence intervals per SD increase were 0.82 (0.73 to 0.93) and 0.86 (0.77 to 0.97), respectively. In contrast, DHEA/-S showed no statistically significant association with the risk of CBD events. The association between DHEA and CHD risk remained significant after adjustment for traditional cardiovascular risk factors, serum total testosterone and estradiol, C-reactive protein, and renal function, and remained unchanged after exclusion of the first 2.6 years of follow-up to reduce reverse causality. Conclusions: Low serum levels of DHEA and its sulfate predict an increased risk of CHD, but not CBD, events in elderly men.

Keywordscardiovascular disease; dehydroepiandrosterone; men
Year2014
JournalJournal of the American College of Cardiology
Journal citation64 (17), pp. 1801 - 1810
PublisherElsevier Inc.
ISSN0735-1097
Digital Object Identifier (DOI)https://doi.org/10.1016/j.jacc.2014.05.076
Scopus EID2-s2.0-84908193694
Page range1801 - 1810
Research GroupMary MacKillop Institute for Health Research
Publisher's version
File Access Level
Controlled
Place of publicationUnited States of America
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Genome analyses of > 200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders
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Assessment of the genetic and clinical determinants of fracture risk: Genome wide association and mendelian randomisation study
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Serum DHEA and Its Sulfate Are Associated With Incident Fall Risk in Older Men: The MrOS Sweden study
Ohlsson, Claes, Nethander, Maria, Karlsson, Magnus K., Rosengren, Björn E., Ribom, Eva, Mellström, Dan and Vandenput, Liesbeth. (2018). Serum DHEA and Its Sulfate Are Associated With Incident Fall Risk in Older Men: The MrOS Sweden study. Journal of Bone and Mineral Research. 33(7), pp. 1227 - 1232. https://doi.org/10.1002/jbmr.3418
Genetic determinants of circulating estrogen levels and evidence of a causal effect of estradiol on bone density in men
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The limited clinical utility of testosterone, estradiol, and sex hormone binding globulin measurements in the prediction of fracture risk and bone loss in older men
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Large meta-analysis of genome-wide association studies identifies five loci for lean body mass
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Umbilical cord blood androgen levels in girls and boys assessed by gas chromatography-tandem mass spectrometry
Lundell, Anna-Carin, Ryberg, Henrik, Vandenput, Liesbeth, Rudin, Anna, Ohlsson, Claes and Tivesten, Åsa. (2017). Umbilical cord blood androgen levels in girls and boys assessed by gas chromatography-tandem mass spectrometry. The Journal of Steroid Biochemistry and Molecular Biology. 171, pp. 195 - 200. https://doi.org/10.1016/j.jsbmb.2017.03.022
Increased adipose tissue aromatase activity improves insulin sensitivity and reduces adipose tissue inflammation in male mice
Ohlsson, Claes, Hammarstedt, Ann, Vandenput, Liesbeth, Saarinen, Niina, Ryberg, Henrik, Windahl, Sara H., Farman, Helen H., Jansson, John-Olov, Movérare-Skrtic, Sofia, Smith, Ulf, Zhang, Fu-Ping, Poutanen, Matti, Hedjazifar, Shahram and Sjögren, Klara. (2017). Increased adipose tissue aromatase activity improves insulin sensitivity and reduces adipose tissue inflammation in male mice. American Journal of Physiology - Endocrinology and Metabolism. 313(4), pp. E450 - E462. https://doi.org/10.1152/ajpendo.00093.2017
Low testosterone, but not estradiol, is associated with incident falls in older men: The international MrOS study
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Low-frequency synonymous coding variation in CYP2R1 has large effects on vitamin d levels and risk of multiple sclerosis
Manousaki, Despoina, Dudding, Tom, Haworth, Simon, Hsu, Yi-Hsiang, Liu, Chiang-Ti, Medina-Gómez, Carolina, Voortman, Trudy, van der Velde, Nathalie, Melhus, Håkan, Robinson-Cohen, Cassianne, Cousminer, Diana L., Nethander, Maria, Vandenput, Liesbeth, Noordam, Raymond, Forgetta, Vincenzo, Greenwood, Celia M. T., Biggs, Mary L., Psaty, Bruce M., Rotter, Jerome I., ... Richards, J. Brent. (2017). Low-frequency synonymous coding variation in CYP2R1 has large effects on vitamin d levels and risk of multiple sclerosis. American Journal of Human Genetics. 101(2), pp. 227 - 238. https://doi.org/10.1016/j.ajhg.2017.06.014
