Genetic determinants of serum testosterone concentrations in men.

Abstract

Testosterone concentrations in men are associated with cardiovascular morbidity, osteoporosis, and mortality and are affected by age, smoking, and obesity. Because of serum testosterone's high heritability, we performed a meta-analysis of genome-wide association data in 8,938 men from seven cohorts and followed up the genome-wide significant findings in one in silico (n = 871) and two de novo replication cohorts (n = 4,620) to identify genetic loci significantly associated with serum testosterone concentration in men. All these loci were also associated with low serum testosterone concentration defined as <300 ng/dl. Two single-nucleotide polymorphisms at the sex hormone-binding globulin (SHBG) locus (17p13-p12) were identified as independently associated with serum testosterone concentration (rs12150660, p = 1.2×10(-41) and rs6258, p = 2.3×10(-22)). Subjects with ≥ 3 risk alleles of these variants had 6.5-fold higher risk of having low serum testosterone than subjects with no risk allele. The rs5934505 polymorphism near FAM9B on the X chromosome was also associated with testosterone concentrations (p = 5.6×10(-16)). The rs6258 polymorphism in exon 4 of SHBG affected SHBG's affinity for binding testosterone and the measured free testosterone fraction (p<0.01). Genetic variants in the SHBG locus and on the X chromosome are associated with a substantial variation in testosterone concentrations and increased risk of low testosterone. rs6258 is the first reported SHBG polymorphism, which affects testosterone binding to SHBG and the free testosterone fraction and could therefore influence the calculation of free testosterone using law-of-mass-action equation.

• Authors: Claes Ohlsson, Henri Wallaschofski, Kathryn L Lunetta, Lisette Stolk, John R B Perry, Annemarie Koster, Ann-Kristin Petersen, Joel Eriksson, Terho Lehtimäki, Ilpo T Huhtaniemi, Geoffrey L Hammond, Marcello Maggio, Andrea D Coviello, EMAS Study Group, Luigi Ferrucci, Margit Heier, Albert Hofman, Kate L Holliday, John-Olov Jansson, Mika Kähönen, David Karasik, Magnus K Karlsson, Douglas P Kiel, Yongmei Liu, Osten Ljunggren, Mattias Lorentzon, Leo-Pekka Lyytikäinen, Thomas Meitinger, Dan Mellström, David Melzer, Iva Miljkovic, Matthias Nauck, Maria Nilsson, Brenda Penninx, Stephen R Pye, Ramachandran S Vasan, Martin Reincke, Fernando Rivadeneira, Abdelouahid Tajar, Alexander Teumer, André G Uitterlinden, Jagadish Ulloor, Jorma Viikari, Uwe Völker, Henry Völzke, H Erich Wichmann, Tsung-Sheng Wu, Wei Vivian Zhuang, Elad Ziv, Frederick C W Wu, Olli Raitakari, Anna Eriksson, Martin Bidlingmaier, Tamara B Harris, Anna Murray, Frank H de Jong, Joanne M Murabito, Shalender Bhasin, Liesbeth Vandenput, Robin Haring
• Journal: PLoS genetics (PLoS Genet) Vol. 7 Issue 10 Pg. e1002313 (Oct 2011) ISSN: 1553-7404 [Electronic] United States
• PMID: 21998597 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• FAM9B protein, human
• Nuclear Proteins
• Sex Hormone-Binding Globulin
• Testosterone

Topics

• Adult
• Aged, 80 and over
• Alleles
• Body Mass Index
• Chromosomes, Human, X (genetics)
• Genome-Wide Association Study
• Humans
• Male
• Middle Aged
• Nuclear Proteins (genetics)
• Polymorphism, Single Nucleotide
• Sex Hormone-Binding Globulin (genetics)
• Testosterone (blood)