Genetic makeup affects testosterone concentrations in men

Genetics play an important role in the variation in, and risk of, low testosterone concentrations in men. A study by the CHARGE Sex Hormone Consortium, published in the open-access journal PLoS Genetics on Thursday, 6th October, is the first genome-wide association study to examine the effects of common genetic variants on serum testosterone concentrations in men.

Testosterone is the principal male sex hormone and a potent anabolic steroid. It exerts a variety of important physiological effects on the human body. Low testosterone concentrations in men are associated with increased risk of cardiovascular morbidity, type 2 diabetes, atherosclerosis, osteoporosis, metabolic syndrome, and sarcopenia. Testosterone concentrations are known to decrease with age, but the observed inter-individual variability in testosterone concentrations in men is poorly understood.

By pooling the data of 14,429 Caucasian men, an international collaboration of 10 independent cohorts, co-led by the University of Gothenburg and the University of Greifswald, discovered genetic variants at the sex hormone-binding globulin (SHBG) gene and on the X chromosome associated with an increased risk of low testosterone.

Lead author Prof. Claes Ohlsson from the University of Gothenburg says: "This is the first large-scale study to identify specific genes for low serum testosterone concentrations. It is very interesting that the genetic contribution of the identified genetic variants to testosterone concentrations is substantial."

Co-senior author Dr. Robin Haring from the University of Greifswald concludes: "The reported associations may now be used in order to better understand the functional background of recently identified disease associations related to low testosterone concentrations in men."

List consortium members: The members of the consortium include: The Framingham Heart Study (FHS), Study of Health in Pomerania (SHIP), The Gothenburg Osteoporosis and Obesity Determinants (GOOD) Study, Cooperative Research in the Region of Augsburg (KORA), The Health, Aging, and Body Composition (Health ABC) Study, Rotterdam Study baseline (RS1), Invecchiare in Chianti (InCHIANTI), European Male Ageing Study (EMAS), The Osteoporotic Fractures in Men Study – Sweden (MrOS Sweden), The Cardiovascular Risk in Young Finns Study (YFS).