Causal relationship between obesity and serum testosterone status in men: A bi-directional mendelian randomization analysis
Eriksson, Joel, Haring, Robin, Grarup, Niels, Vandenput, Liesbeth, Wallaschofski, Henri, Lorentzen, Erik, Hansen, Torben, Mellström, Dan, Pedersen, Oluf, Nauck, Matthias, Lorentzon, Mattias, Husemoen, Lise Lotte Nystrup, Völzke, Henry, Karlsson, Magnus, Baumeister, Sebastian E., Linneberg, Allan and Ohlsson, Claes. (2017). Causal relationship between obesity and serum testosterone status in men: A bi-directional mendelian randomization analysis. PLoS ONE. 12(4), pp. 1 - 15. https://doi.org/10.1371/journal.pone.0176277
Low serum DHEAS predicts increased fracture risk in older men: The MrOS Sweden study
Ohlsson, Claes, Nethander, Maria, Kindmark, Andreas, Ljunggren, Östen, Lorentzon, Mattias, Rosengren, Björn E., Karlsson, Magnus K., Mellström, Dan and Vandenput, Liesbeth. (2017). Low serum DHEAS predicts increased fracture risk in older men: The MrOS Sweden study. Journal of Bone and Mineral Research. 32(8), pp. 1607 - 1614. https://doi.org/10.1002/jbmr.3123
New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
Lu, Yingchang, Day, Felix R., Gustafsson, Stefan, Buchkovich, Martin L., Na, Jianbo, Bataille, Veronique, Cousminer, Diana L., Dastani, Zari, Drong, Alexander W., Esko, Tõnu, Evans, David M., Falchi, Mario, Feitosa, Mary F., Ferreira, Teresa, Hedman, Åsa K., Haring, Robin, Hysi, Pirro G., Iles, Mark M., Justice, Anne E., ... Loos, Ruth J. F.. (2016). New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk. Nature Communications. 7, p. Article 10495. https://doi.org/10.1038/ncomms10495
A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape
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High serum SHBG predicts incident vertebral fractures in elderly men
Vandenput, Liesbeth, Mellström, Dan, Kindmark, Andreas, Johansson, Helena, Lorentzon, Mattias, Leung, Jason, Redlund-Johnell, Inga, Rosengren, Björn E., Karlsson, Magnus K., Wang, Yi-Xiang, Kwok, Timothy and Ohlsson, Claes. (2016). High serum SHBG predicts incident vertebral fractures in elderly men. Journal of Bone and Mineral Research. 31(3), pp. 683 - 689. https://doi.org/10.1002/jbmr.2718
Novel genetic variants associated with increased vertebral volumetric BMD, reduced vertebral fracture risk, and increased expression of SLC1A3 and EPHB2
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The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study
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Genetic studies of body mass index yield new insights for obesity biology
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Hydroxysteroid (17 beta)-dehydrogenase 1–deficient female mice present with normal puberty onset but are severely subfertile due to a defect in luteinization and progesterone production
Hakkarainen, Janne, Jokela, Heli, Pakarinen, Pirjo, Heikelä, Hanna, Kätkänaho, Laura, Vandenput, Liesbeth, Ohlsson, Claes, Zhang, Fu-Ping and Poutanen, Matti. (2015). Hydroxysteroid (17 beta)-dehydrogenase 1–deficient female mice present with normal puberty onset but are severely subfertile due to a defect in luteinization and progesterone production. The FASEB Journal. 29(9), pp. 3806 - 3816. https://doi.org/10.1096/fj.14-269035
Measurement of a comprehensive sex steroid profile in rodent serum by high-sensitive gas chromatography-tandem mass spectrometry
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Sleep duration and disturbances were associated with testosterone level, muscle mass, and muscle strength - A cross-sectional study in 1274 older men
Auyeung, Tung Wai, Kwok, Tung Wai, Leung, Jason, Shun Wah Lee, Jenny, Ohlsson, Claes, Vandenput, Liesbeth, Wing, Yun Kwok and Woo, Jean. (2015). Sleep duration and disturbances were associated with testosterone level, muscle mass, and muscle strength - A cross-sectional study in 1274 older men. Journal of the American Medical Directors Association (JAMDA). 16(7), pp. 630.e1 - 630.e6. https://doi.org/10.1016/j.jamda.2015.04.006
