Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women.
BACKGROUND
Circulating levels of sex hormone-binding globulin (SHBG) are inversely associated with breast cancer risk in postmenopausal women. Three polymorphisms within the SHBG gene have been reported to affect SHBG levels, but there has been no systematic attempt to identify other such variants.


METHODS
We looked for associations between SHBG levels in 1,134 healthy, postmenopausal women and 11 tagging single nucleotide polymorphisms (SNP) in or around the SHBG gene. Associations between SHBG SNPs and breast cancer were tested in up to 6,622 postmenopausal breast cancer cases and 6,784 controls.


RESULTS
Ten SNPs within or close to the SHBG gene were significantly associated with SHBG levels as was the (TAAAA)(n) polymorphism. The best-fitting combination of rs6259, rs858521, and rs727428 and body mass index, waist, hip, age, and smoking status accounted for 24% of the variance in SHBG levels (natural logarithm transformed). Haplotype analysis suggested that rs858518, rs727428, or a variant in linkage disequilibrium with them acts to decrease SHBG levels but that this effect is neutralized by rs6259 (D356N). rs1799941 increases SHBG levels, but the previously reported association with (TAAAA)(n) repeat length appears to be a consequence of linkage disequilibrium with these SNPs. One further SHBG SNP was significantly associated with breast cancer (rs6257, per-allele odds ratio, 0.88; 95% confidence interval, 0.82-0.95; P = 0.002).


CONCLUSIONS
At least 3 SNPs showed associations with SHBG levels that were highly significant but relatively small in magnitude. rs6257 is a potential breast cancer susceptibility variant, but relationships between the genetic determinants of SHBG levels and breast cancer are complex.
Thompson
Deborah J
DJ
Cambridge University, Strangeways Research Laboratories, Worts Causeway, Cambridge CB1 8RN, United Kingdom. deborah.thompson@phpc.com.ac.uk
Healey
Catherine S
CS
Baynes
Caroline
C
Kalmyrzaev
Bolot
B
Ahmed
Shahana
S
Dowsett
Mitch
M
Folkerd
Elizabeth
E
Luben
Robert N
RN
Cox
David
D
Ballinger
Dennis
D
Pharoah
Paul D P
PD
Ponder
Bruce A J
BA
Dunning
Alison M
AM
Easton
Douglas F
DF
D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016014:Linear Models; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D012306:Risk; D012738:Sex Hormone-Binding Globulin / Q000235:genetics*
D012738:Sex Hormone-Binding Globulin