FINANCIAL DISCLOSURE: Framingham Heart Study (FHS): The FHS phenotype-genotype analyses for this work were supported by the National Institute of Aging (Genetics of Reproductive Life Period and Health Outcomes, R21AG032598; JM Murabito, KL Lunetta, D Karasik, DP Kiel, WV Zhuang). The Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine is supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study Contract No. N01-HC-25195 and its contract with Affymetrix for genotyping services (Contract No. N02-HL-6-4278). Sex hormone measurements were funded primarily by National Institute on Aging grant 1RO1AG31206 (PIs: S Bhasin and RS Vasan); additional support was provided by the Boston Claude D. Pepper Older Americans Independence Center (5P30AG031679) and a grant from the National Institute on Aging and the National Institute of Arthritis Musculoskeletal and Skin Diseases to DP Kiel (R01 AR/AG 41398). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II), funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Study of Health in Pomerania (SHIP): Computing resources have been made available by the Leibniz Supercomputing Centre of the Bavarian Academy of Sciences and Humanities (HLRB project h1231). SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg – West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany, and the Federal State of Mecklenburg West Pomerania. The University of Greifswald is a member of the ''Center of Knowledge Interchange'' program of the Siemens AG. This work is also part of the research project Greifswald Approach to Individualized Medicine (GANI_MED). The GANI_MED consortium is funded by the Federal Ministry of Education and Research and the Ministry of Cultural Affairs of the Federal State of Mecklenburg – West Pomerania (03IS2061A). The testosterone reagents used were sponsored by Siemens Healthcare Diagnostics, Eschborn, formerly DPC Biermann GmbH, Bad Nauheim, Germany. Novo Nordisc provided partial grant support for the determination of serum samples and data analysis. Gothenburg Osteoporosis and Obesity Determinants (GOOD) Study: Financial support was received from the Swedish Research Council (K2010-54X-09894-19-3, 2006-3832, and K2010-52X-20229-05-3), the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar So¨derberg's Foundation, Petrus and Augusta Hedlunds Foundation, the Va¨stra Go¨ taland Foundation, the Go¨ teborg Medical Society, the Novo Nordisk foundation, the Canadian Institutes of Health Research (MOP-15261), and the European Commission grant HEALTH-F2-2008-201865-GEFOS. We would like to acknowledge Maria Nethander at the genomics core facility at University of Gothenburg for statistical analyses. We would also like to thank Dr. Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national GermanMediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G for access to their grid resources. Cooperative Research in the Region of Augsburg (KORA): The KORA research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Part of this work was financed by the German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823). Our research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. This study was in part supported by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.). Health, Aging, and Body Composition (Health ABC) Study: This study was supported by National Institute on Aging contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106. The genome-wide association study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported (in part) by the Intramural Research Program of the NIH, National Institute on Aging. Rotterdam study (RS1): The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI) – Netherlands Consortiumof Healthy Aging (NCHA) project nr. 050-060-810, and funding fromthe European Commision (HEALTH-F2-2008-201865, GEFOS; HEALTH-F2-2008-35627, TREAT-OA). The RotterdamStudy is funded by Erasmus Medical Center and Erasmus University Rotterdam; Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture, and Science; the Ministry for Health, Welfare, and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. We thank Pascal Arp, Mila Jhamai, Dr. Michael Moorhouse, Marijn Verkerk, and Sander Bervoets for their help in creating the GWAS database. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practioners and pharmacists. We would like to thank Dr. Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G for access to their grid resources. Invecchiare in Chianti (InCHIANTI): The InCHIANTI study baseline (1998�) was supported as a ''targeted project'' (ICS110.1/RF97.71) by the ItalianMinistry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336); the InCHIANTI Follow-up 1 (2001�) was funded by the U.S. National Institute on Aging (Contracts: N.1-AG-1-1 and N.1-AG-1-2111); the InCHIANTI Follow-ups 2 and 3 studies (2004�) were financed by the U.S. National Institute on Aging (Contract: N01-AG-5-0002); supported in part by the Intramural research program of the National Institute on Aging, National Institutes of Health, Baltimore,Maryland. European Male Ageing Study (EMAS): The EMAS is funded by the Commission of the European Communities Fifth Framework Programme ''Quality of Life and Management of Living Resources'' Grant QLK6-CT- 2001-00258 and supported by funding from the UK Arthritis Research Campaign. The EMAS Principal Investigator is Professor Frederick Wu, MD; Dept of Endocrinology, Manchester Royal Infirmary, UK. The ''EMAS Study Group'' consists of the following people: Gyorgy Bartfai, Steven Boonen, Felipe Casanueva, Joseph D Finn, Gianni Forti, Aleksander Giwercman, Thang S Han, Kate L Holliday, Ilpo T Huhtaniemi, Krzysztof Kula, Michael EJ Lean, David M Lee, Terence W O'Neill, Neil Pendleton, Margus Punab, Stephen R Pye, Alan J Silman, Abdelouahid Tajar, Wendy Thomson, Dirk Vanderschueren, and Frederick CW Wu. The authors wish to thank the men who participated in the eight countries and the research/nursing staff in the eight centres: C Pott, Manchester, E Wouters, Leuven, M Nilsson, Malmo¨, M del Mar Fernandez, Santiago de Compostela,M Jedrzejowska, Lodz, H-M Tabo, Tartu, A Heredi, Szeged for their data collection and C Moseley, Manchester for data entry and project coordination. Dr. Vanderschueren is a senior clinical investigator supported by the Clinical Research Fund of the University Hospitals Leuven, Belgium. Dr. Boonen is a senior clinical investigator of the Fund for Scientific Research-Flanders, Belgium(F.W.O.–Vlaanderen). Dr. Boonen is holder of the Leuven University Chair in Metabolic Bone Diseases. The Osteoporotic Fractures in Men Study – Sweden (MrOS Sweden): Financial support was received from the Swedish Research Council (K2010-54X-09894-19-3, 2006-3832), the Swedish Foundation for Strategic Research, the ALF/LUA research grant in Gothenburg, the Lundberg Foundation, the Torsten and Ragnar So¨derberg's Foundation, Petrus and Augusta Hedlunds Foundation, the Va¨stra Go¨ taland Foundation, the Go¨ teborg Medical Society, the Novo Nordisk Foundation, and the European Commission grant HEALTH-F2-2008-201865-GEFOS. The Cardiovascular Risk in Young Finns Study (YFS): YFS has been financially supported by the Academy of Finland (grant no. 117797, 121584, and 126925), the Social Insurance Institution of Finland, Turku University Foundation, Tampere and Turku University Hospital Medical Funds, Emil Aaltonen Foundation (T.L), Juho Vainio Foundation, Paavo Nurmi Foundation, the Tampere Tubeculosis Foundation, the Orion-Farmos Research Foundation, Finnish Foundation of Cardiovascular Research, and Finnish Cultural Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

COMPETING INTERESTS: The authors have declared that no competing interests exist.

CITATION: Ohlsson C, Wallaschofski H, Lunetta KL, Stolk L, Perry JRB, et al. (2011) Genetic Determinants of Serum Testosterone Concentrations in Men. PLoS Genet 7(10): e1002313. doi:10.1371/journal.pgen.1002313

CONTACT: Dr. Robin Haring
Institute of Clinical Chemistry and Laboratory Medicine
University of Greifswald
Ferdinand-Sauerbruch-Straße
17475 Greifswald, Germany
Tel.: 03834 8619656
Fax: 03834 865502
robin.haring@uni-greifswald.de

Prof. Claes Ohlsson
Center for Bone and Arthritis Research
Department of Internal Medicine
Institute of Medicine
Sahlgrenska Academy
University of Gothenburg
Vita Stråket 11
S-41345
Gothenburg
Sweden
Tel.: +46 706 832966
claes.ohlsson@medic.gu.se

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