Limited clinical utility of a genetic risk score for the prediction of fracture risk in elderly subjects
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Sex steroid actions in male bone
Vanderschueren, Dirk, Laurent, Michaël R., Claessens, Frank, Gielen, Evelien, Lagerquist, Marie K., Vandenput, Liesbeth, Börjesson, Anna E. and Ohlsson, Claes. (2014). Sex steroid actions in male bone. Endocrine Reviews. 35(6), pp. 906-960. https://doi.org/10.1210/er.2014-1024
Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus
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Serum estradiol levels are inversely associated with cortical porosity in older men
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Serum estradiol associates with blood hemoglobin in elderly men: The MrOS Sweden study
Lewerin, Catharina, Nilsson-Ehle, Herman, Jacobsson, Stefan, Johansson, Helena, Sundh, Valter, Karlsson, Magnus K., Lorentzon, Mattias, Barrett-Connor, Elizabeth, Vandenput, Liesbeth, Ohlsson, Claes and Mellström, Dan. (2014). Serum estradiol associates with blood hemoglobin in elderly men: The MrOS Sweden study. The Journal of Clinical Endocrinology and Metabolism. 99(7), pp. 2549 - 2556. https://doi.org/10.1210/jc.2013-4111
Genome-wide association studies on serum sex steroid levels
Vandenput, Liesbeth and Ohlsson, Claes. (2014). Genome-wide association studies on serum sex steroid levels. Molecular and Cellular Endocrinology. 382(1), pp. 758 - 766. https://doi.org/10.1016/j.mce.2013.03.009
Does bone resorption stimulate periosteal expansion? A cross-sectional analysis of β-C-telopeptides of type i collagen (CTX), genetic markers of the RANKL pathway, and periosteal circumference as measured by pQCT
Kemp, John P., Sayers, Adrian, Paternoster, Lavinia, Evans, David M., Deere, Kevin, St. Pourcain, Beate, Timpson, Nicholas J., Ring, Susan M., Lorentzon, Mattias, Lehtimäki, Terho, Eriksson, Joel, Kähönen, Mika, Raitakari, Olli, Laaksonen, Marika, Sievänen, Harri, Viikari, Jorma, Lyytikäinen, Leo-Pekka, Smith, George Davey, Fraser, William D., ... Tobias, Jon H.. (2014). Does bone resorption stimulate periosteal expansion? A cross-sectional analysis of β-C-telopeptides of type i collagen (CTX), genetic markers of the RANKL pathway, and periosteal circumference as measured by pQCT. Journal of Bone and Mineral Research. 29(4), pp. 1015 - 1024. https://doi.org/10.1002/jbmr.2093
Genetics of endocrine disorders in the era of genome-wide association studies
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Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels
Kwan, Johnny S. H., Hsu, Yi-Hsiang, Cheung, Ching-Lung, Dupuis, Josée, Saint-Pierre, Aude, Eriksson, Joel, Handelman, Samuel K., Aragaki, Aaron K., Karasik, David, Pramstaller, Peter P., Kooperberg, Charles, Lacroix, Andrea Z., Larson, Martin G., Lau, Kam-Shing, Lorentzon, Mattias, Pichler, Irene, Sham, Pak Chung, Taliun, Daniel, Vandenput, Liesbeth, ... Kung, Annie Wai Chee. (2014). Meta-analysis of genome-wide association studies identifies two loci associated with circulating osteoprotegerin levels. Human Molecular Genetics. 23(24), pp. 6684 - 6693. https://doi.org/10.1093/hmg/ddu386
Causal relationship between obesity and vitamin d status : Bi-directional mendelian randomization analysis of multiple cohorts
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Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
Berndt, Sonja I., Gustafsson, Stefan, Mägi, Reedik, Ganna, Andrea, Wheeler, Eleanor, Feitosa, Mary F., Justice, Anne E., Monda, Keri L., Croteau-Chonka, Damien C., Day, Felix R., Esko, Tonu, Fall, Tove, Ferreira, Teresa, Gentilini, Davide, Jackson, Anne U., Luan, Jianan, Randall, Joshua C., Vedantam, Sailaja, Willer, Cristen J., ... Lorentzon, Mattias. (2013). Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. Nature Genetics. 45, pp. 501 - 512. https://doi.org/10.1038/ng.2606
Comparisons of immunoassay and mass spectrometry measurements of serum estradiol levels and their influence on clinical association studies in men
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Assessment of gene-by-sex interaction effect on bone mineral density
