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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.

SUBMITTER: Ohlsson C 

PROVIDER: S-EPMC3188559 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Genetic determinants of serum testosterone concentrations in men.

Ohlsson Claes C   Wallaschofski Henri H   Lunetta Kathryn L KL   Stolk Lisette L   Perry John R B JR   Koster Annemarie A   Petersen Ann-Kristin AK   Eriksson Joel J   Lehtimäki Terho T   Huhtaniemi Ilpo T IT   Hammond Geoffrey L GL   Maggio Marcello M   Coviello Andrea D AD   Ferrucci Luigi L   Heier Margit M   Hofman Albert A   Holliday Kate L KL   Jansson John-Olov JO   Kähönen Mika M   Karasik David D   Karlsson Magnus K MK   Kiel Douglas P DP   Liu Yongmei Y   Ljunggren Osten O   Lorentzon Mattias M   Lyytikäinen Leo-Pekka LP   Meitinger Thomas T   Mellström Dan D   Melzer David D   Miljkovic Iva I   Nauck Matthias M   Nilsson Maria M   Penninx Brenda B   Pye Stephen R SR   Vasan Ramachandran S RS   Reincke Martin M   Rivadeneira Fernando F   Tajar Abdelouahid A   Teumer Alexander A   Uitterlinden André G AG   Ulloor Jagadish J   Viikari Jorma J   Völker Uwe U   Völzke Henry H   Wichmann H Erich HE   Wu Tsung-Sheng TS   Zhuang Wei Vivian WV   Ziv Elad E   Wu Frederick C W FC   Raitakari Olli O   Eriksson Anna A   Bidlingmaier Martin M   Harris Tamara B TB   Murray Anna A   de Jong Frank H FH   Murabito Joanne M JM   Bhasin Shalender S   Vandenput Liesbeth L   Haring Robin R  

PLoS genetics 20111006 10


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 testosteron  ...[more]

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