Polymorphisms of the SHBG gene contribute to the interindividual variation of sex steroid hormone blood levels in young, middle-aged and elderly men.
OBJECTIVE
In men there is a large interindividual variation of SHBG levels and consequently of testosterone (T) and E(2) levels. Family and twin studies suggested a strong genetic contribution, besides metabolic and hormonal influences. The aim of this study was to examine the influence of a missense mutation in exon 8 (Asp327Asn) and a (TAAAA)(n)-repeat in the promoter region of the SHBG gene, on SHBG and sex steroid serum concentrations in a population of healthy men.


METHODS
SHBG and hormone levels were measured in 1485 men, contributed by three independent cohort studies and representing three different age groups (young, middle-aged and elderly men). The number of TAAAA-repeats was determined by fragment-analysis; carriers of the Asn(327)-allele were identified using restriction fragment length polymorphism analysis.


RESULTS
In the different age groups, carriers of six TAAAA-repeats presented with higher SHBG (young 19%, middle-aged 20% and elderly 26%; P < 0.001) and T (young 9%, middle-aged 22% and elderly 21%; P < 0.05) levels compared to non-carriers. For free T, a modest increase was found for carriers in the middle-aged group, but not for the young and elderly group. E(2) and free E(2) did not differ between carriers and non-carriers in the different age-groups. The Asn(327)-allele was associated with higher mean SHBG (14.20%, P < 0.001) and T levels (7.33%; P = 0.01) in the middle-aged group only.


CONCLUSIONS
Our findings show that and the (TAAAA)(n)-repeat and the Asp327Asn polymorphism contribute to the genetically determined interindividual variation in total serum T levels in healthy men through variation in SHBG concentrations.
Vanbillemont
Griet
G
Department of Endocrinology, Ghent University Hospital, Ghent, Belgium. griet.vanbillemont@ugent.be
Bogaert
Veerle
V
De Bacquer
Dirk
D
Lapauw
Bruno
B
Goemaere
Stefan
S
Toye
Kaatje
K
Van Steen
Kristel
K
Taes
Youri
Y
Kaufman
Jean-Marc
JM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood* / Q000235:genetics*; D000483:Alleles; D000728:Androgens / Q000097:blood; D015992:Body Mass Index; D004247:DNA / Q000235:genetics; D004967:Estrogens / Q000097:blood*; D005838:Genotype; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012738:Sex Hormone-Binding Globulin / Q000235:genetics* / Q000378:metabolism*; D013739:Testosterone / Q000097:blood*
D000728:Androgens; D004967:Estrogens; D012738:Sex Hormone-Binding Globulin; D013739:Testosterone; D004247:DNA