Liu, Ching-Ti, Estrada, Karol, Yerges-Armstrong, Laura, Amin, Najaf, Evangelou, Evangelos, Li, Guo, Minster, Ryan L., Carless, Melanie, Kammerer, Candace M., Oei, Ling, Zhou, Yanhua, Alonso, Nerea, Vandenput, Liesbeth, Lorentzon, Karl Mattias, Dailiana, Zoe, Eriksson, Joel, Garcia-Giralt, Natalia, Giroux, Sylvie, Husted, Lise Bjerre, ... al, et. (2012). Assessment of gene-by-sex interaction effect on bone mineral density. Journal of Bone and Mineral Research. 27(10), pp. 2051-2064. https://doi.org/10.1002/jbmr.1679
A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation
Coviello, A.D., Haring, Robin, Wellons, Melissa, Vaidya, Dhananjay, Lehtimaki, Terho, Keildson, S., Lunetta, Kathryn, He, Chunyan, Fornage, Myriam, Lagou, Vasiliki, Mangino, Massimo, Onland-Moret, N. Charlotte, Vandenput, Liesbeth, Lorentzon, Karl Mattias and et. al.. (2012). A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple loci implicated in sex steroid hormone regulation. PLoS Genetics. 8(7), pp. 1-12. https://doi.org/10.1371/journal.pgen.1002805
Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture
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WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk
Zheng, Hou-Feng, Tobias, Jon H., Duncan, Emma, Evans, David M., Eriksson, Joel, Paternoster, Lavinia, Yerges-Armstrong, Laura M., Lehtimäki, Terho, Bergström, Ulrica, Kähönen, Mika, Leo, Paul J., Raitakari, Olli, Laaksonen, Marika, Nicholson, Geoffrey C., Viikari, Jorma, Ladouceur, Martin, Lehtimäki, Leo-Pekka, Medina-Gomez, Carolina, Rivadeneira, Fernando, ... Lorentzon, Mattias. (2012). WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk. PLoS Genetics. 8(7), pp. 1 - 13. https://doi.org/10.1371/journal.pgen.1002745
The role of IGF-1 for fracture risk in men
Vandenput, Liesbeth, Sjögren, Klara, Svensson, Johan and Ohlsson, Claes. (2012). The role of IGF-1 for fracture risk in men. Frontiers in Endocrinology. 3, pp. 1 - 3. https://doi.org/10.3389/fendo.2012.00051
Sex steroids and bone health in men
Ohlsson, Claes, Börjesson, Anna E. and Vandenput, Liesbeth. (2012). Sex steroids and bone health in men. BoneKEy Reports. 1(2), pp. 1 - 7. https://doi.org/10.1038/bonekey.2012.3
Sex steroids and bone health in older Chinese men
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Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus
Medina-Gomez, Carolina, Kemp, John P., Estrada, Karol, Eriksson, Joel, Liu, Jeff, Reppe, Sjur, Evans, David M., Heppe, Denise H. M., Vandenput, Liesbeth, Herrera, Lizbeth, Ring, Susan M., Kruithof, Claudia J., Timpson, Nicholas J., Zillikens, M. Carola, Olstad, Ole K., Zheng, Hou-Feng, Richards, J. Brent, St. Pourcain, Beate, Hofman, Albert, ... Rivadeneira, Fernando. (2012). Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus. PLoS Genetics. 8(7), pp. 1 - 14. https://doi.org/10.1371/journal.pgen.1002718
Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile
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Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms
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Low DHEAS levels are associated with depressive symptoms in elderly Chinese men: results from a large study
Wong, Samuel Y. S., Leung, Jason, Kwok, Timothy, Ohlsson, Claes, Vandenput, Liesbeth, Leung, Ping C. and Woo, Jean. (2011). Low DHEAS levels are associated with depressive symptoms in elderly Chinese men: results from a large study. Asian Journal of Andrology. 13(6), pp. 898 - 902. https://doi.org/10.1038/aja.2011.116
Older men with low serum IGF-1 have an increased risk of incident fractures: The MrOS Sweden study
Ohlsson, Claes, Mellström, Dan, Carlzon, Daniel, Orwoll, Eric, Ljunggren, Östen, Karlsson, Magnus K. and Vandenput, Liesbeth. (2011). Older men with low serum IGF-1 have an increased risk of incident fractures: The MrOS Sweden study. Journal of Bone and Mineral Research. 26(4), pp. 865 - 872. https://doi.org/10.1002/jbmr.281
Testosterone but not estradiol level is positively related to muscle strength and physical performance independent of muscle mass: a cross-sectional study in 1489 older men
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High serum testosterone is associated with reduced risk of cardiovascular events in elderly men - The MrOS (Osteoporotic Fractures in Men) study in Sweden
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