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Genetic determinants of serum testosterone concentrations in men.
PLoS Genet. 7:e1002313 (2011)
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.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
hormone-binding globulin; population-based cohort; elderly-men; older men; androgen deficiency; metabolic syndrome; risk-factors; shbg gene; mortality; health
Language
english
Publication Year
2011
HGF-reported in Year
2011
ISSN (print) / ISBN
1553-7390
e-ISSN
1553-7404
Journal
PLoS Genetics
Quellenangaben
Volume: 7,
Issue: 10,
Article Number: e1002313
Publisher
Public Library of Science (PLoS)
Reviewing status
Peer reviewed
Institute(s)
Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)
Institute of Human Genetics (IHG)
Institute of Epidemiology (EPI)
Institute of Human Genetics (IHG)
POF-Topic(s)
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30202 - Environmental Health
30503 - Chronic Diseases of the Lung and Allergies
30202 - Environmental Health
30503 - Chronic Diseases of the Lung and Allergies
Research field(s)
Genetics and Epidemiology
PSP Element(s)
G-504100-001
G-504000-002
G-503900-001
G-500700-001
G-504000-002
G-503900-001
G-500700-001
PubMed ID
21998597
Scopus ID
80155172604
Erfassungsdatum
2011-11-28